Bioorganic & Medicinal Chemistry

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Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
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Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
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1,2,4-Triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A3 receptor antagonists. Synthesis, structure–affinity relationships and molecular modeling studies ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Daniela Catarzi , Flavia Varano , Daniela Poli , Lucia Squarcialupi , Marco Betti , Letizia Trincavelli , Claudia Martini , Diego Dal Ben , Ajiroghene Thomas , Rosaria Volpini , Vittoria Colotta The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2–15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor–ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16–23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor–ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a K i value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24–27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.
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Synthesis, structural characterization and effect on human granulocyte intracellular cAMP levels of abscisic acid analogs ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Marta Bellotti , Annalisa Salis , Alessia Grozio , Gianluca Damonte , Tiziana Vigliarolo , Andrea Galatini , Elena Zocchi , Umberto Benatti , Enrico Millo The phytohormone abscisic acid (ABA), in addition to regulating physiological functions in plants, is also produced and released by several mammalian cell types, including human granulocytes, where it stimulates innate immune functions via an increase of the intracellular cAMP concentration ([cAMP]i). We synthesized several ABA analogs and evaluated the structure–activity relationship, by the systematical modification of selected regions of these analogs. The resulting molecules were tested for their ability to inhibit the ABA-induced increase of [cAMP]i in human granulocytes. The analogs with modified configurations at C-2′ and C-3′ abrogated the ABA-induced increase of the [cAMP]i and also inhibited several pro-inflammatory effects induced by exogenous ABA on granulocytes and monocytes. Accordingly, these analogs could be suitable as novel putative anti-inflammatory compounds. Graphical abstract image
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Synthesis and hybridization property of a boat-shaped pyranosyl nucleic acid containing an exocyclic methylene group in the sugar moiety ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Kazuto Mori , Tetsuya Kodama , Satoshi Obika A boat-shaped pyranosyl nucleic acid (BsNA) having an exocyclic methylene group in the sugar moiety was synthesized to investigate the possibility that the axial H3′ of original BsNA is the cause of its duplex destabilization. The synthesized BsNA analog was chemically stable against various nucleophiles. From the thermal stability of duplex oligonucleotides including the BsNA analog, it was found that the duplex-forming ability can be sensitive to the size of functional groups at the 3′-position. Graphical abstract image
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Bioactive constituents from the green alga Caulerpa racemosa ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Peng Yang , Ding-Quan Liu , Tong-Jun Liang , Jia Li , Hai-Yan Zhang , Ai-Hong Liu , Yue-Wei Guo , Shui-Chun Mao Three diterpenoids, including a pair of epimers, racemobutenolids A and B (1 and 2), and 4′,5′-dehydrodiodictyonema A (3), an α-tocopheroid, α-tocoxylenoxy (8), and an 28-oxostigmastane steroid, (23E)-3β-hydroxy-stigmasta-5,23-dien-28-one (11), together with 12 known compounds, were isolated from the green alga Caulerpa racemosa. The structures of the new compounds were elucidated by detailed analysis of spectroscopic data, and by comparison with data for related known compounds. The epimers (1 and 2) are two unusual diterpenoid lactones bearing a β-methyl-γ-substituted butenolide moiety, and 3 and 8 represent the first naturally occurring natural products with a hematinic acid ester group and 3,5-dimethylphenoxy functionality, respectively. The enzyme inhibitory activities of the isolated compounds were evaluated in vitro against PTP1B and related PTPs (TCPTP, CDC25B, LAR, SHP-1, and SHP-2). Compounds 3, 5, 6, and 9–14 exhibited different levels of PTP1B inhibitory activities with IC50 values ranging from 2.30 to 50.02μM. Of these compounds, 3, 9, and 11 showed the most potent inhibitory activities towards PTP1B with IC50 values of 2.30, 3.85, and 3.80μM, respectively. More importantly, the potent PTP1B inhibitors 3, 9, and 11 also displayed high selectivity over the highly homologous TCPTP and other PTPs. Also, the neuroprotective effects of the isolates against Aβ25-35-induced cell damage in SH-SY5Y cells were investigated. Compounds 10, 11, and 14 exhibited significant neuroprotective effects against Aβ25-35-induced SH-SY5Y cell damage with 11.31–15.98% increases in cell viability at 10μM. In addition, the cytotoxic activities of the isolated compounds were tested against the human cancer cell lines A-549 and HL-60. Graphical abstract image
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Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H-pyrazole thiazole derivatives as BRAFV600E inhibitors ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Meng-Yue Zhao , Yong Yin , Xiao-Wei Yu , Chetan B. Sangani , Shu-Fu Wang , Ai-Min Lu , Li-Fang Yang , Peng-Cheng Lv , Ming-Guo Jiang , Hai-Liang Zhu Many reports implied that the BRAF serine/threonine kinase was mutated in various types of human tumors, which were related with cell growth, survival and differentiation. To provide new therapeutic opportunities, a series of novel 4,5-dihydro-1H-pyrazole derivatives (6a–10d) containing thiazole moiety as potential V600E mutant BRAF kinase (BRAFV600E) inhibitors were designed and synthesized. All compounds were evaluated in vitro for anticancer activities against WM266.4 human melanoma cell line and breast cancer MCF-7 cell line. Compound 10d displayed the most potential antiproliferative activity with an IC50 value of 0.12μM against cell line WM266.4 and 0.16μM against MCF-7 with positive control Sorafenib. Results of the inhibitory activity against BRAFV600E revealed that compound 10d was bearing the best bioactivity with IC50 of 0.05μM as well. On the basis of the result of flow cytometry, with the dose of compound 10d increasing, more and more cancer cell gradually encountered apoptosis or died, which indicated the compound 10d could induce remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. Furthermore, docking simulation of inhibitor analogues and 3D-QSAR modeling provided potential binding model and further knowledge of pharmacophore. Graphical abstract image
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Clofazimine analogs with antileishmanial and antiplasmodial activity ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Anna Barteselli , Manolo Casagrande , Nicoletta Basilico , Silvia Parapini , Chiara M. Rusconi , Michele Tonelli , Vito Boido , Donatella Taramelli , Fabio Sparatore , Anna Sparatore A set of novel riminophenazine derivatives has been synthesized and evaluated for in vitro activity against chloroquine–sensitive (CQ-S) and chloroquine–resistant (CQ-R) strains of Plasmodium falciparum and against different species of Leishmania promastigotes. Most of the new compounds inhibited the growth of Leishmania promastigotes as well as CQ-S and CQ-R strains of P. falciparum with IC50 in submicromolar range, resulting in the best cases 1–2 orders of magnitude more potent than the parent compound clofazimine. Graphical abstract image
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Synthesis of prenylated quinolinecarboxylic acid derivatives and their anti-obesity activities ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Haruhisa Kikuchi , Toshiyuki Suzuki , Masato Ogura , Miwako K. Homma , Yoshimi Homma , Yoshiteru Oshima Mitochondrial uncoupling is one of the therapeutic strategies used to control energy metabolism in various metabolic diseases and in obesity. Ppc-1 (1), a prenylated quinolinecarboxylic acid isolated from cellular slime molds, shows uncoupling activity in vitro and anti-obesity activity in vivo. In this study, we synthesized Ppc-1 (1) and its derivatives, and revealed the structure–activity relationship of uncoupling activities. The triprenylated compound 18 showed mitochondrial uncoupling activity that was more potent than that of Ppc-1 (1). Compound 18 also suppressed weight gain in mice without undesired effects such as lesions on tissues. These results indicate that compound 18 could be used as a seed compound for new anti-obesity drugs. Graphical abstract image
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Identification of a novel glycan processing enzyme with exo-acting β-allosidase activity in the Golgi apparatus using a new platform for the synthesis of fluorescent substrates ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Wataru Hakamata , Kazuki Miura , Takako Hirano , Toshiyuki Nishio The majority of eukaryotic proteins undergo post-translational modifications (PTMs) involving the attachment of complex glycans, predominantly through N-glycosylation and O-glycosylation. PTMs play important roles in virtually all cellular processes, and aberrant regulation of protein glycosylation and glycan processing has been implicated in various diseases. However, glycan processing on proteins in various cellular contexts has not been visualized. We had previously developed a quinone methide cleavage (QMC) platform for enhanced substrate design. This platform was applied here to screen for novel glycan-processing enzymes. We designed and synthesized fluorescent substrates with β-allopyranoside residues using the QMC platform. When applied in cell-based assays, the fluorescent substrates allowed rapid and clear visualization of β-allosidase activity in the Golgi apparatus of human cultured cells. The QMC platform will likely find broad applications in visualizing the activities of glycan processing enzymes in living cells and in studying PTMs. Graphical abstract image
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4(α-l-Rhamnosyloxy)-benzyl isothiocyanate, a bioactive phytochemical that attenuates secondary damage in an experimental model of spinal cord injury ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Sabrina Giacoppo , Maria Galuppo , Gina Rosalinda De Nicola , Renato Iori , Placido Bramanti , Emanuela Mazzon 4(α-l-Rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG-ITC) is released from the precursor 4(α-l-rhamnosyloxy)-benzyl glucosinolate (glucomoringin; GMG) by myrosinase (β-thioglucoside glucohydrolase; E.C. 3.2.1.147) catalyzed hydrolysis. GMG is an uncommon member of the glucosinolate group as it presents a unique characteristic consisting in a second glycosidic residue within the side chain. It is a typical glucosinolate found in large amounts in the seeds of Moringa oleifera Lam., the most widely distributed plant of the Moringaceae family. GMG was purified from seed-cake of M. oleifera and was hydrolyzed by myrosinase at neutral pH in order to form the corresponding GMG-ITC. This bioactive phytochemical can play a key role in counteracting the inflammatory response connected to the oxidative-related mechanisms as well as in the control of the neuronal cell death process, preserving spinal cord tissues after injury in mice. Spinal cord trauma was induced in mice by the application of vascular clips (force of 24g) for 1min., via four-level T5–T8 after laminectomy. In particular, the purpose of this study was to investigate the dynamic changes occurring in the spinal cord after ip treatment with bioactive GMG-ITC produced 15min before use from myrosinase-catalyzed hydrolysis of GMG (10mg/kg body weight+5μl Myr mouse/day). The following parameters, such as histological damage, distribution of reticular fibers in connective tissue, nuclear factor (NF)-κB translocation and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) degradation, expression of inducible Nitric Oxide Synthases (iNOS), as well as apoptosis, were evaluated. In conclusion, our results show a protective effect of bioactive GMG-ITC on the secondary damage, following spinal cord injury, through an antioxidant mechanism of neuroprotection. Therefore, the bioactive phytochemical GMG-ITC freshly produced before use by myrosinase-catalyzed hydrolysis of pure GMG, could prove to be useful in the treatment of spinal cord trauma. Graphical abstract image
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Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Tetsuyoshi Matsufuji , Kousei Shimada , Shozo Kobayashi , Masanori Ichikawa , Asuka Kawamura , Teppei Fujimoto , Tsuyoshi Arita , Takashi Hara , Masahiro Konishi , Rie Abe-Ohya , Masanori Izumi , Yoshitaka Sogawa , Yoko Nagai , Kazuhiro Yoshida , Yasuyuki Abe , Takako Kimura , Hisashi Takahashi Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile. Graphical abstract image
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Design, syntheses and evaluation of 4-oxo-5-cyano thiouracils as SecA inhibitors ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Arpana S. Chaudhary , Jinshan Jin , Weixuan Chen , Phang C. Tai , Binghe Wang Protein translocation is essential for bacterial survival and the most important translocation mechanism is the secretion (Sec) pathway in which SecA is a central core driving force. Thus targeting SecA is a promising strategy for developing novel antibacterial therapeutics. Herein, we report the syntheses and evaluation of a series of nearly 60 4-oxo-5-cyano thiouracil derivatives based upon our previously reported core pyrimidine structure. Introduction of polar group such as –N3 and linker groups such as –CH2–O– enhanced the potency several fold. Apart from being potential antibacterial agents, these inhibitors can be indispensable tools for biologists to probe the mechanism of protein translocation via the SecA machinery in bacteria. Graphical abstract image
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Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Hanyi Tan , Guolin Wang , Jiajun Li , Guangrong Meng , Zhenfeng Liu , Mengjie Dong , Yubin Li , Dianwen Ju , Qian Zhang A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by 1H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels–Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I. Graphical abstract image
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Bioactive metabolites from Chaetomium aureum: Structure elucidation and inhibition of the Hsp90 machine chaperoning activity ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Fatima Zahra Kabbaj , Su Lu , My El Abbés Faouzi , Bouchra Meddah , Peter Proksch , Yahya Cherrah , Hans-Josef Altenbach , Amal H. Aly , Ahmed Chadli , Abdessamad Debbab Chemical investigation of the EtOAc extract of the fungus Chaetomium aureum, an endophyte of the Moroccan medicinal plant Thymelaea lythroides, afforded one new resorcinol derivative named chaetorcinol, together with five known metabolites. The structures of the isolated compounds were determined on the basis of one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry as well as by comparison with the literature. All compounds were tested for their activity towards the Hsp90 chaperoning machine in vitro using the progesterone receptor (PR) and rabbit reticulocyte lysate (RRL). Among the isolated compounds, only sclerotiorin efficiently inhibited the Hsp90 machine chaperoning activity. However, sclerotiorin showed no cytotoxic effect on breast cancer Hs578T, MDA-MB-231 and prostate cancer LNCaP cell lines. Interestingly, deacetylation of sclerotiorin increased its cytotoxicity toward the tested cell lines over a period of 48h. Graphical abstract image
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Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Xuekun Wang , Tianxiao Zhao , Baowei Yang , Zheng Li , Jian Cui , Yuxuan Dai , Qianqian Qiu , Hao Qiang , Wenlong Huang , Hai Qian Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50 =62.3nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus. Graphical abstract image
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Discovery of 2-[2-(5-nitrofuran-2-yl)vinyl]quinoline derivatives as a novel type of antimetastatic agents ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Chih-Hua Tseng , Cherng-Chyi Tzeng , Chien-Chih Chiu , Chih-Yao Hsu , Chon-Kit Chou , Yeh-Long Chen A number of 2-furanylvinylquinoline derivatives were synthesized and evaluated for antiproliferative activities against the growth of four cancer cell lines including non-small cell lung cancer (A549 and H1299), breast cancer (MCF-7 and MDA-MB-231) and normal diploid embryonic lung cell line (MRC-5). Among them, (E)-6-methoxy-3-(4-methoxyphenyl)-2-[2-(5-nitrofuran-2-yl)vinyl]quinoline (10c) was found low cytotoxic in all cancer cells and normal cell. The aim of this study was to investigate the anti-invasive and anti-metastatic activity of compound 10c in H1299 human lung cancer cells. In this study, compound 10c inhibited the migration and invasion of cells in a concentration-dependent manner by wound healing assay and transwell invasion assay. Furthermore, the inhibition of both phosphorylation of Akt and ERK by compound 10c may be critical for cell migration and this may result in the down-regulation of several factors associated with cellular migration, including β-catenin transcription factor, Bcl-2 and COX-2. Interestingly, the treatment of compound 10c did not affect the expression level but reduced the activities of the MMP-2 and -9. The phosphorylation level of stress-activated kinase p38 was significantly increased following compound 10c treatment. To sum up, compound 10c had potential to suppress the migration and invasion of H1299 cancer cells in vitro and it could serve as a promising drug for the treatment of cancer metastasis. Graphical abstract image
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Synthesis and biological evaluation of pyridinone analogues as novel potent HIV-1 NNRTIs ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Yuanyuan Cao , Yu Zhang , Shaotong Wu , Quanzhi Yang , Xuefeng Sun , Jianxiong Zhao , Fen Pei , Ying Guo , Chao Tian , Zhili Zhang , Haining Wang , Liying Ma , Junyi Liu , Xiaowei Wang A novel 2-pyridinone scaffold was rationally designed and synthesized based on the active anti-HIV agent 1 (LAM-trans) via an efficient method. The biological results revealed that some target compounds inhibited HIV-1 reverse transcriptase in the lower micromolar concentration range (IC50 0.089–0.68μm). Notably, the most promising compound 25b exhibited extremely potent inhibitory activity against HIV-1 replication with an EC50 value of 0.0563μM and the viral selectivity index amounted to 3466.8. Molecular modeling studies were performed, and some SARs were rationalized. Graphical abstract image
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Design and synthesis of novel 2,4-diaryl-5H-indeno[1,2-b]pyridine derivatives, and their evaluation of topoisomerase inhibitory activity and cytotoxicity ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Tara Man Kadayat , Chanmi Park , Kyu-Yeon Jun , Til Bahadur Thapa Magar , Ganesh Bist , Han Young Yoo , Youngjoo Kwon , Eung-Seok Lee For the development of potential anticancer agents, we designed and synthesized 30 new 2,4-diaryl-5H-indeno[1,2-b]pyridine derivatives containing aryl moiety such as furyl, thienyl, pyridyl, and phenyl at 2- and 4-position of 5H-indeno[1,2-b]pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines. Among prepared 30 compounds, 7, 8, 9, 10, 12, 14, 16, 19, 20, 22, and 23 with 2- or 3-furyl and/or 2- or 3-thienyl either at 2- or 4-position of central pyridine showed the significant or moderate topoisomerase II inhibitory activity. Compounds 7, 8, 11, 12, 13, and 22 with 2-furyl, 2-thienyl or 3-thienyl at 2-position of central pyridine showed the significant or moderate topoisomerase I inhibitory activity. Especially, compound 12 with strong topoisomerase II inhibitory activity at 100μM and 20μM, and moderate topoisomerase I inhibitory activity displayed strong cytotoxicity against several human cancer cell lines. Graphical abstract image
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Synthesis and antimycobacterial evaluation of 5-alkylamino-N-phenylpyrazine-2-carboxamides ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Jan Zitko , Barbora Servusová , Alena Janoutová , Pavla Paterová , Jana Mandíková , Vladimír Garaj , Marcela Vejsová , Jan Marek , Martin Doležal Substitution of chlorine in 5-chloro-N-phenylpyrazine-2-carboxamide (1) with simple n-alkylamines yielded a series of 5-alkylamino-N-phenylpyrazine-2-carboxamides (propylamino to octylamino derivatives), which possessed similar or increased activity against Mycobacterium tuberculosis H37Rv compared to parent 5-chloro derivative (1), with MIC ranging from 2.5 to 12.2μM. 5-Butylamino to 5-heptylamino derivatives exerted similar activity also against Mycobacterium kansasii. Importantly, the substitution led also to significant decrease of in vitro cytotoxicity in HepG2 cell line. 5-Heptylamino-N-phenylpyrazine-2-carboxamide (1e) exerted MIC=2.5μM (M. tbc) and IC50 >250μM (HepG2). Further modification of alkylamino chain with terminal methoxy or hydroxy group lead to compounds with decreased or none activity, the decrease was proportional to the decrease of lipophilicity. 5-(2-Phenylethylamino) and 5-(3-phenylpropylamino) derivatives were also of decreased activity. On contrary to alkylamino derivatives derived from 1, alkylamino derivatives derived from 5-chloro-N-2-chlorophenylpyrazine-2-carboxamide (2) possessed substantially decreased or none activity. None of the prepared compounds was active against Mycobacterium avium. Graphical abstract image
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Norbornane-based nucleoside and nucleotide analogues locked in North conformation ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Milan Dejmek , Michal Šála , Hubert Hřebabecký , Martin Dračínský , Eliška Procházková , Dominika Chalupská , Martin Klíma , Pavla Plačková , Miroslav Hájek , Graciela Andrei , Lieve Naesens , Pieter Leyssen , Johan Neyts , Jan Balzarini , Evzen Boura , Radim Nencka We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad antiviral and cytostatic assay panel. Graphical abstract image
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A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Nathalie Matusiak , Riccardo Castelli , Adriaan W. Tuin , Herman S. Overkleeft , Rosalina Wisastra , Frank J. Dekker , Laurette M. Prély , Rainer P.M. Bischoff , Aren van Waarde , Rudi A.J.O. Dierckx , Philip H. Elsinga Background Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with 18F and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo. Materials and methods ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) for PET (positron emission tomography). The resulting radiotracer [18F]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [18F]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5mg/kg ML5. Results ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4±2.0, 19.5±2.8, 2.0±0.2 and 5.7±2.2nM and 12.5±3.1, 31.5±13.7, 138.0±10.9 and 24.7±2.8nM. Radiochemical yield of HPLC-purified [18F]FB-ML5 was 13–16% (corrected for decay). Cellular binding of [18F]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10μM of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [18F]FB-ML5 showed a SUVmean of 0.145±0.064 (n =6) which decreased to 0.041±0.027 (n =6) after target blocking (p <0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2±7.3% (n =2) of total radioactivity in plasma, at 90min post injection (p.i.). Conclusion The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with 18F. [18F]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [18F]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [18F]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs. Graphical abstract image
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Modified 2,4-diaminopyrimidine-based dihydrofolate reductase inhibitors as potential drug scaffolds against Bacillus anthracis ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Baskar Nammalwar , Christina R. Bourne , Nancy Wakeham , Philip C. Bourne , Esther W. Barrow , N. Prasad Muddala , Richard A. Bunce , K. Darrell Berlin , William W. Barrow The current Letter describes the synthesis and biological evaluation of dihydrophthalazine-appended 2,4-diaminopyrimidine (DAP) inhibitors (1) oxidized at the methylene bridge linking the DAP ring to the central aromatic ring and (2) modified at the central ring ether groups. Structures 4a–b incorporating an oxidized methylene bridge showed a decrease in activity, while slightly larger alkyl groups (CH2CH3 vs CH3) on the central ring oxygen atoms (R2 and R3) had a minimal impact on the inhibition. Comparison of the potency data for previously reported RAB1 and BN-53 with the most potent of the new derivatives (19b and 20a–b) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.5–2μg/mL). Compounds 29–34 with larger ester and ether groups containing substituted aromatic rings at R3 exhibited slightly reduced activity (MICs 2–16μg/mL). One explanation for this attenuated activity could be encroachment of the extended R3 into the neighboring NADPH co-factor. These results indicate that modest additions to the central ring oxygen atoms are well tolerated, while larger modifications have the potential to act as dual-site inhibitors of dihydrofolate reductase (DHFR). Graphical abstract image
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Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT1A receptor functional profile ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Anna Partyka , Grażyna Chłoń-Rzepa , Anna Wasik , Magdalena Jastrzębska-Więsek , Adam Bucki , Marcin Kołaczkowski , Grzegorz Satała , Andrzej J. Bojarski , Anna Wesołowska Continuing our earlier study in a group of purine-2,6-dione derivatives of long chain arylpiperazines (LCAPs), a series of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl (4–14) and 7-tetrahydroisoquinolinyl-alkyl (15–17) analogues were synthesized and their serotonin 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D2 receptor affinities were determined. The study allowed us to identify some potent 5-HT1A receptor ligands with additional moderate affinity for 5-HT2A, 5-HT7 and dopamine D2 receptors. Compounds 9, 12, 13 and 14, with the highest 5HT1A receptor affinity, were selected for further functional in vivo studies and behavioural evaluation of antidepressant- and antianxiety-like activity. Compounds 9, 12 and 13 showed features of agonists of pre- and/or post-synaptic 5-HT1A receptors, whereas 14 was classified as an antagonist of postsynaptic sites. Moreover, derivatives 9 and 14 acted as antagonists of 5-HT2A receptors. In behavioural studies, compounds 9 and 13 showed antidepressant-like activity in the mouse forced swim test, and their effects were similar or stronger than those of imipramine. Compounds 9, 12 and 14 displayed potential anxiolytic-like properties in the mouse four-plate test, similar or even greater than those of the reference anxiolytic drug, diazepam. Graphical abstract image
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Ether modifications to 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503): Effects on binding affinity and selectivity for sigma receptors and monoamine transporters ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Rong Xu , Sarah A. Lord , Ryan M. Peterson , Emily A. Fergason-Cantrell , John R. Lever , Susan Z. Lever Two series of novel ether analogs of the sigma (σ) receptor ligand 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) have been prepared. In one series, the alkyl portion of the 4-methoxy group was replaced with allyl, propyl, bromoethyl, benzyl, phenethyl, and phenylpropyl moieties. In the second series, the 3,4-dimethoxy was replaced with cyclic methylenedioxy, ethylenedioxy and propylenedioxy groups. These ligands, along with 4-O-des-methyl SA4503, were evaluated for σ1 and σ2 receptor affinity, and compared to SA4503 and several known ether analogs. SA4503 and a subset of ether analogs were also evaluated for dopamine transporter (DAT) and serotonin transporter (SERT) affinity. The highest σ1 receptor affinities, K i values of 1.75–4.63nM, were observed for 4-O-des-methyl SA4503, SA4503 and the methylenedioxy analog. As steric bulk increased, σ1 receptor affinity decreased, but only to a point. Allyl, propyl and bromoethyl substitutions gave σ1 receptor K i values in the 20–30nM range, while bulkier analogs having phenylalkyl, and Z- and E-iodoallyl, ether substitutions showed higher σ1 affinities, with K i values in the 13–21nM range. Most ligands studied exhibited comparable σ1 and σ2 affinities, resulting in little to no subtype selectivity. SA4503, the fluoroethyl analog and the methylenedioxy congener showed modest six- to fourteen-fold selectivity for σ1 sites. DAT and SERT interactions proved much more sensitive than σ receptor interactions to these structural modifications. For example, the benzyl congener (σ1 K i =20.8nM; σ2 K i =16.4nM) showed over 100-fold higher DAT affinity (K i =121nM) and 6-fold higher SERT affinity (K i =128nM) than the parent SA4503 (DAT K i =12650nM; SERT K i =760nM). Thus, ether modifications to the SA4503 scaffold can provide polyfunctional ligands having a broader spectrum of possible pharmacological actions. Graphical abstract image
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Synthesis of aminoalkyl-substituted aurone derivatives as acetylcholinesterase inhibitors ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Young Hun Lee , Min Cheol Shin , Yong Don Yun , Seo Young Shin , Jong Min Kim , Jeong Moo Seo , Nam-Jung Kim , Jong Hoon Ryu , Yong Sup Lee Alzheimer’s disease (AD), a progressive and neurodegenerative disorder of the brain, is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, aurone derivatives were designed and synthesized as AChE inhibitors based on the lead structure of sulfuretin. Of those synthesized, compound 10d showed ca. 1700-fold and 6-fold higher AChE inhibitory activity than sulfuretin and galantamine, respectively. This compound also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2mg/kg. Graphical abstract image
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Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Matteo Gianella-Borradori , Ivy Christou , Carole J.R. Bataille , Rebecca L. Cross , Graham M. Wynne , David R. Greaves , Angela J. Russell The cannabinoid receptor 2 (CB2R) has been linked with the regulation of inflammation, and selective receptor activation has been proposed as a target for the treatment of a range of inflammatory diseases such as atherosclerosis and arthritis. In order to identify selective CB2R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, we first performed a ligand-based virtual screen. Subsequent medicinal chemistry optimisation studies led to the identification of a new class of selective CB2R agonists. Several examples showed high levels of activity (EC50 <200nM) and binding affinity (K i <200nM) for the CB2R, and no detectable activity at the CB1R. The most promising example, DIAS2, also showed favourable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases. Graphical abstract image
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Design, synthesis and biological activity of a novel Rutin analogue with improved lipid soluble properties ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Anna Baldisserotto , Silvia Vertuani , Alessia Bino , Daniela De Lucia , Ilaria Lampronti , Roberta Milani , Roberto Gambari , Stefano Manfredini Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis. Graphical abstract image
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Retraction notice to “3-Benzhydryl-4-piperidones as novel neurokinin-1 receptor antagonists and their efficient synthesis” [Bioorg. Med. Chem. 19 (2011) 5175–5182] ()
Publication date: 1 January 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1 Author(s): Junya Shirai , Minoru Nakamura , Naoki Tarui , Tadatoshi Hashimoto , Yoshinori Ikeura
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Synthesis and biological activities of some new isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.02.7]tridec-13-ylidene)-hydrazides ()
Publication date: Available online 26 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Lilia Matei , Coralia Bleotu , Ion Baciu , Carmen Cristina Diaconu , Anamaria Hanganu , Otilia Banu , Petre Ionita , Anca Paun , Arnaud Tatibouët , Irina Zarafu A series of several new isoniazid derivatives, isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.02.7]tridec-13-ylidene)-hydrazides, were synthesized and fully characterized. These new isoniazid derivatives were studied regarding their antibacterial activity and cytotoxicity, as well as their influences on some metabolizing enzymes. The best anti-mycobacterial activity was observed in the case of compounds containing alkyl side chains in the 8 position of tricyclo[7.3.1.02.7]tridec-13-ylidene group. On contrary, the antimicrobial activity of these new compounds against various non-tuberculosis strains showed the best activity to be with the phenyl side chain of compound 6. It proved also to be the most toxic, inducing apoptosis and blocking the cell cycle in G0/G1 phase. The cell cycle was blocked in G0/G1 phase also by compound 3, but this compound did not show any toxicity. All compounds induced the expression of NAT1 and NAT2 genes in HT-29 cell line, and the expression of CYP1A1 in HT-29 and HCT-8 cell lines. The expression level of CYP3A4 was increased by compounds 1, 6 and 7 in HCT-8 cells. These results indicated that the activation of other metabolizing pathways, apart from those of isoniazid, take place. It might also point out the possibility of an increased isoniazid acetylation ratio by co-administration with new compounds in slow acetylators. Graphical abstract image
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Synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl and sulfamoyl acetamides and ethyl acetates as potent COX-2 inhibitors ()
Publication date: Available online 26 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Sara Consalvi , Salvatore Alfonso , Angela Di Capua , Giovanna Poce , Adele Pirolli , Manuela Sabatino , Rino Ragno , Maurizio Anzini , Stefania Sartini , Concettina La Motta , Lorenzo Di Cesare Mannelli , Carla Ghelardini , Mariangela Biava We report herein the synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl, sulfamoyl acetamides and ethyl acetates that selectively inhibit cyclooxygenase-2 (COX-2) isoform. Among the newly synthesized compounds, some of them were endowed with a good activity against COX-2 and a good selectivity COX-2/COX-1 in vitro as well as a desirable analgesic activity in vivo, proving that replacement of the ester moiety with an amide group gave access to more stable derivatives, characterized by a good COX-inhibition. Graphical abstract image
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Investigation of fatty acid conjugates of 3,5-bisarylmethylene-4-piperidone derivatives as antitumor agents and human topoisomerase-IIα inhibitors ()
Publication date: Available online 26 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Elizabeth Potter , Mamta Jha , Khushwant S. Bhullar , H.P. Vasantha Rupasinghe , Jan Balzarini , Amitabh Jha A series of five 3,5-bisarylidene-4-piperidones designed as analogs of curcumin and their twenty five fatty acid conjugates were synthesized as candidate anticancer agents. The fatty acid conjugates were designed for efficient delivery of these compounds at the targeted cancer sites. The cytostatic potential of these compounds was evaluated against three representative cancer cell lines namely murine leukemic L1210 cells, and human T-lymphocyte CEM cells and cervical HeLa cells. Most compounds were found to exhibit significant anti-cancer activity in-vitro. QSAR studies indicated electrophilicity of these compounds towards cellular nucleophiles may have a key role to play in their cytostatic activity. Representative compounds were also tested for topoisomerase IIα inhibitory potential, which indicated strong catalytic inhibition of the enzyme in vitro. The data showed that the fatty acid conjugates also possessed robust antioxidant activity in multiple analyses. This study also indicated that these compounds prompted significantly lower cellular damage in human fibroblasts than a currently used cancer drug sorafenib in vitro. The wide spectrum of anticancer action, supplemented with antioxidant potential along with non-toxic manifestations, certainly augment the anticancer candidacy of the novel fatty acid conjugates. Graphical abstract image
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Synthesis and evaluation of multi-functional NO-donor/ insulin-secretagogue derivatives for the treatment of type II diabetes and its cardiovascular complications ()
Publication date: Available online 26 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Maria Digiacomo , Alma Martelli , Lara Testai , Annalina Lapucci , Maria C. Breschi , Vincenzo Calderone , Simona Rapposelli Although there is a significant effort in the discovery of effective therapies to contrast both the pathological endocrine and metabolic aspects of diabetes and the endothelial dysfunction associated with this disease, no hypoglycemic drug has been proven to defeat the cardiovascular complications associated with type II diabetes. The aim of this research was to design new compounds exhibiting a double profile of hypoglycemic agents/NO-donors. The synthesis of molecules obtained by the conjunction of NO-donor moieties with two oral insulin-secretagogue drugs (repaglinide and nateglinide) was reported. NO-mediated vasorelaxing effects of the synthesised compounds were evaluated by functional tests on isolated endothelium-denuded rat aortic rings. The most potent molecule (4) was tested to evaluate the hypoglycaemic and the anti-ischemic cardioprotective activities. This study indicate that 4 should represent a new insulin-secretagogue/NO-donor prodrug with an enhanced cardiovascular activity, which may contrast the pathological aspects of diabetes and endowed of cardioprotective activity. Graphical abstract image
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Development of potent dopamine-norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template ()
Publication date: Available online 25 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Soumava Santra , Horrick Sharma , Seenuvasan Vedachalam , Tamara Antonio , Maarten Reith , Aloke Dutta Current therapy of depression is less than ideal with remission rates of only 25–35% and response rates of 45–60%. It has been hypothesized that a dysfunctional dopaminergic system in the mesocorticolimbic pathway in depressive disorder may lead to development of anhedonia associated with loss of pleasure and interest along with loss of motivation. The current antidepressants do not address dopamine dysfunction which might explain their low efficacy. In this report, we have described an SAR study on our pyran-based triple reuptake inhibitors (TRIs) which are being investigated as the next-generation antidepressants. In the present work we demonstrate that our lead TRIs can be modified with appropriate aromatic substitutions to display a highly potent SSRI profile for compounds 2a and 4a (K i (SERT); 0.71 and 2.68nM, respectively) or a potent DNRI profile for compounds 6b and 6h (K i (DAT/NET); 8.94/ 4.76 and 13/ 7.37nM, respectively). Compounds 4g–4i exhibited potencies at all three monoamine transporters. The results provide insights into the structural requirements for developing selective dual- and triple-uptake inhibitors from a unique pyran molecular template for an effective management of depression and related disorders. Graphical abstract image
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Synthesis and biological evaluation of phosphoramidate prodrugs of two analogues of 2-deoxy-D-ribose-1-phosphate directed to the discovery of two carbasugars as new potential anti-HIV leads ()
Publication date: Available online 25 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Nadège Hamon , Magdalena Slusarczyk , Michaela Serpi , Jan Balzarini , Christopher McGuigan 2-Deoxy-α-D-ribose-1-phosphate is of great interest as it is involved in the biosynthesis and/or catabolic degradation of several nucleoside analogues of biological and therapeutic relevance. However due to the lack of a stabilising group at its 2 position, it is difficult to synthesize stable prodrugs of this compound. In order to overcome this lack of stability, the synthesis of carbasugar analogues of 2-deoxyribose-1-phosphate was envisioned. Herein the preparation of a series of prodrugs of two carbocyclic analogues of 2-deoxyribose-1-phosphate using the phosphoramidate ProTide technology, along with their biological evaluation against HIV and cancer cell proliferation, is reported. Graphical abstract image
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Transformation of naltrexone into mesembrane and investigation of the binding properties of its intermediate derivatives to opioid receptors ()
Publication date: Available online 24 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Kazuya Konoura , Hideaki Fujii , Satomi Imaide , Hiroaki Gouda , Shigeto Hirayama , Shuichi Hirono , Hirosh Nagase We transformed naltrexone (5) with the morphinan skeleton into mesembrane (4) belonging to the Sceletium alkaloids via key intermediate 6, characterized by a cis-fused hydroindole skeleton with a suspended phenyl ring fixed by an epoxy bridge. We then investigated the binding affinities of 4 and the key intermediate 6 derivatives to the opioid receptors. Among the tested compounds, 15′, with a cis-fused hydroindole core, bound to the three opioid receptor types with strong to moderate affinities. The observed differences of binding affinities among the tested compounds were reasonably explained by the conformational analyses of the compounds. The structure-activity relationship (SAR) of the tested compounds like 15′ with the hydroindole structure was completely different from the reported SAR of morphinan derivatives with the hydroisoquinoline skeleton. Compound 15′ with a structure that differs from the morphinans represents a useful fundamental skeleton with a novel chemotype that may contribute to the development of new opioid ligands. Graphical abstract image
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Synthesis, structure activity relationship, radiolabeling and preclinical evaluation of high affinity ligands for the ion channel of the N-methyl-D-aspartate receptor as potential imaging probes for positron emission tomography ()
Publication date: Available online 24 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Pieter J. Klein , Johannes A.M. Christiaans , Athanasios Metaxas , Robert C. Schuit , Adriaan A. Lammertsma , Bart N.M. van Berckel , Albert D. Windhorst The N-Methyl-D-Aspartate receptor (NMDAr) is involved in many neurological and psychiatric disorders including Alzheimer’s disease and schizophrenia. Currently, it is not possible to assess NMDAr availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NMDAr ion channel. A series of di- and tri-N-substituted diarylguanidines was synthesized. In addition, in vitro binding affinity for the NMDAr ion channel in rat forebrain membrane fractions was assessed. Compounds 10, 11 and 32 were radiolabeled with either carbon-11 or fluorine-18. Ligands [11C]10 and [18F]32 were evaluated ex vivo in B6C3 mice. Biodistribution studies showed higher uptake of [11C]10 and [18F]32 in forebrain regions compared with cerebellum. In addition, for [11C]10 54% and for [18F]32 70% of activity in the brain at 60 min was due to intact tracer. Pre-treatment with MK-801 (0.6 mg kg-1, i.p.) slightly decreased uptake in NMDAr-specific regions for [18F]32, but not for [11C]10. As such [18F]32 has the best characteristics as a PET tracer for the ion channel of the NMDAr. Graphical abstract image
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Perspective: Challenges and Opportunities in TB drug discovery from phenotypic screening ()
Publication date: Available online 24 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Ujjini H. Manjunatha , Paul W. Smith Tuberculosis poses a major global health problem and multi-drug resistant strains are increasingly prevalent. Hence there is an urgent need to discover new TB drugs. Cell based phenotypic screening represents a powerful approach to identify anti-mycobacterial compounds and elucidate novel targets. Three high throughput phenotypic screens were performed at NITD against mycobacterium. Hits were identified and chemical series selected for optimisation. This produced compounds with good in vitro anti-mycobacterial activity and pharmacokinetic properties. Some compounds displayed oral activity in mouse efficacy models of TB. Herein, we review the TB discovery efforts at NITD and share experiences in optimisation of phenotypic hits, describing challenges encountered and lessons learned. We also offer perspectives to facilitate future selection and advancement of phenotypic hits. Graphical abstract image
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Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis ()
Publication date: Available online 24 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Michelle S. Frei , Matthew K. Bilyard , Thomas A. Alanine , Warren R.J.D. Galloway , Jamie E. Stokes , David R. Spring Herein, we report on work towards the development of a new strategy for the synthesis of rare and biologically interesting indolizin-5(3H)-ones, which is based around the use of ring-closing metathesis to construct the carbocyclic ring system. This study has provided insights into the general stability of indolizin-5(3H)-ones and their tendency to exist as the tautomeric indolizin-5-ols. Furthermore, this approach has allowed access to other novel structurally related compounds based around unusual 6,5-azabicyclic scaffolds, which are also difficult to generate using typical methods. The azabicyclic compounds synthesized in this study reside in attractive regions of heterocyclic chemical space that are underexploited in current drug and agrochemical discovery efforts. Graphical abstract image
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GPCR Crystal Structures: Medicinal Chemistry in the Pocket ()
Publication date: Available online 24 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Jeremy Shonberg , Ralf C. Kling , Peter Gmeiner , Stefan Löber Recent breakthroughs in GPCR structural biology have significantly increased our understanding of drug action at these therapeutically relevant receptors, and this will undoubtedly lead to the design of better therapeutics. In recent years, crystal structures of GPCRs from classes A, B, C and F have been solved, unveiling a precise snapshot of ligand-receptor interactions. Furthermore, some receptors have been crystallized in different functional states in complex with antagonists, partial agonists, full agonists, biased agonists and allosteric modulators, providing further insight into the mechanisms of ligand-induced GPCR activation. It is now obvious that there is enormous diversity in the size, shape and position of the ligand binding pockets in GPCRs. In this review, we summarise the current state of solved GPCR structures, with a particular focus on ligand-receptor interactions in the binding pocket, and how this can contribute to the design of GPCR ligands with better affinity, subtype selectivity or efficacy. Graphical abstract image
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Design and synthesis of new bioisosteres of Spirooxindoles (MI-63/219) as anti-breast cancer agents ()
Publication date: Available online 23 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Atul Kumar , Garima Gupta , Ajay Kumar Bishnoi , Ruchi Saxena , Karan Singh Saini , Rituraj Konwar , Sandeep Kumar , Anila Dwivedi We report herein the design and synthesis of bioisosteres of spirooxindole (MI-63/219) , a small-molecule inhibitors of the MDM2-p53 interaction as anti-breast cancer agents. Compound 5b has been exhibiting significant anti-proliferative activity in nude mice bearing MCF-7 xenograft tumor. The compound 5b was found to act via modulation of MDM2 and p53 expression in breast cancer cells expressing wild type p53. Compound 5b stimulated p53 activation, caused modulation of downstream effectors p21, pRb, and cyclinD1 which regulate cell cycle. Thus, compound triggered G1-S phase cell cycle arrest, which was evident by flow cytometric analysis of treated breast cancer cells. Thus, compound 5b restores the p53 function, which triggers molecular events consistent with cell cycle arrest at G1/S phase. Graphical abstract image
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Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy ()
Publication date: Available online 23 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Zhongli Gao , William J. Hurst , Daniel Hall , Ryan Hartung , William Reynolds , Jiesheng Kang , Raisa Nagorny , James A. Hendrix , Pascal G. George Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3’]bipyrrolidinyl-1’-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [(2S,3’S)-2-methyl-[1,3’]bipyrrolidinyl-1’-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [(2S,3’S)-2-methyl-[1,3’]bipyrrolidinyl-1’-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3’S)-2-methyl-[1,3’]bipyrrolidinyl-1’-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3’S)-2-methyl-[1,3’]bipyrrolidinyl-1’-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10 μM, and no significant induction of any major haemodynamic effect when intravenously administered at 3 mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class. Graphical abstract image
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Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif ()
Publication date: Available online 23 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Kevin J. Frankowski , Stephen R. Slauson , Kimberly M. Lovell , Angela M. Phillips , John M. Streicher , Lei Zhou , David A. Whipple , Frank J. Schoenen , Thomas E. Prisinzano , Laura M. Bohn , Jeffrey Aubé Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure–activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists. Graphical abstract image
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Saccharin: a Lead Compound for Structure-Based Drug Design of Carbonic Anhydrase IX Inhibitors ()
Publication date: Available online 23 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Brian P. Mahon , Alex M. Hendon , Jenna M. Driscoll , Gregory M. Rankin , Sally-Ann Poulsen , Claudiu T. Supuran , Robert McKenna Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition. Graphical abstract image
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Synthesis and Comparative Biological Evalution of Bifunctional Ligands for Radiotherapy Applications of 90Y and 177Lu ()
Publication date: Available online 23 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Hyun-Soon Chong , Xiang Sun , Yunwei Chen , Inseok Sin , Chi Soo Kang , Michael R. Lewis , Dijie Liu , Varyanna C. Ruthengael , Ningjie Wu , Hyun A Song Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope (90Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin’s lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides 90Y and 177Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with 90Y and 177Lu, and the corresponding 90Y or 177Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding 90Y and 177Lu, and the corresponding 90Y- and 177Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of 90Y and 177Lu. Graphical abstract image
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Identification of the dioxygenase-generated intermediate formed during biosynthesis of the dihydropyrrole moiety common to anthramycin and sibiromycin ()
Publication date: Available online 20 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Shalini Saha , Wei Li , Barbara Gerratana , Steven E. Rokita A description of pyrrolo[1,4]benzodiazepine (PBD) biosynthesis is a prerequisite for engineering production of analogs with enhanced antitumor activity. Predicted dioxygenases Orf12 and SibV associated with dihydropyrrole biosynthesis in PBDs anthramycin and sibiromycin, respectively, were expressed and purified for activity studies. UV-visible spectroscopy revealed that these enzymes catalyze the regiospecific 2,3-extradiol dioxygenation of L-3,4-dihydroxyphenylalanine (L-DOPA) to form L-2,3-secodopa (λmax = 368 nm). 1H NMR spectroscopy indicates that L-2,3-secodopa cyclizes into the α-keto acid tautomer of L-4-(2-oxo-3-butenoic-acid)-4,5-dihydropyrrole-2-carboxylic acid (λmax = 414 nm). Thus, the dioxygenases arekey for establishing thescaffold of the dihydropyrrole moiety. Kinetic studies suggest the dioxygenase product is relatively labile and is likely consumed rapidly by subsequent biosynthetic steps. The enzymatic product and dimeric state of these dioxygenases are conserved in dioxygenases involved in dihydropyrrole or pyrrolidine biosynthesiswithin both PBD and non-PBD pathways. Graphical abstract image
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Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors ()
Publication date: Available online 20 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Yasuhiro Shimamoto , Yasunao Hattori , Kazuya Kobayashi , Kenta Teruya , Akira Sanjoh , Atsushi Nakagawa , Eiki Yamashita , Kenichi Akaji The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α−nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CLpro, which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CLpro inhibitor. X-ray crystallographic analyses of the SARS 3CLpro in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor. Graphical abstract image
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MCR synthesis of a tetracyclic tetrazole scaffold ()
Publication date: Available online 20 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Pravin Patil , Kareem Khoury , Eberhardt Herdtweck , Alexander Dömling Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds. Graphical abstract image
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Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity ()
Publication date: Available online 20 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Kathryn J. Wicht , Jill M. Combrinck , Peter J. Smith , Timothy J. Egan A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against P. falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5,000 commercially available compounds (AldrichCPR) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively. Graphical abstract image
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Natural antitubulin agents: importance of 3,4,5-trimethoxyphenyl fragment ()
Publication date: Available online 20 December 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Arvind S. Negi , Yashvir Gautam , Sarfraz Alam , Debabrata Chanda , Suaib Luqman , Jayanta Sarkar , Feroz Khan , Rituraj Konwar Microtubules are polar cytoskeletal filaments assembled from head-to-tail and comprised of lateral associations of α/β-tubulin heterodimers that play key role in various cellular processes. Because of their vital role in mitosis and various other cellular processes, microtubules have been attractive targets for several disease conditions and especially for cancer. Antitubulin is the most successful class of antimitotic agents in cancer chemotherapeutics. The target recognition of antimitotic agents as a ligand is not much explored so far. However, 3,4,5-trimethoxyphenyl fragment has been much highlighted and discussed in such type of interactions. In this review, some of the most important naturally occurring antimitotic agents and their interactions with microtubules are discussed with a special emphasis on the role of 3,4,5-trimethoxyphenyl unit. At last, some emerging naturally occurring antimitotic agents have also been tabulated. Graphical abstract image
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