Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
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Recent synthetic and medicinal perspectives of tryptanthrin ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Ramandeep Kaur, Sundeep Kaur Manjal, Ravindra K. Rawal, Kapil Kumar Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A–C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities. Graphical abstract image
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Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Hongying Gao, Zimo Yang, Xinglin Yang, Yu Rao Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1–6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N′-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy. Graphical abstract image
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1,3-Oxazole-based selective picomolar inhibitors of cytosolic human carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is supported by X-ray crystallography of two leads ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Marta Ferraroni, Laura Lucarini, Emanuela Masini, Mikhail Korsakov, Andrea Scozzafava, Claudiu T. Supuran, Mikhail Krasavin Two lead 1,3-oxazole-based carbonic anhydrase inhibitors (CAIs) earlier identified as selective, picomolar inhibitors of hCA II (a cytosolic target for treatment of glaucoma) have been investigated further. Firstly, they were found to be conveniently synthesized on multigram scale, which enables further development. These compounds were found to be comparable in efficacy to dorzolamide eye drops when applied in the eye drop form as well. Finally, the reasons for unusually high potency of these compounds became understood from their high-resolution X-ray crystallography structures. These data significantly expand our understanding of heterocycle-based primary sulfonamides, many of which have recently emerged from our labs - particularly, from the corneal permeability standpoint. Graphical abstract image
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Brassinolide-like activity of castasterone analogs with varied side chains against rice lamina inclination ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Bunta Watanabe, Shuji Yamamoto, Taiyo Yokoi, Airi Sugiura, Shinri Horoiwa, Takanori Aoki, Hisashi Miyagawa, Yoshiaki Nakagawa Brassinolide (BL) and castasterone (CS) are the representative members of brassinosteroid class of plant steroid hormone having plant growth promoting activity. In this study, eleven CS analogs bearing a variety of side chains were synthesized to determine the effect of the side chain structures on the BL-like activity. The plant hormonal activity was evaluated in a dwarf rice lamina inclination assay, and the potency was determined as the reciprocal logarithm of the 50% effective dose (ED50) from each dose-response curve. The reciprocal logarithm of ED50 (pED50) was decreased dramatically upon deletion of the C-28 methyl group of CS. The introduction of oxygen-containing groups such as hydroxy, methoxy, and ethoxycarbonyl was also unfavorable to the activity. The pED50 was influenced by the geometry of carbon-carbon double bond between C-24 and C-25 (cis and trans), but the introduction of a fluorine atom at the C-25 position of the double bond did not significantly change the activity. The binding free energy (ΔG) was calculated for all ligand–receptor binding interactions using molecular dynamics, resulting that ΔG is linearly correlated with the pED50. Graphical abstract image
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Cycloalkane analogues of sinefungin as EHMT1/2 inhibitors ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Qing Liu, Xiaoqing Cai, Dehua Yang, Yi Chen, Yafang Wang, Liming Shao, Ming-Wei Wang A series of cycloalkyl substituted analogues of the natural product sinefungin lacking the amino-acid moiety was designed and synthesized. Two stereoisomers (6-R and 6-S) were separated and their bioactivities examined against EHMT1/2. Of which, compound 14d showed an inhibitory activity against EHMT1/2 (88.9%, IC50 =21.8μM for EHMT1 and 77.6%, IC50 =39.6μM for EHMT2, respectively) similar to that of sinefungin (100.0%, IC50 =28.4μM for EHMT1 and 79.5%, IC50 =30.1μM for EHMT2, respectively). Further studies against other methyltransferases such as PRMT1 showed no activity except that 12d displayed about 20% inhibition. Graphical abstract image
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pH responsive biodegradable nanogels for sustained release of bleomycin ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Prashant Sahu, Sushil K. Kashaw, Varun Kushwah, Samaresh Sau, Sanyog Jain, Arun K. Iyer Site specific drug delivery with desired therapeutic effect still remains challenging task due to suboptimal release, tissue toxicity, low selectivity and meager therapeutic efficacy in skin cancers. The aim of the current study was to fabricate pH responsive, self-assembled, chemically cross-linked biodegradable chitosan nanogel loaded with bleomycin to target the dermal area of the skin. The nanogel synthesized by ion gelation technique and was characterized for drug loading, swelling and thermal stability followed by in vitro analysis. HaCaT (Human Keratinocyte cell) and HDF (Human dermal fibroblast) cell line were used for the biocompatibility and cytocompatibility evaluation prior to the hemolysis assay and coagulation assessment. The nanogel had a size range of 150nm as determined by TEM and DLS. The nanogel possessed optimum thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). Biodegradation was confirmed by lysozyme enzyme degradation assays. The drug entrapment efficacy was about 55% in the swollen state. The In vitro drug release profile revealed sustained release pattern. The hemolysis of 2.39% and prothrombin time (PT) and activated partial thromboplastin time (APTT) of 12.9 and 31s revealed the biocompatibility of nanogels. The cell uptake and localization profile was validated by fluorescence and confocal microscopy using HDF and HaCaT cell lines. Finally, the MTT assay demonstrated the cytocompatibility of nanogels. In conclusion, the present findings suggest that biodegradable chitosan nanogels with stimuli responsive nature can release the anticancer drug cargo in a sustained and controlled manner and offer promising potentials for treating skin cancers. Statement of Significance Drug delivery to the targeted site is a major challenge in clinical medicine. The newly constructed pH responsive biodegradable nanogel consisting of bleomycin revealed pH triggered drug release in a sustained manner to the dermal area offering novel approach against skin cancer. The nanogel system is biodegradable in nature possessing high drug entrapment efficiency and offers patient compliance with biocompatible and cytocompatible characteristics. This nanogel system can thus be highly useful for delivery of anticancer drugs to the skin in a controlled and sustained manner. Graphical abstract image
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Discovery of a tetrahydroisoquinoline-based HDAC inhibitor with improved plasma stability ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Nan Zhou, Yugang Yan, Chunxi Liu, Jinning Hou, Wenfang Xu, Yingjie Zhang Histone deacetylase inhibitors with desirable pharmacokinetic profiles which can be delivered to solid tumor tissues in large amount might be promising to treat solid tumor effectively. Herein, structural modification of a previously reported tetrahydroisoquinoline-based HDAC inhibitor 1 was carried out to improve its plasma stability for more feasible drug delivery. Among three newly synthesized analogs, the in vitro rat plasma stability of compound 2 (t1/2 =630min) was over 5-fold improved than its parent 1 (t1/2 =103min). In vitro activity evaluation showed that compound 2 and 1 exhibited similar HDACs inhibitory activity, which was validated by western blot analysis and antiproliferative assay. Moreover, compared with 1, compound 2 exhibited comparable, if not higher, in vivo antitumor activity in a human breast carcinoma (MDA-MB-231) xenograft model. Graphical abstract image
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Asymmetric synthesis and evaluation of epoxy-α-acyloxycarboxamides as selective inhibitors of cathepsin L ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Deborah A. dos Santos, Anna Maria Deobald, Vivian E. Cornelio, Roberta M.D. Ávila, Renata C. Cornea, Gilberto C.R. Bernasconi, Marcio W. Paixão, Paulo C. Vieira, Arlene G. Corrêa Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent. Investigations of the mechanism suggested a tight binding uncompetitive inhibition. Graphical abstract image
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KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Jorge González-Bacerio, Sarah El Chamy Maluf, Yanira Méndez, Isel Pascual, Isabelle Florent, Pollyana M.S. Melo, Alexandre Budu, Juliana C. Ferreira, Ernesto Moreno, Adriana K. Carmona, Daniel G. Rivera, Maday Alonso del Rivero, Marcos L. Gazarini Malaria is a global human parasitic disease mainly caused by the protozoon Plasmodium falciparum. Increased parasite resistance to current drugs determines the relevance of finding new treatments against new targets. A novel target is the M1 alanyl-aminopeptidase from P. falciparum (PfA-M1), which is essential for parasite development in human erythrocytes and is inhibited by the pseudo-peptide bestatin. In this work, we used a combinatorial multicomponent approach to produce a library of peptidomimetics and screened it for the inhibition of recombinant PfA-M1 (rPfA-M1) and the in vitro growth of P. falciparum erythrocytic stages (3D7 and FcB1 strains). Dose-response studies with selected compounds allowed identifying the bestatin-based peptidomimetic KBE009 as a submicromolar rPfA-M1 inhibitor (Ki =0.4μM) and an in vitro antimalarial compound as potent as bestatin (IC50 =18μM; without promoting erythrocyte lysis). At therapeutic-relevant concentrations, KBE009 is selective for rPfA-M1 over porcine APN (a model of these enzymes from mammals), and is not cytotoxic against HUVEC cells. Docking simulations indicate that this compound binds PfA-M1 without Zn2+ coordination, establishing mainly hydrophobic interactions and showing a remarkable shape complementarity with the active site of the enzyme. Moreover, KBE009 inhibits the M1-type aminopeptidase activity (Ala-7-amido-4-methylcoumarin substrate) in isolated live parasites with a potency similar to that of the antimalarial activity (IC50 =82μM), strongly suggesting that the antimalarial effect is directly related to the inhibition of the endogenous PfA-M1. These results support the value of this multicomponent strategy to identify PfA-M1 inhibitors, and make KBE009 a promising hit for drug development against malaria. Graphical abstract image
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New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Marcela Krečmerová, Martin Dračínský, Robert Snoeck, Jan Balzarini, Karel Pomeisl, Graciela Andrei New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC50’s of 0.15–1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug. Graphical abstract image
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A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca2+ channel blocker and endothelin A/B2 receptor antagonist ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Byong-Gon Park, Woon-Seob Shin, Sangtae Oh, Gab-Man Park, Nam Ik Kim, Seokjoon Lee We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK+)-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63μM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50 =9.8±0.6μM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca2+ channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension. Graphical abstract image
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Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Jin Han Kim, Hui Rak Jeong, Da Woon Jung, Hong Bin Yoon, Sun Young Kim, Hyoung Ja Kim, Kyung-Tae Lee, Vinicius M. Gadotti, Junting Huang, Fang-Xiong Zhang, Gerald W. Zamponi, Jae Yeol Lee As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC50 =5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav3.2 channels. Graphical abstract image
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5-Bromoindirubin 3′-(O-oxiran-2-ylmethyl)oxime: A long-acting anticancer agent and a suicide inhibitor for epoxide hydrolase ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Yoshimi Ichimaru, Takeshi Fujii, Hiroaki Saito, Makoto Sano, Taketo Uchiyama, Shinichi Miyairi Indirubin 3′-oxime (Indox (1b)) suppresses cancer cell growth (IC50: 15μM towards HepG2 cells) and inhibits cell cycle-related kinases such as cyclin-dependent kinases and glycogen synthase kinase-3β. We have previously reported that the conjugation of 1b with oxirane, a protein-reactive component, enhanced the cytotoxic activity of Indox as determined from the IC50 value (1.7μM) of indirubin 3′-(O-oxiran-2-ylmethyl)oxime (Epox/Ind (1c)). Here we prepared Epox/Ind derivatives with one or two halogen atoms or a methoxy group on the aromatic ring(s) of an Indox moiety and studied the structure-activity relationships of the substituent(s). We found that bromine-substitution at the 5-position on 1c or any Epox/Ind derivative(s) having bromine on the aromatic ring except Epox/6′-Br-Ind was efficient to improving anticancer activity. Of the 22 Epox/Ind derivatives, 5-bromoindirubin 3′-(O-oxiran-2-ylmethyl)oxime (Epox/5-Br-Ind (2c)) was the best anticancer agent in both short- (24h) (IC50: 0.67μM) and extended-duration (72h) cultures. The high anticancer activity of 2c was partly due to it being a poor substrate and a suicide inhibitor for epoxide hydrolase as epoxide hydrolase was identified as the enzyme primarily responsible for the metabolism of 2c. Graphical abstract image
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Synthesis and diabetic neuropathic pain-alleviating effects of 2N-(pyrazol-3-yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Jin Ri Hong, Young Jin Choi, Gyochang Keum, Ghilsoo Nam A novel series of fused-benzensulfonamide 2-N-(pyrazol-3-yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives was designed and synthesized as metabolically stable T-type calcium channel inhibitors. Several compounds, 9, 10, and 17, displayed potent T-type channel inhibitory activity. Among them, compounds 10 and 17 showed good metabolic stability in human liver microsomes, and low hERG channel and CYP450 inhibition. Compound 10 exhibited diabetic neuropathic pain-alleviating effects in a streptozotocin-induced peripheral diabetic neuropathy (PDN) model. The maximum efficacy of compound 10, which was 3-fold more potent than gabapentin, was observed at 1h after administration, and co-administration of compound 10 with gabapentin showed a considerable synergic effect. Graphical abstract image
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Platinum(IV) complexes conjugated with phenstatin analogue as inhibitors of microtubule polymerization and reverser of multidrug resistance ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Xiaochao Huang, Rizhen Huang, Shaohua Gou, Zhimei Wang, Zhixin Liao, Hengshan Wang Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively. Mechanism study suggested that complex 10 induced cell-cycle arrest at the G2/M phase and caused apoptotic cell death of human lung cancer NCI-H460 cells through the mitochondrial mediated pathway. Moreover, complex 10 effectively inhibited the tumor growth in the NCI-H460 xenograft model. Graphical abstract image
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Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Jianwei Yan, Gaihong Wang, Xiangyu Dang, Binbin Guo, Wuhong Chen, Ting Wang, Limin Zeng, Heyao Wang, Youhong Hu A series of diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors with a picolinoylpyrrolidine-2-carboxylic acid moiety were designed and synthesized. Of these compounds, compound 22 exhibited excellent DGAT-1-inhibitory activity (hDGAT-1 enzyme assay, 50% inhibitory concentration [IC50]=3.5±0.9nM) and effectively reduced the intracellular triglyceride contents in 3T3-L1, HepG2 and Caco-2 cells. A preliminary study of the plasma and tissue distributions of compound 22 in mice revealed low plasma exposure and high concentrations in different segments of the intestine and liver, which may facilitate targeting DGAT-1. Furthermore, in an acute lipid challenge test, compound 22 showed a dose-dependent inhibitory effect on high-serum triglycerides in C57/KSJ mice induced by olive oil (1, 3, and 10mg/kg, i.g.). Graphical abstract image
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Synthesis and biological evaluation in vitro and in mammalian cells of new heteroaryl carboxyamides as HIV-protease inhibitors ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): M. Funicello, L. Chiummiento, F. Tramutola, M.F. Armentano, F. Bisaccia, R. Miglionico, L. Milella, F. Benedetti, F. Berti, P. Lupattelli New heteroaryl HIV-protease inhibitors bearing a carboxyamide spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core modifying the type of heteroarene and the central core, with the presence of either H or benzyl group. Their in vitro inhibition activity against recombinant protease showed a general beneficial effect of carboxyamide moiety, the IC50 values ranging between 1 and 15nM. In particular benzofuryl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such benzofuryl derivatives in terms of number of interactions in the active site, supporting the experimental results on activity. The inhibition activity of such molecules has been also evaluated in HEK293 cells expressing the protease fused to green fluorescent protein, by western blotting analysis, fluorescence microscopy and cytofluorimetry. Graphical abstract image
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Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazolin-4(3H)-one derivatives as potential PPARγ and SUR agonists ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Mohamed K. Ibrahim, Ibrahim H. Eissa, Mohamed S. Alesawy, Ahmed M. Metwaly, Mohamed M. Radwan, Mahmoud A. ElSohly Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a , 19d , 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARγ binding affinities and insulin-secreting abilities. Compounds 19b , 19d , 19f , 25f and 25g exhibited the highest affinities against PPARγ with IC50 values of 0.371, 0.350, 0.369, 0.408 and 0.353µM, respectively. In addition, compounds 19d , 19f , and 25d showed the highest insulin-secreting activities with EC50 values of 0.97, 1.01 and 1.15µM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARγ and SUR. Graphical abstract image
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Development of novel LP1-based analogues with enhanced delta opioid receptor profile ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Lorella Pasquinucci, Rita Turnaturi, Orazio Prezzavento, Emanuela Arena, Giuseppina Aricò, Zafiroula Georgoussi, Rosalba Parenti, Giuseppina Cantarella, Carmela Parenti Pain relief achieved by co-administration of drugs acting at different targets is more effective than that obtained with conventional MOR selective agonists usually associated to relevant side effects. It has been demonstrated that simultaneously targeting different opioid receptors is a more effective therapeutic strategy. Giving the promising role for DOR in pain management, novel LP1-based analogues with different N-substituents were designed and synthesized with the aim to improve DOR profile. For this purpose, we maintained the phenyl ring in the N-substituent of 6,7-benzomorphan scaffold linked to an ethyl spacer bearing a hydroxyl/methyl or methoxyl group at carbon 2 or including it in a 1,4-benzodioxane ring. LP1 analogues were tested by competition binding assays. Compounds 6 (Ki MOR =2.47nM, Ki DOR =9.6nM), 7 (Ki MOR =0.5nM and Ki DOR =0.8nM) and 9 (Ki MOR =1.08nM, Ki DOR =6.6nM) retained MOR affinity but displayed an improved DOR binding capacity as compared to LP1 (Ki MOR =0.83nM, Ki DOR =29.1nM). Moreover, GPI and MVD functional assays indicated that compounds 6 (IC50 =49.2 and IC50 =10.8nM), 7 (IC50 =9.9 and IC50 =11.8nM) and 9 (IC50 =21.5 and IC50 =4.4nM) showed a MOR/DOR agonist profile, unlike LP1 that was a MOR agonist/DOR antagonist (IC50 =1.9 and IC50 =1240nM). Measurements of their antinociceptive effect was evaluated by mice radiant tail flick test displaying for compounds 6, 7 and 9 ED50 values of 1.3, 1.0 and 0.9mg/kg, i.p., respectively. Moreover, the antinociceptive effect of compound 9 was longer lasting with respect to LP1. In conclusion the N-substituent nature of compounds 6, 7 and 9 shifts the DOR profile of LP1 from antagonism to agonism. Graphical abstract image
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Discovery of spiro[indole-3,2′-pyrrolidin]-2(1H)-one based inhibitors targeting Brr2, a core component of the U5 snRNP ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Masahiro Ito, Misa Iwatani, Takeshi Yamamoto, Toshio Tanaka, Tomohiro Kawamoto, Daisuke Morishita, Atsushi Nakanishi, Hironobu Maezaki Bad response to refrigeration 2 (Brr2) is a member of the Ski2-like RNA helicases, and an essential component of the U5 small nuclear ribonucleoprotein (snRNP). A particularly important role of Brr2 is the ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step in spliceosomal activation. Despite its biological importance, selective inhibitor for Brr2 had not been reported until our recent report. Here, we describe novel and structurally distinct spiro[indole-3,2′-pyrrolidin]-2(1H)-one based Brr2 inhibitors with superior activity to the previously reported 4,6-dihydropyrido[4,3-d]pyrimidine-2,7(1H,3H)-dione series. Using an RNA dependent ATPase assay as a guide, high-throughput screening, hit validation by structure–activity relationship (SAR) study, and subsequent chemical optimization to increase the ATPase inhibitory activity were performed. Thereafter, selectivity and helicase inhibitory activity of optimized compounds were confirmed. In the course of the study, compounds were synthesized using a three-component reaction, which accelerated the optimization process. All these efforts finally culminated in the discovery of the potent and selective Brr2 inhibitors (32a and 33a) exhibiting helicase inhibitory activity at submicromolar concentrations. Thus, compounds 32a and 33a could be valuable molecular probes to study the functions of Brr2 and molecular machinery of RNA splicing. Graphical abstract image
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3-O-Substituted-3′,4′,5′-trimethoxyflavonols: Synthesis and cell-based evaluation as anti-prostate cancer agents ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Xiang Li, Maizie Lee, Guanglin Chen, Qiang Zhang, Shilong Zheng, Guangdi Wang, Qiao-Hong Chen Twenty-two 3-O-substituted-3′,4′,5′-trimethoxyflavonols have been designed and synthesized for their anti-proliferative activity towards three human prostate cancer cell lines. Our results indicate that most of them are significantly more potent than the parent 3′,4′,5′-trimethoxyflavonol in inhibiting the cell proliferation in PC-3 and LNCaP prostate cancer cell models. 3-O-Substituted-3′,4′,5′-trimethoxyflavonols have generally higher potency towards PC-3 and LNCaP cell lines than the DU145 cell line. Incorporation of an ethyl group to 3-OH of 3′,4′,5′-trimethoxyflavonol leads to 3-O-ethyl-3′,4′,5′-trimethoxyflavonol as the optimal derivative with up to 36-fold enhanced potency as compared with the corresponding lead compound 3′,4′,5′-trimethoxyflavonol, but with reversed PC-3 cell apoptotic response. Introduction of a dipentylaminopropyl group to 3-OH increases not only the antiproliferative potency but also the ability in activating PC-3 cell apoptosis. Our findings imply that modification on 3-OH of trimethoxyflavonol can further enhance its in vitro anti-proliferative potency and PC-3 cell apoptosis induction. Graphical abstract image
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Chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes as novel σ1 receptor ligands ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Lena Fanter, Christoph Müller, Dirk Schepmann, Franz Bracher, Bernhard Wünsch Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15, 26, and 39. The configuration in 2-position does not influence the σ1 affinity and selectivity over related receptors. A cyclohexylmethyl or a butyl group are the preferred substituents in 4-position, whereas a methyl moiety in 2-position and a (substituted) benzyl moiety in 1-position result in the highest σ1 affinity. These results fit nicely to the reported σ1 pharmacophore models. The compounds did not inhibit the structurally related fungal enzyme sterol Δ8,7-isomerase, but showed inhibition of diverse enzymes in late cholesterol biosynthesis at high concentrations. In a screening against more than 50 target proteins, (2S)-1-benzyl-4-(4-methoxybenzyl)-2-methyl-1,4-diazepane ((S)-28b, K i(σ1)=0.86nM) showed a clean receptor profile. The dose dependent potentiation of electrically stimulated contractions of guinea pig vas deferens indicates σ1 agonistic activity of (S)-28b. Even at a dose of 100mg/kg (S)-28b did not induce severe toxic or behavioral effects in the Irwin screen. Clear cognition enhancing effects were observed for (S)-28b after inducing amnesia by scopolamine. Graphical abstract image
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Anion inhibitors of the β-carbonic anhydrase from the pathogenic bacterium responsible of tularemia, Francisella tularensis ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Sonia Del Prete, Daniela Vullo, Sameh M. Osman, Zeid AlOthman, William A. Donald, Jean-Yves Winum, Claudiu T. Supuran, Clemente Capasso A β-class carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Francisella tularensis (FtuβCA) was cloned and purified, and the anion inhibition profile was investigated. Based on the measured kinetic parameters for the enzyme catalyzed CO2 hydration reaction (kcat of 9.8×105 s−1 and a kcat/KM of 8.9×107 M−1 s−1), FtuβCA is a highly effective enzyme. The activity of FtuβCA was not inhibited by a range of anions that do not typically coordinate Zn(II) effectively, including perchlorate, tetrafluoroborate, and hexafluorophosphate. Surprisingly, some anions which generally complex well with many cations, including Zn(II), also did not effectively inhibit FtuβCA, e.g., fluoride, cyanide, azide, nitrite, bisulphite, sulfate, tellurate, perrhenate, perrhuthenate, and peroxydisulfate. However, the most effective inhibitors were in the range of 90–94µM (sulfamide, sulfamic acid, phenylarsonic and phenylboronic acid). N,N-Diethyldithiocarbamate (K I of 0.31mM) was a moderately potent inhibitor. As Francisella tularensis is the causative agent of tularemia, the discovery of compounds that can interfere with the life cycle of this pathogen may result in novel opportunities to fight antibiotic drug resistance. Graphical abstract image
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Synthesis of different heterocycles-linked chalcone conjugates as cytotoxic agents and tubulin polymerization inhibitors ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Nagula Shankaraiah, Shalini Nekkanti, Uma Rani Brahma, Niggula Praveen Kumar, Namrata Deshpande, Daasi Prasanna, Kishna Ram Senwar, Uppu Jaya Lakshmi A series of new heterocycles-linked chalcone conjugates has been designed and synthesized by varying different alkane spacers. These conjugates were tested for their in vitro cytotoxic potential against a panel of selected human cancer cell lines namely, lung (A549 and NCI-H460), prostate (DU-145 and PC-3), colon (HCT-15 and HCT-116), and brain (U-87 glioblastoma) by MTT assay. Notably, among all the tested compounds, 4a exhibited potent cytotoxicity on NCI-H460 (lung cancer) cells with IC50 of 1.48±0.19µM. The compound 4a showed significant inhibition of tubulin polymerization and disruption of the formation of microtubules (IC50 of 9.66±0.06μM). Moreover, phase contrast microscopy and DAPI staining studies indicated that compound 4a can induce apoptosis in NCI-H460 cells. Further, the flow-cytometry analysis revealed that compound 4a arrests NCI-H460 cells in the G2/M phase of the cell cycle. In addition, molecular docking studies of the most active compounds 4a and 4b into the colchicine site of the tubulin, revealed the possible mode of interaction by these new conjugates. Graphical abstract image
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Design, synthesis, and pharmacological evaluation of a novel series of hormone sensitive lipase inhibitor ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Tomoko Ogiyama, Mitsuhiro Yamaguchi, Nobuya Kurikawa, Shoko Honzumi, Koji Terayama, Nobumi Nagaoka, Yuka Yamamoto, Takako Kimura, Daisuke Sugiyama, Shin-ichi Inoue HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability. Graphical abstract image
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Isolation and lipolytic activity of eurycomanone and its epoxy derivative from Eurycoma longifolia ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Lucy Lahrita, Ryota Hirosawa, Eisuke Kato, Jun Kawabata Eurycomanone (1) and 13β,21-epoxyeurycomanone (2) were isolated from Eurycoma longifolia for studies of lipolytic activity. Compound 1 enhanced lipolysis in adipocytes with an EC50 of 14.6μM, while its epoxy derivate, compound 2, had a stronger activity with an EC50 of 8.6μM. Based on molecular mechanistic study using several specific inhibitors to lipolytic signaling pathways, it was found that PKA inhibitor totally diminished the lipolytic activity of 1 and 2. Further immunoblotting analysis confirmed the activation of phosphorylated PKA by both 1 and 2. With the growing need to develop new anti-obesity agents, eurycomanone and its epoxy derivate can be used as promising lead compounds to target lipid catabolism. Graphical abstract image
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Discovery of new leads against Mycobacterium tuberculosis using scaffold hopping and shape based similarity ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Ravindra D. Wavhale, Elvis A.F. Martis, Premlata K. Ambre, Baojie Wan, Scott G. Franzblau, Krishna R. Iyer, Kavita Raikuvar, Katarzyna Macegoniuk, Łukasz Berlicki, Santosh R. Nandan, Evans C. Coutinho BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile. Using the scaffold hopping approach, three structurally diverse heterocycles – 2,3-disubstituted imidazopyridines, 2,3-disubstituted benzimidazoles and 1,2,4-trisubstituted imidazoles emerged as promising antitubercular agents. All compounds were synthesized through easy and convenient methods and their structures confirmed by IR, 1H NMR, 13C NMR and MS. In-vitro cytotoxicity studies on normal kidney monkey cell lines and HepG2 cell lines, as well as metabolic stability studies on rat liver microsomes for some of the most active compounds, established that these compounds have negligible cytotoxicity and are metabolically stable. Interestingly the benzimidazole compound (4a) is as potent as the parent molecule BM212 (MIC 2.3μg/ml vs 0.7–1.5μg/ml), but is devoid of the toxicity against HepG2 cell lines (IC50 203.10µM vs 7.8µM). Graphical abstract image
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5- or/and 20-O-alkyl-2,3-dehydrosilybins: Synthesis and biological profiles on prostate cancer cell models ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Bao Vue, Xiaojie Zhang, Timmy Lee, Nandini Nair, Sheng Zhang, Guanglin Chen, Qiang Zhang, Shilong Zheng, Guangdi Wang, Qiao-Hong Chen To investigate the effects of alkylation at 5-OH and 20-OH of 2,3-dehydrosilybin on prostate cancer cell proliferation, the synthetic approaches to 5- or/and 20-O-alkyl-2,3-dehydrosilybins, through a multi-step sequence from commercially available silybin, have been successfully developed. The first three reactions in the syntheses were completed through a one-pot procedure by managing anaerobic and aerobic conditions. With these synthetic methods in hand, twenty-one 2,3-dehydrosilybins, including seven 20-O-alkyl, seven 5,20-O-dialkyl, and seven 5-O-alkyl-2,3-dehydrosilybins, have been achieved for the evaluation of their biological profiles. Our WST-1 cell proliferation assay data indicate that nineteen out of the twenty-one 2,3-dehydrosilybins possess significantly improved antiproliferative potency as compared with silybin toward both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145). 5-O-Alkyl-2,3-dehydrosilybins were identified as the optimal subgroup that can consistently inhibit cell proliferation in three prostate cancer cell models with all IC50 values lower than 8µM. Our flow cytometry-based assays also demonstrate that 5-O-heptyl-2,3-dehydrosilybin effectively arrests the cell cycle in the G0/G1 phase and activates PC-3 cell apoptosis. Graphical abstract image
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Structure based drug design of Pim-1 kinase followed by pharmacophore guided synthesis of quinolone-based inhibitors ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Lubna Swellmeen, Rand Shahin, Yusuf Al-Hiari, Amani Alamiri, Alaa Hasan, Omar Shaheen Over expression of Human phosphatidyl inositol mannoside kinases isoform 1 (Pim-1 kinase) has been reported in several leukemia and solid tumors. Our continuous interest to reveal the secrecies of the mysterious Pim-1 kinase binding pocket has led us to employ a structure based drug design procedure based on receptor-ligand pharmacophore generation protocol implemented in Discovery Studio 4.5 (DS 4.5). Subsequently, we collected 104 crystal structures of Pim-1 kinase from the Protein Data Bank (PDB) and used them to generate pharmacophores based on the anticipated co-crystallized ligand-Pim 1 kinase receptor interactions. All selected pharmacophoric features were enumerated and only those that had corresponding valuable receptor-ligand interactions were retained. This was followed by modeling all pharmacophore combinations and scoring them according to their Receiver Operating Characteristic (ROC) curve analysis parameters as well as a DS.4.5 built-in Genetic Function Algorithm (GFA) validating model. Accordingly, 111 pharmacophores resulted with acceptable ROC performances; 1XWS_2_04, 2BIK_2_06, and 1XWS_2_06 (ROC AUC value of: 0.770, 0.743 and 0.741 respectively) were the best pharmacophores. These pharmacophores were employed to guide the synthesis of new series of 7-[(2-Carboxyethyl)amino]-1-substituted-6-fluoro-8-nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and their reduced 8-amino derivatives. The synthesized compounds were later evaluated for their Pim-1 kinase inhibitory potencies. Of which the most potent illustrated an IC50 value of 0.29µM against Pim-1 kinase. Graphical abstract image
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Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Takeshi Yasui, Takeshi Yamamoto, Nozomu Sakai, Kouhei Asano, Takafumi Takai, Yayoi Yoshitomi, Melinda Davis, Terufumi Takagi, Kotaro Sakamoto, Satoshi Sogabe, Yusuke Kamada, Weston Lane, Gyorgy Snell, Masashi Iwata, Masayuki Goto, Hiroshi Inooka, Jun-ichi Sakamoto, Yoshihisa Nakada, Yasuhiro Imaeda B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein–protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6–corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6–corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50 =0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50 =0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies. Graphical abstract image
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Design, synthesis and bioactivities of Celecoxib analogues or derivatives ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Shiyang Zhou, Shanbin Yang, Gangliang Huang A series of Celecoxib analogues or derivatives were designed and synthesized, and their biological activities were studied. The results of inhibitory activity in vitro proved that compounds 1a, 1h, 1i, 1l and 1p had better inhibitory effect on COX-2, and the selectivity was higher. Among them, the inhibitory activity of compound 1h to COX-2 was IC50 =0.049μmol/L and SI >1000. Moreover, the experimental results of anti-inflammatory activity in vivo showed that they had good anti-inflammatory activity and could inhibit the release of PGE-2. Therefore, these compounds have better druggability. Graphical abstract image
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Fluoro and pentafluorothio analogs of the antitumoral curcuminoid EF24 with superior antiangiogenic and vascular-disruptive effects ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Florian Schmitt, Madeleine Gold, Gerrit Begemann, Ion Andronache, Bernhard Biersack, Rainer Schobert A series of 14 analogs of the curcuminoid EF24, (3E,5E)-3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone, bearing fluorine or pentafluorothio substituents, were prepared and tested for antiproliferative, vascular-disruptive, and antiangiogenic activity, as well as for their influence on other cancer-relevant targets. They proved antiproliferative against eight cancer cell lines with IC50 values in the low single-digit micromolar to triple-digit nanomolar range. Like EF24, the hexafluoro 3c and 3d and bis(pentafluorothio) 4f derivatives arrested HT-29 colon carcinoma cells in G2/M phase of the cell cycle, yet inhibited angiogenesis, e.g. in zebrafish larvae, to a much greater extent. The antimigratory effects in 518A2 melanoma cells of 3c, its regioisomer 3d, and of 4f, originate from an inhibition of NF-κB translocation. Moreover, 3c and 3d showed potential as vascular-disruptive agents in chorioallantoic/vitelline membrane (CA/VM) assays. Graphical abstract image
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Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Hainimu Xiamuxi, Zhen Wang, Jianfeng Li, Yu Wang, Chunhui Wu, Feipu Yang, Xiangrui Jiang, Yongjian Liu, Qingjie Zhao, Weiming Chen, Jian Zhang, Yuanchao Xie, Tianwen Hu, Mingshuo Xu, Shuang Guo, Haji Akber Aisa, Yang He, Jingshan Shen In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for α 1A, 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development. Graphical abstract image
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9,19-Cycloartenol glycoside G3 from Cimicifuga simplex regulates immune responses by modulating Th17/Treg ratio ()
Publication date: 1 September 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17 Author(s): Yang Su, Lun Wu, Guangrui Mu, Qiuhong Wang, Bingyou Yang, Genhong Cheng, Haixue Kuang Cimicifuga simplex is a medicinal herb which has a wide range of biological activities. We isolated seven 9,19-cycloartenol glycosides from the roots of C. simplex, and among the glycosides, G3 exhibited the strongest inhibitory effect on immune responses, including suppressing the differentiation of CD4+ T cells and directly suppressing the cytokine-induced JAK/STAT signaling pathways. In the IL-23-induced mouse ear model of skin disease, G3 repressed disease development by inhibiting the expression of pro-inflammatory mediators in murine ear skin. Moreover, G3 affected the maturation of DCs in vitro, thereby inducing T cell differentiation, resulting in an increased Treg phenotype and decreased Th17 phenotype. This study provides new evidence that G3 might ameliorate chronic inflammatory skin diseases by suppressing pathogenic CD4+ T cell differentiation and the IL-17+RORγt+/IL-10+FoxP3+ ratio. These findings suggest that G3 might mediate the therapeutic effects observed in psoriasis patients following treatment with C. simplex. Graphical abstract image
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Seek & Destroy, use of targeting peptides for cancer detection and drug delivery ()
Publication date: Available online 1 September 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Vadim Le Joncour, Pirjo Laakkonen Accounting for 16 million new cases and 9 million deaths annually, cancer leaves a great number of patients helpless. It is a complex disease and still a major challenge for the scientific and medical communities. The efficacy of conventional chemotherapies is often poor and patients suffer from off-target effects. Each neoplasm exhibits molecular signatures - sometimes in a patient specific manner - that may completely differ from the organ of origin, may be expressed in markedly higher amounts and/or in different location compared to the normal tissue. Although adding layers of complexity in the understanding of cancer biology, this cancer-specific signature provides an opportunity to develop targeting agents for early detection, diagnosis, and therapeutics. Chimeric antibodies, recombinant proteins or synthetic polypeptides have emerged as excellent candidates for specific homing to peripheral and central nervous system cancers. Specifically, peptide ligands benefit from their small size, easy and affordable production, high specificity, and remarkable flexibility regarding their sequence and conjugation possibilities. Coupled to imaging agents, chemotherapies and/or nanocarriers they have shown to increase the on-site delivery, thus allowing better tumor mass contouring in imaging and increased efficacy of the chemotherapies associated with reduced adverse effects. Therefore, some of the peptides alone or in combination have been tested in clinical trials to treat patients. Peptides have been well-tolerated and shown absence of toxicity. This review aims to offer a view on tumor targeting peptides that are either derived from natural peptide ligands or identified using phage display screening. We also include examples of peptides targeting the high-grade malignant tumors of the central nervous system as an example of the complex therapeutic management due to the tumor’s location. Peptide vaccines are outside of the scope of this review. Graphical abstract image
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Highly potent antiobesity effect of a short-length peptide YY analog in mice ()
Publication date: Available online 1 September 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Naoki Nishizawa, Ayumu Niida, Yusuke Adachi, Yoko Kanematsu-Yamaki, Yasushi Masuda, Satoshi Kumano, Kotaro Yokoyama, Yoko Noguchi, Tomoko Asakawa, Hideki Hirabayashi, Nobuyuki Amano, Shiro Takekawa, Tetsuya Ohtaki, Taiji Asami Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[D-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23–36) (4), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N-terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans-4-hydroxy-D-proline (D-Hyp)24, isovaline (Iva)25, and γ-methylleucine (γMeLeu)28, not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[D-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23–36) (31, PYY-1119) at a dose of 0.03 mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction. Graphical abstract image
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Synthesis of Damaged DNA Containing the Oxidative Lesion 3'-Oxothymidine ()
Publication date: Available online 1 September 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Mel F. Bedi, Weiye Li, Taylor Gutwald, Amanda C. Bryant-Friedrich Oxidative events that take place during regular oxygen metabolism can lead to the formation of organic or inorganic radicals. The interaction of these radicals with macromolecules in the organism and with DNA in particular is suspected to lead to apoptosis, DNA lesions and cell damage. Independent generation of DNA lesions resulting from oxidative damage is used to promote the study of their effects on biological systems. An efficient synthesis of oligodeoxyribonucleotides (ODNs) containing the oxidative damage lesion 3'-oxothymidine has been accomplished via incorporation of C3'-hydroxymethyl thymidine as its corresponding 5'-phosphoramidite. Through oxidative cleavage using sodium periodate in aqueous solution, the lesion of interest is easily generated. Due to its inherent instability it cannot be directly isolated, but must be generated in situ. 3'-Oxothymidine is a demonstrated damage product formed upon generation of the C3'-thymidinyl radical in ODN. Graphical abstract image
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Development of sulfonamides incorporating phenylacrylamido functionalities as carbonic anhydrase isoforms I, II, IX and XII inhibitors ()
Publication date: Available online 1 September 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Srinivas Angapelly, P.V. Sri Ramya, Andrea Angeli, Sonia Del Prete, Clemente Capasso, Mohammed Arifuddin, Claudiu T. Supuran A series of novel sulfonamides incorporating phenylacrylamido functionalities were synthesized and investigated for the inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The physiologically and pharmacologically relevant human (h) isoforms hCA I and II (cytosolic isozymes), as well as the transmembrane tumor-associated hCA IX and XII were included in the study. These compounds showed low nanomolar or sub-nanomolar inhibition constants against hCA II (KIs in the range of 0.50-50.5 nM), hCA IX (KIs of 1.8-228.5nM), and hCA XII (KIs of 3.5-96.2 nM) being less effective as inhibitors of the off target isoform hCA I. A detailed structure-activity relationship study demonstrates that the nature and position of substituents present on the aromatic part of the scaffold strongly influence the inhibition of CA isoforms. As hCA II, IX and XII are involved in pathologies such as glaucoma and hypoxic, and metastatic tumors, compounds of the type reported in this work may be useful preclinical candidates. Graphical abstract image
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Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors ()
Publication date: Available online 1 September 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Gaopeng Song, Xiang Zhu, Junhua Li, Dekun Hu, Dongsheng Zhao, Yixian Liao, Juntong Lin, Lian-Hui Zhang, Zi-Ning Cui Improvement of subtype selectivity of an inhibitor’s binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC50 = 0.60 μM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation. Graphical abstract image
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Synthesis and β-sheet propensity of constrained N-amino peptides ()
Publication date: Available online 31 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Matthew P. Sarnowski, Kyle P. Pedretty, Nicole Giddings, H. Lee Woodcock, Juan R. Del Valle The stabilization of β-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable β-hairpin folds based on peptide strand N-amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between -hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N-amino peptide building blocks were then evaluated for their effect on β-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong β-sheet stabilizing effect of the peptide N-amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on β-sheet folding. Graphical abstract image
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Improving Oral Bioavailability of Cyclic Peptides by N-Methylation ()
Publication date: Available online 31 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Andreas F.B. Räder, Florian Reichart, Michael Weinmüller, Horst Kessler The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization –biological activity and oral availability– is required to overcome this problem. Moreover, most simple “rules” for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N–methylation of cyclic peptides in strategies to optimize bioavailabilities. Graphical abstract image
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Identification of novel PDEδ interacting proteins ()
Publication date: Available online 31 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Philipp Küchler, Gunther Zimmermann, Michael Winzker, Herbert Waldmann, Slava Ziegler Prenylation is a post-translational modification that increases the affinity of proteins for membranes and mediates protein-protein interactions. The retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDEδ) is a prenyl binding protein that is essential for the shuttling of small GTPases between different membrane compartments and, thus, for their proper functioning. Although the prenylome comprises up to 2% of the mammalian proteome, only few prenylated proteins are known to interact with PDEδ. A proteome-wide approach was employed to map the PDEδ interactome among the prenylome and revealed RAB23, CDC42 and CNP as novel PDEδ interacting proteins. Moreover, PDEδ associates with the lamin A mutant progerin in a prenyl-dependent manner. These findings shed new light on the role of PDEδ in binding (and regulating) prenylated proteins in cells. Graphical abstract image
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Towards semisynthetic natural compounds with a biaryl axis: oxidative phenol coupling in Aspergillus niger ()
Publication date: Available online 31 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Katharina Gloria Hugentobler, Michael Müller Regio- and stereoselective phenol coupling is difficult to achieve using synthetic strategies. However, in nature, cytochrome P450 enzyme-mediated routes are employed to achieve complete axial stereo- and regiocontrol in the biosynthesis of compounds with potent bioactivity. Here, we report a synthetic biology approach whereby the bicoumarin metabolic pathway in Aspergillus niger was specifically tailored towards the formation of new coupling products. This strategy represents a manipulation of the bicoumarin pathway in A. niger via interchange of the phenol-coupling biocatalyst and could be applied to other components of the pathway to access a variety of atropisomeric natural product derivatives. Graphical abstract image
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Linker structure-activity relationships in fluorodeoxyglucose chlorambucil conjugates for tumor-targeted chemotherapy ()
Publication date: Available online 30 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Mostafa El Hilali, Bastien Reux, Eric Debiton, Fernand Leal, Marie-Josephe Galmier, Magali Vivier, Jean-Michel Chezal, Elisabeth Miot-Noirault, Pascal Coudert, Valérie Weber Nitrogen mustards, such as chlorambucil (CLB), can cause adverse side-effects due to ubiquitous distribution in non-target organs. To minimize this toxicity, strategies of tumor-targeting drug delivery have been developed, where a cytotoxic warhead is linked to a tumor-cell-specific small ligand. Malignant cells exhibit marked glucose avidity and an accelerated metabolism by aerobic glycolysis, known as the Warburg effect, and recognized as a hallmark of cancer. A targeting approach exploiting the Warburg effect by conjugation of CLB to 2-fluoro-2-deoxyglucose (FDG) was previously reported and identified two peracetylated glucoconjugates 2 and 3 with promising antitumor activities in vivo. These results prompted us to investigate the importance of the spacer in this tumor-targeting glucose-based conjugates. Here we report the chemical synthesis and an in vitro cytotoxicity evaluation, using a 5-member panel of human carcinoma cell lines and human fibroblasts, of 16 new CLB glucoconjugates in which the alkylating drug is attached to the C-1 position of FDG via different linkages. We studied the structure-activity relationships in the linker, and evidenced the positive impact of an aromatic linker on in vitro cytotoxicity: compound 51 proved to be the most active FDG-CLB glucoside, characterized by a bis-aromatic spacer tethered to CLB through an amide function. Graphical abstract image
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Synthesis and evaluation of 1H-pyrrole-2,5-dione derivatives as cholesterol absorption inhibitors for suppressing the formation of foam cells and inflammatory response ()
Publication date: Available online 30 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Xinrui Yuan, Yineng Xia, Peng Lu, Lijuan Zhu, Yuejiao Zhong, Yubin Wang Excess lipid accumulation in the arterial intima and formation of macrophage-derived foam cells in the plaque could cause atherosclerotic lesion. Cholesterol absorption inhibitors could suppress the lipid accumulation of human macrophage, inflammatory response and the development of atherosclerosis. In this research, a series of 1H-pyrrole-2,5-dione derivatives were synthesized as cholesterol absorption inhibitor and tested in in vitro experiments. One of the most active inhibitors, compound 20 exhibited stronger in vitro cholesterol absorption activity than ezetimibe, no cytotoxicity in HEK293 and RAW264.7 cell lines and satisfied lipophilicity. The further study indicated that 20 could inhibit lipid accumulation of macrophage and reduce the secretion of LDH, MDA, TNF-α and ROS in a concentration-dependent manner. In conclusion, as a novel and potent cholesterol absorption inhibitor, compound 20 could suppress the formation of foam cells and inflammatory response. Graphical abstract image
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A prodrug design for improved oral absorption and reduced hepatic interaction ()
Publication date: Available online 24 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Gulzar Ahmed, Walter Elger, Frederick Meece, Hareesh B. Nair, Birgitt Schneider, Ralf Wyrwa, Klaus Nickisch A series of estradiol-17-β esters of N-(p-sulfomylbenzamide)-amino acids were prepared and evaluated for systemic and hepatic estrogenic activity after oral administration in ovariectomized rats. The alkyl substitution at nitrogen of amino acids such as proline or N-methyl-alanine produced compounds that exhibit potent oral activity. The proline analog (EC508) was further evaluated along with 17 β -estradiol (E2) and ethinyl-estradiol (EE) and compared their effects on the uterus, angiotensin and HDL-cholesterol after oral administration to ovariectomized female rats. Orally administered EC508 produced systemic estrogenic activity 10 times greater than EE and a 100 times higher activity than E2 with no influence on levels of angiotensin and HDL-cholesterol, whereas EE and E2 reduced the HDL-cholesterol and increased the angiotensine plasma levels. EC 508 might offer significant advantages in indications like fertility control and HRT based on its high oral bioavailability and lack of hepatic estrogenicity. Graphical abstract image
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β-Arrestin biased dopamine D2 receptor partial agonists: synthesis and pharmacological evaluation ()
Publication date: Available online 24 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Barbara Männel, Harald Hübner, Dorothée Möller, Peter Gmeiner β-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to display substantial β-arrestin-2 recruitment, while being nearly devoid of activity in a GTPγS binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable β-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D2R. Graphical abstract image
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Pyrrolizines: design, synthesis, anticancer evaluation and investigation of the potential mechanism of action ()
Publication date: Available online 24 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Ahmed M. Gouda, Ahmed H. Abdelazeem, Hany A. Omar, Ashraf N. Abdalla, Mohammed A.S. Abourehab, Hamed I. Ali A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B cancer cell lines. Compound 10c was the most active against MCF-7 with IC50 value of 4.72 µM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and apoptosis induction were suggested as potential molecular mechanisms for the anticancer activity of the novel pyrrolizines based on their structural features. The new compounds significantly inhibited COX-1 and COX-2 with IC50 values in the ranges of 5.78-11.96 µM and 0.1-0.78 µM, respectively with high COX-2 selectivity over COX-1. Interestingly, the most potent compound in MTT assay, compound 12b, exhibited high inhibitory activity against COX-2 with selectivity index (COX-1/COX-2) > 100. Meanwhile, compound 12b displayed weak to moderate inhibition of six kinases with inhibition% (7-20%) compared to imatinib (inhibition% = 1-38%). The results of cell cycle analysis, annexin V PI/FITC apoptosis assay and caspase-3/7 assay revealed that compound 12b has the ability to induce apoptosis. The docking results of compound 12b into the active sites of COXs, ALK1 and Aurora A indicated that it fits nicely inside their active sites. Overall, the current study highlighted the significant anticancer activity of the newly synthesized pyrrolizines with a potential multi-targeted mechanism which could serve as a base for future studies and further structural optimization into potential anticancer agents. Graphical abstract image
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Design and Synthesis of Benzoacridines as Estrogenic and Anti-Estrogenic Agents ()
Publication date: Available online 24 August 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Kohei Torikai, Rintaro Koga, Xiaohui Liu, Kaoru Umehara, Tatsuya Kitano, Kenji Watanabe, Tohru Oishi, Hiroshi Noguchi, Yasuyuki Shimohigashi Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC50 < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs). Graphical abstract image
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