Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10
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Synthesis of 4(3H)quinazolinimines with selective cytotoxic effect on human acute promyelocytic leukemia cells ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Alexandra Becerra, Celso Quintero, Valeria Morales, Mauricio Valderrama, Adam Aguirre, Mario A. Faúndez, Rene S. Rojas We synthesized a new family of six 4(3H)quinazolinimines based on the reaction between (E)-N-(2-cyanophenyl)benzimidoyl chloride and substituted anilines reaching the formation of their corresponding C2, N3-substituted quinazoliniminium chlorides. This method provides novel, direct and flexible access to diverse substituted 4(3H)quinazolinimines. New compounds obtained following the proposed synthesis were fully characterized and, including the thirteen 4(3H)quinazolinimines synthesized by this method and previously reported by us, were used to study its cytotoxic effect on neoplastic cell lines. The mechanism involved in cell toxicity was also studied. Results showed that these compounds were highly cytotoxic, in particular on Human Promyelocytic Leukemia cells (HL60) and Chronic Myelogenous Leukemia cells (K562) when compared with conventional antineoplastic drugs such as etoposide and cisplatin. The mechanism associated to cytotoxic effect was mainly apoptosis, which not was decreased by antioxidant addition, thereby suggesting that the compounds exert apoptotic death through a mechanism unrelated with oxidative stress. Graphical abstract image
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Rapid screening the potential mechanism-based inhibitors of CYP3A4 from Tripterygium wilfordi based on computer approaches combined with in vitro bioassay ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Lili Wang, Yue Hai, Lijun An, Junxiu Chen, Rongjia Liang, Xin He CYP3A4 is the main human metabolizing enzyme, and many clinically relevant drug/herb-drug interactions (DDIs/HDIs) involving CYP3A4 are due to mechanism-based inhibition. In this study, pharmacophore model together with molecular docking (MD) are used to rapidly screen the potential CYP3A4 mechanism-based inhibitors from Tripterygium wilfordii, and in vitro experiments are conducted to validate the computational data. The results showed that the rate of computational prediction could be improved based on a combination of pharmacophore model and MD, and a combination of computational approaches might be a useful tool to identify potential mechanism-based inhibitor of CYP3A4 from herbal medicines. Graphical abstract image
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Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H3R ligands ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Kamil J. Kuder, Dorota Łażewska, Maria Kaleta, Gniewomir Latacz, Tim Kottke, Agnieszka Olejarz, Tadeusz Karcz, Andrzej Fruziński, Katarzyna Szczepańska, Janina Karolak-Wojciechowska, Holger Stark, Katarzyna Kieć-Kononowicz As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2–21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6–8 (K i =8.8–23.4nM range) and among them piperidine derivative 6 with K i =8.8nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50 =157 and 164nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2–4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30mg/kg at 0.5h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate “drug-likeness” of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed. Graphical abstract image
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Design and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Harun M. Patel, Rahul Pawara, Azim Ansari, Malleshappa Noolvi, Sanjay Surana The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC50 value of 0.031μM against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant. Graphical abstract image
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C-2 (E)-4-(Styryl)aniline substituted diphenylpyrimidine derivatives (Sty-DPPYs) as specific kinase inhibitors targeting clinical resistance related EGFRT790M mutant ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Anran Song, Jianbin Zhang, Yang Ge, Changyuan Wang, Qiang Meng, Zeyao Tang, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma With the aim to overcome the drug resistance induced by the EGFR T790M mutation (EGFRT790M), herein, a family of diphenylpyrimidine derivatives (Sty-DPPYs) bearing a C-2 (E)-4-(styryl)aniline functionality were designed and synthesized as potential EGFRT790M inhibitors. Among them, the compound 10e displayed strong potency against the EGFRT790M enzyme, with the IC50 of 11.0nM. Compound 10e also showed a higher SI value (SI=49.0) than rociletinib (SI=21.4), indicating its less side effect. In addition, compound 10e could effectively inhibit the proliferation of H1975 cells harboring the EGFRT790M mutation, within the concentration of 2.91μM. Significantly, compound 10e has low toxicity against the normal HBE cell (IC50 =22.48μM). This work provided new insights into the discovery of potent and selective inhibitor against EGFRT790M over wild-type (EGFRWT). Graphical abstract image
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Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Fernando Fernandez Diaz-Rullo, Francesco Zamberlan, Ryan E. Mewis, Marianna Fekete, Lionel Broche, Lesley A. Cheyne, Sergio Dall'Angelo, Simon B. Duckett, Dana Dawson, Matteo Zanda Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of l-arginine into l-citrulline. NO is a free radical gas with a short half-life in vivo (≈5s), therefore direct NO quantification is challenging. An indirect method – based on quantifying conversion of an l-Arg- to l-Cit-derivative by 1H NMR spectroscopy – is herein proposed. A small library of pyridyl containing l-Arg derivatives was designed and synthesised. In vitro tests showed that compounds 4a–j and 11a–c were better or equivalent substrates for the eNOS enzyme (NO2 − production=19–46μM) than native l-Arg (NO2 − production=25μM). Enzymatic conversion of l-Arg to l-Cit derivatives could be monitored by 1H NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo. Graphical abstract image
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Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Skylar J. Ferrara, J. Matthew Meinig, Andrew T. Placzek, Tapasree Banerji, Peter McTigue, Meredith D. Hartley, Hannah S. Sanford-Crane, Tania Banerji, Dennis Bourdette, Thomas S. Scanlan Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing. Graphical abstract image
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Antiplasmodial activity of targeted zinc(II)-dipicolylamine complexes ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Douglas R. Rice, María de Lourdes Betancourt Mendiola, Claribel Murillo-Solano, Lisa A. Checkley, Michael T. Ferdig, Juan C. Pizarro, Bradley D. Smith This study measured the antiplasmodial activity of nine zinc-dipicolylamine (ZnDPA) complexes against three strains of Plasmodium falciparum, the causative parasite of malaria. Growth inhibition assays showed significant activity against all tested strains, with 50% inhibitory concentrations between 5 and 600nM and almost no toxic effect against host cells including healthy red blood cells. Fluorescence microscopy studies with a green-fluorescent ZnDPA probe showed selective targeting of infected red blood cells. The results suggest that ZnDPA coordination complexes are promising antiplasmodial agents with potential for targeted malaria treatment. Graphical abstract image
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Mycobacterium tuberculosis lysine-ɛ-aminotransferase a potential target in dormancy: Benzothiazole based inhibitors ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Rudraraju Srilakshmi Reshma, Variam Ullas Jeankumar, Nidhi Kapoor, Shalini Saxena, Karyakulam Andrews Bobesh, Astakala Rishi Vachaspathy, Pappachan E. Kolattukudy, Dharmarajan Sriram MTB lysine-ɛ-aminotransferase (LAT) was found to play a crucial role in persistence and antibiotic tolerance. LAT serves as a potential target in the management of latent tuberculosis. In present work we attempted to derivatize the benzothiazole lead identified through high throughput virtual screening of Birla Institute of Technology and Science in house database. For Structure activity relationship purpose 22 derivatives were synthesized and characterized. Among synthesized compounds, eight compounds were found to be more efficacious in terms of LAT inhibition when compared to lead compound (IC50 10.38±1.21µM). Compound 22 exhibits bactericidal action against nutrient starved Mycobacterium tuberculosis (MTB). It also exhibits significant activity in nutrient starvation model (2.9log folds) and biofilm model (2.3log folds). Graphical abstract image
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Discovery of acylguanidine oseltamivir carboxylate derivatives as potent neuraminidase inhibitors ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Zhaoliang Li, Yanchun Meng, Shengtao Xu, Wang Shen, Zhaoqing Meng, Zhenzhong Wang, Gang Ding, Wenzhe Huang, Wei Xiao, Jinyi Xu In search of novel anti-influenza agents with higher potency, a series of acylguanidine oseltamivir carboxylate analogues were synthesized and evaluated against influenza viruses (H1N1 and H3N2) in vitro. The representative compounds with strong inhibitory activities (IC50 <40nM) against neuraminidase (NA) were further tested against the NA from oseltamivir-resistant strain (H259Y). Among them, compounds 9 and 17 were potent NA inhibitors that exhibited a 5 and 11-fold increase in activity comparing with oseltamivir carboxylate (2, OC) against the H259Y mutant, respectively. Furthermore, the effect against influenza virus H259Y mutant (H1N1) replication and cytotoxicity assays indicated that compounds 9 and 17 exhibited a 20 and 6-fold increase than the parent compound 2, and had no obvious cytotoxicity in vitro. Moreover, the molecular docking studies revealed that the docking modes of compounds 9 and 17 were different from that of oseltamivir, and the new hydrogen bonds and hydrophobic interaction were formed in this case. This work provided unique insights in the discovery of potent inhibitors against NAs from wild-type and oseltamivir-resistant strains. Graphical abstract image
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Synthesis of new 3-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-benzenesulfonamides with strong inhibition properties against the tumor associated carbonic anhydrases IX and XII ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Murat Bozdag, Ahmed Mahmoud Alafeefy, Abdul Malik Altamimi, Fabrizio Carta, Claudiu T. Supuran, Daniela Vullo We report a series of novel metanilamide-based derivatives 3a–q bearing the 2-mercapto-4-oxo-4H-quinazolin-3-yl moiety as tail. All compounds were synthesized by means of straightforward condensation procedures and were investigated in vitro for their inhibition potency against the human (h) carbonic anhydrase (CA; EC 4.2.1.1.1) isoforms I, II, IX and XII. Among all compounds tested the 6-iodo 3g and the 7-fluoro 3i derivatives were the most potent inhibitors against the tumor associated CA IX and XII isoform (KIs 1.5 and 2.7nM respectively for the hCA IX and KIs 0.57 and 1.9nM respectively for the hCA XII). The kinetic data reported here strongly support compounds of this type for their future development as radiotracers in tumor pathologies which are strictly dependent on the enzymatic activity of the hCA IX and XII isoforms. Graphical abstract image
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Novel 5-HT7R antagonists, arylsulfonamide derivatives of (aryloxy)propyl piperidines: Add-on effect to the antidepressant activity of SSRI and DRI, and pro-cognitive profile ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Vittorio Canale, Anna Partyka, Rafał Kurczab, Martyna Krawczyk, Tomasz Kos, Grzegorz Satała, Bartłomiej Kubica, Magdalena Jastrzębska-Więsek, Anna Wesołowska, Andrzej J. Bojarski, Piotr Popik, Paweł Zajdel A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT7R antagonists. Among the compounds evaluated herein, 3-chloro-N-{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide (25) exhibited antagonistic properties at 5-HT7R and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.625–2.5mg/kg, i.p.) and in the tail suspension test (1.25mg/kg, i.p.), augmented the antidepressant effect of inactive doses of escitalopram (selective serotonin reuptake inhibitor) and bupropion (dopamine reuptake inhibitor) in the FST in mice, and similarly to SB-269970, exerted pro-cognitive properties in the novel object recognition task in cognitively unimpaired conditions in rats (0.3mg/kg, i.p.). Such an extended pharmacological profile, especially the augmentation effect of the identified 5-HT7R antagonist on SSRI activity, seems promising regarding the complexity of affective disorders and potentially improved outcomes, including mnemonic performance. Graphical abstract image
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Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Xiaoqing Sun, Zexin Hong, Moyi Liu, Su Guo, Di Yang, Yong Wang, Tian Lan, Linyu Gao, Hongxia Qi, Ping Gong, Yajing Liu A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC50 (FXa) value of 0.14μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor. Graphical abstract image
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Erratum to “Discovery and optimization of a series of imidazo[4,5-b]pyrazine derivatives as highly potent and exquisitely selective inhibitors of the mesenchymal–epithelial transition factor (c-Met) protein kinase” [Bioorg. Med. Chem. 24 (2016) 4281–4290] ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Fei Zhao, Jing Zhang, Leduo Zhang, Yu Hao, Chen Shi, Guangxin Xia, Jianxin Yu, Yanjun Liu
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Corrigendum to “Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3” [Bioorg. Med. Chem. 23 (2015) 4871–4883] ()
Publication date: 15 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 10 Author(s): Yutaka Nakajima, Takayuki Inoue, Kazuo Nakai, Koichiro Mukoyoshi, Hisao Hamaguchi, Keiko Hatanaka, Hiroshi Sasaki, Akira Tanaka, Fumie Takahashi, Shigeki Kunikawa, Hiroyuki Usuda, Ayako Moritomo, Yasuyuki Higashi, Masamichi Inami, Shohei Shirakami
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Editorial board ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9
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Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Sergey S. Laev, Nariman F. Salakhutdinov, Olga I. Lavrik Human apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein which is essential in the base excision repair (BER) pathway of DNA lesions caused by oxidation and alkylation. This protein hydrolyzes DNA adjacent to the 5′-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3′-hydroxyl group and a 5′-deoxyribose phosphate moiety or activates the DNA-binding activity of certain transcription factors through its redox function. Studies have indicated a role for APE1/Ref-1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs. Thus, this protein has potential as a target in cancer treatment. As a result, major efforts have been directed to identify small molecule inhibitors against APE1/Ref-1 activities. These agents have the potential to become anticancer drugs. The aim of this review is to present recent progress in studies of all published small molecule APE1/Ref-1 inhibitors. The structures and activities of APE1/Ref-1 inhibitors, that target both DNA repair and redox activities, are presented and discussed. To date, there is an urgent need for further development of the design and synthesis of APE1/Ref-1 inhibitors due to high importance of this protein target. Graphical abstract image
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Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Wei Bi, Yue Bi, Xiang Gao, Pengfei Li, Shanshan Hou, Yanrong Zhang, Cathy Bammert, Steffen Jockusch, Thomas D. Legalley, K. Michael Gibson, Lanrong Bi Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function. Graphical abstract image
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Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Fabrizio Carta, Daniela Vullo, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran SLC-0111 is a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor (CAI) in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Its antitumor effects are due to inhibition of the enzymatic activity of CA IX, an isoform predominantly found in tumors/metastases, but it also reduces the cancer stem cells population. Here we report the synthesis of analogs of SLC-0111, both of the sulfanilamide and metanilamide series, which possess diverse substitution patterns at the terminal ureido-phenyl moiety, thus including one or more halogens, trifluoromethyl, perchloro-/perfluorophenyl groups instead of the 4-fluorophenyl present in SLC-0111. Most of the sulfanilamide ureido derivatives were highly effective inhibitors of the tumor associated isoform and some showed selective CA IX/XII inhibitory profiles. Most of the sulfanilamide ureido derivatives were highly effective and in some cases selective CA IX/XII inhibitors, whereas the metanilamide ureido derivatives were less effective as transmembrane CA isoforms inhibitors. Structure activity relationship for this class of sulfonamides is discussed in detail. Graphical abstract image
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Inhibition of Malassezia globosa carbonic anhydrase with phenols ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Yeganeh Entezari Heravi, Silvia Bua, Alessio Nocentini, Sonia Del Prete, Ali Akbar Saboury, Hassan Sereshti, Clemente Capasso, Paola Gratteri, Claudiu T. Supuran A panel of 22 phenols was investigated as inhibitors of the β-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa (MgCA), a validated anti-dandruff drug target. The displayed inhibitory activities were compared to the ones previously reported against the off-target widely distributed human (h) isoforms hCA I and II. All tested phenols possessed a better efficacy in inhibiting MgCA than the clinically used sulfonamide acetazolamide, with KIs in the range of 2.5 and 65.0μM. A homology-built model of MgCA was also used for understanding the binding mode of phenols to the fungal enzyme. Indeed, a wide network of hydrogen bonds and hydrophobic interactions between the phenol and active site residues were evidenced. The OH moiety of the inhibitor was observed anchored to the zinc-coordinated water, also making hydrogen bonds with Ser48 and Asp49. The diverse substituents at the phenolic scaffold were observed to interact with different portions of the hydrophobic pocket according to their nature and position. Considering the effective MgCA inhibitory properties of phenols, beside to the rather low inhibition against the off-target hCA I and II, this class of compounds might be of considerable interest in the cosmetics field as potential anti-dandruff drugs. Graphical abstract image
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Comparative assessment of a 99mTc labeled H1299.2-HYNIC peptide bearing two different co-ligands for tumor-targeted imaging ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Seyedeh Atekeh Torabizadeh, Seyed Mohammad Abedi, Zohreh Noaparast, Seyed Jalal Hosseinimehr Peptides are a class of targeting agents that bind to cancer-specific cell surfaces. Since they specifically target cancer cells, they could be used as molecular imaging tools. In this study, the 15-mer peptide Ac-H1299.2 (YAAWPASGAWTGTAP) was conjugated with HYNIC via lysine amino acid on C-terminus and labeled with 99mTc using tricine and EDDA/tricine as the co-ligands. These radiotracers were evaluated for potential utilization in diagnostic imaging of ovarian cancer cells (SKOV-3). The cell-specificity of these radiolabeled peptides was determined based on their binding on an ovarian cancer cell line (SKOV-3), and displaying a low affinity for lung adenocarcinoma cell line (A549) and breast cancer cell line (MCF7). Biodistribution studies were conducted in normal mice as well as in nude mice bearing SKOV-3 ovarian cancer xenografts. HYNIC-peptide was labeled with 99mTc with more than 99% efficiency and showed high stability in buffer and serum. We observed nanomolar binding affinities for both radiolabeled peptides. The tumor uptakes were 3.27%±0.46% and 1.55%±0.20% for tricine and 2.34±1.1% and 1.09%±0.18% for EDDA/tricine at 1 and 4h after injection, respectively. A higher tumor to background ratio and lower radioactivity in the blood were observed for EDDA/tricine co-ligands, leading to clear tumor visualization in imaging with injection of this peptide. This new 99mTc-labeled peptide selectively targeted ovarian cancer and introduction of a (EDDA/tricine) as a co-ligand improved the pharmacokinetics of 99mTc-labeled H1299.2 for tumor imaging in animals. Graphical abstract image
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Discovery of a series of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton as potential FAK inhibitors ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Juan Sun, Shen-Zhen Ren, Xiao-Yuan Lu, Jing-Jing Li, Fa-Qian Shen, Chen Xu, Hai-Liang Zhu Focal adhesion kinase (FAK) is an important drug target that plays a fundamental role in mediating signal transduction system. We report herein the discovery of a novel class of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton with improved potency toward FAK. All of the 17 new synthesized compounds were assayed for the anticancer activities against four cancer cells, HepG2, Hela, SW116 and BGC823. Because of the combination of 1,4-benzodioxan, 1,3,4-oxadiazole and piperazine ring, most of them exhibited remarkable antitumor activities. Notably, compound 5m showed the most potent biological activities (IC50 =5.78μM for HepG2, and IC50 =47.15μM for SW1116), and its anti-FAK inhibitory activity (IC50 =0.78μM) was also the best. Computational docking studies also showed that compound 5m has interaction with FAK key residues in the active site. Graphical abstract image
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Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Wataru Nabeyama, Kenji Ishihara, Hyun Seung Ban, Hiroshi Wada, Hiroyuki Nakamura Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW™ and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1mM, respectively, and a sustained effect was observed 12h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10mM concentration and a sustained effect was not observed even at 6h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients. Graphical abstract image
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Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Ramakrishna Edupuganti, Juliana M. Taliaferro, Qiantao Wang, Xuemei Xie, Eun Jeong Cho, Fnu Vidhu, Pengyu Ren, Eric V. Anslyn, Chandra Bartholomeusz, Kevin N. Dalby Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers. Graphical abstract image
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Development and crystallographic evaluation of histone H3 peptide with N-terminal serine substitution as a potent inhibitor of lysine-specific demethylase 1 ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro. We found that substitutions of the N-terminal amino acid with amino acids having a larger side chain were generally not tolerated, but substitution of Ala1 to Ser unexpectedly resulted in more potent inhibitory activity toward LSD1. X-ray crystallographic analysis of H3K4M derivatives bound to the LSD1·CoREST complex revealed the presence of additional hydrogen bonding between the N-terminal Ser residue of the H3 peptide derivative and LSD1. The present structural and biochemical findings will be helpful for obtaining more potent peptidic inhibitors of LSD1. Graphical abstract image
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Indenocinnoline derivatives as G-quadruplex binders, topoisomerase IIα inhibitors and antiproliferative agents ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Grigoris Zoidis, Alice Sosic, Silvia Da Ros, Barbara Gatto, Claudia Sissi, Fausta Palluotto, Angelo Carotti, Marco Catto DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2-c]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[h]indeno[1,2-c]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G-quadruplex sequences. Inhibition of human topoisomerase IIα and antiproliferative assays on HeLa and MCF7 tumor cell lines outlined a multitarget antiproliferative profile for tetracyclic 6 and pentacyclic derivative 20, both bearing a N,N-dimethylamine as the protonatable moiety. Particularly, compound 6 displayed a very potent inhibition of tumor cell proliferation, while 20 returned the highest thermal stabilization in melting experiments. In summary, these results outlined a potential of such highly planar scaffolds for nucleic acid binding and antiproliferative effects. Graphical abstract image
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Novel pyrazolo[1,5-a]pyridines as orally active EP1 receptor antagonists: Synthesis, structure-activity relationship studies, and biological evaluation ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Kentaro Umei, Yosuke Nishigaya, Atsushi Kondo, Kazuya Tatani, Nobuyuki Tanaka, Yasushi Kohno, Shigeki Seto Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4–6. Structure-activity relationships (SAR) studies of 4–6 were performed, leading to identification of the nanomolar-level EP1 antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats. Graphical abstract image
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Inhibitors of protein arginine deiminases and their efficacy in animal models of multiple sclerosis ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Amit Sarswat, Ewa Wasilewski, Sai K. Chakka, Angelica M. Bello, Andrew V. Caprariello, Chithra M. Muthuramu, Peter K. Stys, Shannon E. Dunn, Lakshmi P. Kotra Protein arginine deiminases (PAD) are implicated in a variety of inflammatory and neurodegenerative diseases including multiple sclerosis (MS). Following the discovery of an in silico hit containing hydantoin and a piperidine moiety, we hypothesized that a 2-carbon linker on the hydantoin would be necessary for a 5-membered heterocycle for optimal PAD inhibitory activity. We designed thirteen compounds as potential inhibitors of PAD2 and PAD4 enzymes—two important PAD enzymes implicated in MS. Two compounds, one with an imidazole moiety (22) and the other with a tetrazole moiety (24) showed good inhibition of PAD isozymes in vitro and in the EAE mouse model of MS in vivo. Further experiments suggested that compound 22, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose-dependent efficacy in the EAE mouse model and in the cuprizone-mediated demyelination model. Graphical abstract image
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Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Carole J.R. Bataille, Méabh B. Brennan, Simon Byrne, Stephen G. Davies, Matthew Durbin, Oleg Fedorov, Kilian V.M. Huber, Alan M. Jones, Stefan Knapp, Gu Liu, Anna Nadali, Camilo E. Quevedo, Angela J. Russell, Roderick G. Walker, Robert Westwood, Graham M. Wynne The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition. Graphical abstract image
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Development of N-hydroxycinnamamide-based HDAC inhibitors with improved HDAC inhibitory activity and in vitro antitumor activity ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Jie Zang, Baowen Shi, Xuewu Liang, Qianwen Gao, Wenfang Xu, Yingjie Zhang Histone deacetylase inhibitors (HDACIs) are promising in the treatment of various diseases, among which cancer treatment has achieved the most success. We have previously developed series of HDACIs combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment, which showed moderate to potent antitumor activities. Herein, further structural derivatization based on our previous structure-activity relationship (SAR) got 25 novel compounds. Most compounds showed much more potent histone deacetylases (HDACs) inhibitory activity than their parent compound 1 and even the positive control SAHA. What’s more, compared with the approved HDACs inhibitor SAHA, compounds 6i, 6k, 6q and 6t displayed better in vitro antiproliferation against multiple tumor cell lines. It is worth noting that though the 4-hydroxycinnamic acid-based compound 2 showed HDAC1/3 dual selectivity, its 4-hydroxy-3-methoxycinnamic acid-based analog 6t turned out to be a pan-HDACs inhibitor as SAHA, indicating that the 3-methoxy group on the N-hydroxycinnamamide fragment could dramatically influence the HDACs isoform selectivity of this series of compounds. Graphical abstract image
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Erratum to “Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors” [Bioorg. Med. Chem. 24 (2016) 3083–3092] ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Sheng-Biao Wang, Mu-Tian Cui, Xiao-Feng Wang, Emika Ohkoshi, Masuo Goto, De-Xuan Yang, Linna Li, Shoujun Yuan, Susan L. Morris-Natschke, Kuo-Hsiung Lee, Lan Xie
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Corrigendum to “Synthesis and biological activity of 2,5-diaryl-3-methylpyrimido[4,5-c]quinolin-1(2H)-one derivatives” [Bioorg. Med. Chem. 15 (2007) 2434–2440] ()
Publication date: 1 May 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 9 Author(s): Kamel Metwally, Omar Aly, Enayat Aly, Abhijit Banerjee, Rudravajhala Ravindra, Susan Bane
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Synthesis and cytotoxic activity of new artemisinin hybrid molecules against human leukemia cells ()
Publication date: Available online 20 April 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Antonios S. Letis, Ean-Jeong Seo, Sotiris S. Nikolaropoulos, Thomas Efferth, Athanassios Giannis, Manolis A. Fousteris A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20–28 showed IC50 values in the range of 0.019 µM to 0.192 µM against CCRF-CEM cells and between 0.345 µM and 7.159 µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC50 value of 0.019 ± 0.001 µM and 0.345 ± 0.031 µM, respectively. A relatively low cross resistance to hybrids 20–28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to all the tested compounds. Interestingly, the lowest cross resistance to 23 was observed (5.7-fold), whereas hybrid 25 showed 18.2-fold cross-resistant to CEM/ADR5000 cells. Hybrid 25 which proved even more potent than clinically used doxorubicin against CEM/ADR5000 cells may serve as a promising antileukemic agent against both sensitive and multidrug-resistant cells. Graphical abstract image
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Antioxidant and anticholinesterase potential of diterpenoid alkaloids from Aconitum heterophyllum ()
Publication date: Available online 19 April 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Hanif Ahmad, Shujaat Ahmad, Syed Adnan Ali Shah, Abdul latif, Mumtaz Ali, Farman Ali Khan, Muhammad Nawaz Tahir, Farzana Shaheen, Abdul Wadood, Manzoor Ahmad Extensive chromatographic separations performed on the basic (pH = 8-10) chloroform soluble fraction of Aconitum heterophyllum resulted in the isolation of three new diterpenoid alkaloids, 6β-Methoxy, 9β-dihydroxylheteratisine (1), 1α,11,13β-trihydroxylhetisine (2), 6,15β-dihydroxylhetisine (3), and the known compounds iso-atisine (4), heteratisine (5), hetisinone (6), 19-epi-isoatisine (7), and atidine (8). Structures of the isolated compounds were established by means of mass and NMR spectroscopy as well as single crystal X-ray crystallography. Compounds 1–8 were screened for their antioxidant and enzyme inhibition activities followed by in silico studies to find out the possible inhibitory mechanism of the tested compounds. This work is the first report demonstrating significant antioxidant and anticholinesterase potentials of diterpenoid alkaloids isolated from a natural source. Graphical abstract image
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Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer’s disease based on the fusion of donepezil and curcumin ()
Publication date: Available online 18 April 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Jun Yan, Jinhui Hu, Anqiu Liu, Lin He, Xingshu Li, Hui Wei By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer’s disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50 = 187 nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aβ1−42 self-aggregation at 20 μM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b−Cu(II) complex. The excellent blood−brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system. Graphical abstract image
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Alkyne-linked reduction-activated protecting groups for diverse functionalization on the backbone of oligonucleotides ()
Publication date: Available online 17 April 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Hisao Saneyoshi, Kazuhiko Kondo, Koichi Iketani, Akira Ono A versatile conjugatable/bioreduction-responsive protecting group for phosphodiester moieties was designed, synthesized and incorporated into oligonucleotide strands. Subsequently, controlled pore glass-supported oligonucleotides were conjugated to a variety of functional molecules using a copper-catalyzed azide-alkyne cycloaddition reaction. The functionalized protecting groups were deprotected by a nitroreductase/NADH reduction system to give “naked” oligonucleotides. This method allowed the synthesis of oligonucleotide prodrugs bearing the functionalized protecting group at the desired sites and desired residues on oligodeoxyribonucleotide (ODN) backbones. Graphical abstract image
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Lathyrol and epoxylathyrol derivatives: modulation of Cdr1p and Mdr1p drug-efflux transporters of Candida albicans in Saccharomyces cerevisiae model ()
Publication date: Available online 16 April 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Andreia Mónico, Shweta Nim, Noélia Duarte, Manpreet Kaur Rawal, Rajendra Prasad, Attilio Di Pietro, Maria-José U. Ferreira Macrocyclic diterpenes were previously found to be able to modulate the efflux pump activity of Candida albicans multidrug transporters. Most of these compounds were jatrophanes, but only a few number of lathyrane-type diterpenes was evaluated. Therefore, the aim of this study was to evaluate the ability of nineteen structurally-related lathyrane diterpenes (1-19) to overcome the drug-efflux activity of Cdr1p and Mdr1p transporters of C. albicans, and get some insights on their structure-activity relationships. The transport assay was performed by monitoring Nile Red (NR) efflux in a Saccharomyces cerevisiae strain overexpressing the referred efflux pumps from C. albicans. Moreover, a chemosensitization assay was performed in order to evaluate the type of interaction between the inhibitory compounds and the antifungal drug fluconazole. Compounds 1-13 were previously isolated from Euphorbia boetica or obtained by derivatization, and compounds 14-19 were prepared by chemical transformations of compound 4. In the transport assays, compounds 14-19 revealed the strongest inhibitory activity of the Cdr1p efflux pump, ranging from 65 to 85%. Concerning Mdr1p efflux pump, the most active compounds were 1, 3, 6, 8, and 12 (75 to 85%). When used in combination with fluconazole, epoxyboetirane K (2) and euphoboetirane N (18) revealed synergistic effects in the AD-CDR1 yeast strain, overexpressing the Cdr1p transporter, through their ability to reduce the effective concentration of the antifungal drug by 23- and 52 fold, respectively. Graphical abstract image
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Editorial board ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8
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Optical probes and sensors as perspective tools in epigenetics ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Zdeněk Kejík, Robert Kaplánek, Martin Havlík, Tomáš Bříza, Milan Jakubek, Jarmila Králová, Ivan Mikula, Pavel Martásek, Vladimír Král Modifications of DNA cytosine bases and histone posttranslational modifications play key roles in the control of gene expression and specification of cell states. Such modifications affect many important biological processes and changes to these important regulation mechanisms can initiate or significantly contribute to the development of many serious pathological states. Therefore, recognition and determination of chromatin modifications is an important goal in basic and clinical research. Two of the most promising tools for this purpose are optical probes and sensors, especially colourimetric and fluorescence devices. The use of optical probes and sensors is simple, without highly expensive instrumentation, and with excellent sensitivity and specificity for target structural motifs. Accordingly, the application of various probes and sensors in the recognition and determination of cytosine modifications and structure of histones and histone posttranslational modifications, are discussed in detail in this review. Graphical abstract image
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A PEGylated analog of short-length Neuromedin U with potent anorectic and anti-obesity effects ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Hiroshi Inooka, Kotaro Sakamoto, Tokuyuki Shinohara, Yasushi Masuda, Michiko Terada, Satoshi Kumano, Kotaro Yokoyama, Jiro Noguchi, Naoki Nishizawa, Hidenori Kamiguchi, Hisashi Fujita, Taiji Asami, Shiro Takekawa, Tetsuya Ohtaki Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethylene glycol (PEG) with a molecular weight of 30kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15 (NMU-0002), which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use. Graphical abstract image
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Synthesis of clarithromycin ketolides chemically modified at the unreactive C10-methyl group ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Hany Fakhry Anwar, Mioara Andrei, Kjell Undheim Chemoselective substitutions in the C10-methyl group of erythromycin A ketolides is reported. The C10-methyl group in the clarithromycin derived substrate 10,11-anhydro-O 6-methyl-descladinosylerythromycin was activated by conversion into an allyl acetate and thereafter to the corresponding allylic cyanide. Both the allylic acetate and the cyanide reacted with carbonyldiimidazole and ammonia to afford a C11,C12-cyclic carbamate with concurrent elimination of the allylic function to yield a methylene α,β-unsaturated ketone. Conjugate addition with amines resulted in stereoselective C–N bond formation between the terminal methylene carbon and the amino nitrogen. Carbylation in the methylene group was effected under Stille conditions for cross-coupling with Pd-catalysis. With anion stabilized nucleophiles, such as a sodium salt of a malonate, stereoselectivity was observed in the formation of the 10-substituent. Stereoselective cycloaddition with trimethylsilyldiazomethane afforded a spirane where the C10 carbon of the macrolide skeleton had become a quaternary spirocarbon. Antibacterial in vitro data for a selected group of compounds against strains of respiratory pathogens S. pneumoniae and S. aureus are reported. Most of the compounds tested showed improved activities over CLA as a reference compound against efflux resistant S. pneumoniae as well as against efflux and inducibly resistant strains of S. aureus. Graphical abstract image
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Identification of compounds with cytotoxic activity from the leaf of the Nigerian medicinal plant, Anacardium occidentale L. (Anacardiaceae) ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Bamigboye J. Taiwo, Amos A. Fatokun, Olujide O. Olubiyi, Olukemi T. Bamigboye-Taiwo, Fanie R. van Heerden, Colin W. Wright Cancer is now the second-leading cause of mortality and morbidity, behind only heart disease, necessitating urgent development of (chemo)therapeutic interventions to stem the growing burden of cancer cases and cancer death. Plants represent a credible source of promising drug leads in this regard, with a long history of proven use in the indigenous treatment of cancer. This study therefore investigated Anacardium occidentale, one of the plants in a Nigerian Traditional Medicine formulation commonly used to manage cancerous diseases, for cytotoxic activity. Bioassay-guided fractionation, spectroscopy, Alamar blue fluorescence-based viability assay in cultured HeLa cells and microscopy were used. Four compounds, zoapatanolide A (1), agathisflavone (2), 1,2-bis(2,6-dimethoxy-4-methoxycarbonylphenyl)ethane (anacardicin, 3) and methyl gallate (4), were isolated, with the most potent being zoapatanolide A with an IC50 value of 36.2±9.8µM in the viability assay. To gain an insight into the likely molecular basis of their observed cytotoxic effects, Autodock Vina binding free energies of each of the isolated compounds with seven molecular targets implicated in cancer development (MAPK8, MAPK10, MAP3K12, MAPK3, MAPK1, MAPK7 and VEGF), were calculated. Pearson correlation coefficients were obtained with experimentally-determined IC50 in the Alamar blue viability assay. While these compounds were not as potent as a standard anticancer compound, doxorubicin, the results provide reasonable evidence that the plant species contains compounds with cytotoxic activity. This study provides some evidence of why this plant is used ethnobotanically in anticancer herbal formulations and justifies investigating Nigerian medicinal plants highlighted in recent ethnobotanical surveys. Graphical abstract image
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Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3′,4′:3,4]benzo[1,2-d]isothiazole derivatives ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Koji Ono, Hiroshi Banno, Masanori Okaniwa, Takaharu Hirayama, Naoki Iwamura, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R. Cary To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3′,4′:3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3′,4′:3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC50: 0.76nM, CDK19 IC50: 1.7nM). To improve the physicochemical properties and kinase selectivity of this compound, we introduced a substituted 3-pyridyloxy group into the scaffold 8-position. The resulting optimized compound 52h showed excellent in vitro potency (CDK8 IC50: 0.46nM, CDK19 IC50: 0.99nM), physicochemical properties, and kinase selectivity (only 5 kinases showed <35% unbound fraction at 300nM. CDK19: 4.6%, CDK8: 8.3%, HASPIN: 23%, DYRK1B: 27%, HIP1: 32%). Based on a docking model of 52h bound to CDK8, we could explain the highly specific kinase activity profile found for this compound, based on the interaction of the pyridyl group of 52h interacting with Met174 of the CDK8 DMG activation loop. In vitro pharmacological evaluation of 52h revealed potent suppression of phosphorylated STAT1 in various cancer cells. The high oral bioavailability found for this compound enabled in vivo studies, in which we demonstrated a mechanism-based in vivo PD effect as well as tumor growth suppression in an RPMI8226 human hematopoietic and lymphoid xenograft model in mouse [T/C: −1% (2.5mg/kg, qd)]. Graphical abstract image
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Xanthine oxidase inhibitory activity of nicotino/isonicotinohydrazides: A systematic approach from in vitro, in silico to in vivo studies ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Humaira Zafar, Muhammad Hayat, Sumayya Saied, Momin Khan, Uzma Salar, Rizwana Malik, M. Iqbal Choudhary, Khalid Mohammed Khan Change in life style and eating habits has led to an increased prevalence of hyperuricemia worldwide. The role of hyperuricemia is no more restricted to gout, but it has a central role in progression of CVD, hypertension, metabolic syndrome, and arthritis. Among the different factors involved in regulation of serum uric acid, xanthine oxidase (XO) is the best pharmacological target to control the levels of serum uric acid as it catalyzes the final steps in uric acid production. In the current study, a systemic search for the inhibitors of xanthine oxidase, starting from synthesis to in vitro screening and leading to in vivo studies is presented. Benzylidene nicotino/isonicotinohydrazides (1–54) were synthesized by treating nicotinic/isonicotinic hydrazides with substituted aromatic aldehyde, and characterized by EI-MS and 1H NMR. Elemental analysis was also performed. All synthetic compounds were screened for xanthine oxidase inhibitory activity initially using an in vitro spectroscopic XO inhibition assay. Among them twenty-two derivatives were found to be active with IC50 values between 0.96 and 330.4μM, as compared to standard drug allopurinol IC50 =2.00±0.01μM. Kinetic studies of five most active compounds (8, 35, 36, 39, and 45) with low IC50 values between 0.96 and 54.8μM showed a competitive mode of inhibition. Further in silico molecular docking was carried out to study the interactions of these inhibitors with catalytically important amino acid residues in XO. Three compounds 8, 35, and 36 with IC50 values of 10, 12.4, and 0.96μM, respectively, were also found to be non-cytotoxic, and thus selected for in vivo studies. A simple and physiologically relevant animal model was used to analyze the in vivo XO inhibitory activity of these compounds. Among these, two compounds 35, and 36 showed a significant inhibition in male Wistar rats, and identified as potential lead molecules for anti-hyperuricemic drug development. Graphical abstract image
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Design, synthesis, and biological evaluation of a highly water-soluble psoralen-based photosensitizer ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Yoshiyuki Uruma, Takuya Nonomura, Priscilla Yoong Mei Yen, Marie Edatani, Ryotaro Yamamoto, Kunishige Onuma, Futoshi Okada In recent years, photodynamic therapy (PDT) has been approved for treating various medical conditions, including cancer. PDT is a treatment that employs a particular drugs, called photosensitizers which work along with specific light source. The growth of this medical industry is expanding as it is another promising alternative to treat cancer which lessen the burden of treatments in patients. This includes the benefits of minimally invasive procedures and delivering high accuracy in targeting mutations. In recent two decades, cancer researchers have produced remarkable studies on developing photosensitizers that enhance understanding of biology and genetics of cancer. It is unfortunate that not all PDT can work as well as other profound treatment because PDT has various limitations like PDT leads photosensitivity reaction that arises when the photosensitizer remains in the body for a long period of time. In this paper, our studies centers on synthesizing a highly soluble photosensitizing agent with improved effectiveness on detecting cancer cells. Graphical abstract image
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Synthesis, properties, antitumor and antibacterial activity of new Pt(II) and Pd(II) complexes with 2,2′-dithiobis(benzothiazole) ligand ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Simona Rubino, Rosalia Busà, Alessandro Attanzio, Rosa Alduina, Vita Di Stefano, Maria Assunta Girasolo, Santino Orecchio, Luisa Tesoriere Mono- and binuclear Pt(II) and Pd(II) complexes with 2,2′-dithiobis(benzothiazole) (DTBTA) ligand are reported. [Pt(DTBTA)(DMSO)Cl]Cl∙CHCl3 (1) and [Pd2(µ-Cl)2(DTBTA)2]Cl2 (2) have been synthesized and structurally characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy, MS spectrometry and the content of platinum and palladium was determined using a flame atomic spectrometer. Two different coordination modes of 1 and 2 complexes were found; in both complexes, the coordination of Pt(II) and Pd(II) ions involves the N(3) atoms of the ligand but the binuclear complex 2, is a cis-chloro-bridged palladium complex. Evaluation of their in vitro antitumor activity against two human tumor cell lines human breast cancer (MCF-7) and hepatocellular carcinoma (HepG2); and their antimicrobial activity against Escherichia coli and Kokuria rhizophila was performed. Only complex 1 showed a dose- and time-dependent cytotoxic activity against the two tumor cell lines, associated to apoptosis and accumulation of treated cells in G0/G1 phase of cell cycle, while both 1 and 2 exhibited antimicrobial activity with complex 1 much more potent. The study on intracellular uptake in both MCF-7 and HepG2 cell lines revealed that only platinum of complex 1 is present inside the cells, suggesting a different mode of action of the two compounds. This was also in agreement with the results obtained for the antitumor and antibacterial activity. Graphical abstract image
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Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Zhikun Liu, Lei Fang, Huan Zhang, Shaohua Gou, Li Chen Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Aβ42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Aβ aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2, can be considered as potential therapeutic agents for Alzheimer’s disease. Graphical abstract image
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Design and characterization of opioid ligands based on cycle-in-macrocycle scaffold ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Anna Adamska-Bartłomiejczyk, Rossella De Marco, Luca Gentilucci, Alicja Kluczyk, Anna Janecka The study reports on a series of novel cyclopeptides based on the structure Tyr-[d-Lys-Phe-Phe-Asp]NH2, a mixed mu and kappa opioid receptor agonist with low nanomolar affinity, in which Phe4 residue was substituted by cyclic amino acids, such as Pro or its six-membered surrogates, piperidine-2-, 3- or 4-carboxylic acids (Pip, Nip and Inp, respectively). All derivatives exhibited high mu- and moderate delta-opioid receptor affinity, and almost no binding to the kappa-opioid receptor. Conformational analysis suggested that the cis conformation of the peptide bond Phe3-Xaa4 influences receptor selectivity through the control of the position of Phe3 side chain. The results substantiate the use of the cycle-macrocyle scaffolds for fine-tuning receptor selectivity. Graphical abstract image
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Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study ()
Publication date: 15 April 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 8 Author(s): Phong M. Truong, Sergio A. Hassan, Yong-Sok Lee, Theresa A. Kopajtic, Jonathan L. Katz, Aaron M. Chadderdon, John R. Traynor, Jeffrey R. Deschamps, Arthur E. Jacobson, Kenner C. Rice The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ 35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S- 16), (1R,5R,9S)-(−) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S- 20), and (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S- 15), had high affinity for the μ-opioid receptor (e.g., 1R,5R,9S- 16: Ki=0.073, 0.74, and 1.99nM, respectively). The 1R,5R,9S- 16 and 1R,5R,9S- 15 were full, high efficacy μ-agonists (EC50 =0.74 and 18.5nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTPγ 35S assay. The enantiomer of 1R,5R,9S- 16, (+)-1S,5S,9R- 16 was unusual, it had good affinity for the μ-OR (Ki=26.5nM) and was an efficacious μ-antagonist (Ke=29.1nM). Molecular dynamics simulations of the μ-OR were carried out with the 1R,5R,9S- 16 μ-agonist and the previously synthesized (1R,5R,9S)-(−)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(−)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9β-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges. Graphical abstract image
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