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Bioorganic & Medicinal Chemistry

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https://www.readbyqxmd.com/read/28624242/facile-access-to-modified-and-functionalized-pnas-through-ugi-based-solid-phase-oligomerization
#1
Jacques Saarbach, Daniela Masi, Claudio Zambaldo, Nicolas Winssinger
Peptide nucleic acids (PNAs) derivatized with functional molecules are increasingly used in diverse biosupramolecular applications. PNAs have proven to be highly tolerant to modifications and different applications benefit from the use of modified PNAs, in particular modifications at the γ position. Herein we report simple protocols to access modified PNAs from iterative Ugi couplings which allow modular modifications at the α, β or γ position of the PNA backbone from simple starting materials. We demonstrate the utility of the method with the synthesis of several bioactive small molecules (a peptide ligand, a kinase inhibitor and a glycan)-PNA conjugates...
June 14, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28622905/discovery-of-novel-somatostatin-receptor-subtype-5-sstr5-antagonists-pharmacological-studies-and-design-to-improve-pharmacokinetic-profiles-and-human-ether-a-go-go-related-gene-herg-inhibition
#2
Takeshi Yamasaki, Hideki Hirose, Tohru Yamashita, Nobuyuki Takakura, Sachie Morimoto, Takashi Nakahata, Asato Kina, Yoshihide Nakano, Yumiko Okano Tamura, Jun Sugama, Tomoyuki Odani, Yuji Shimizu, Shinji Iwasaki, Masanori Watanabe, Tsuyoshi Maekawa, Shizuo Kasai
Somatostatin (SST) is a peptide hormone comprising 14 or 28 amino acids that inhibits endocrine and exocrine secretion via five distinct G-protein-coupled receptors (SSTR1-5). SSTR5 has an important role in inhibiting the secretion of pancreatic and gastrointestinal hormones (e.g., insulin, GLP-1, PYY) through the binding of SSTs; hence, SSTR5 antagonists are expected to be novel anti-diabetic drugs. In the course of our lead generation program of SSTR5 antagonists, we have discovered a novel spiroazetidine derivative 3a...
June 13, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28634039/synthesis-and-biological-activity-of-peptide-proline-boronic-acids-as-proteasome-inhibitors
#3
Liqiang Han, Yanzhao Wen, Ridong Li, Bo Xu, Zemei Ge, Xin Wang, Tieming Cheng, Jingrong Cui, Runtao Li
On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits...
June 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28625715/discovery-of-simplified-leucyladenylate-sulfamates-as-novel-leucyl-trna-synthetase-lrs-targeted-mammalian-target-of-rapamycin-complex-1-mtorc1-inhibitors
#4
Suyoung Yoon, Jong Hyun Kim, Yura Koh, Phuong-Thao Tran, Jihyae Ann, Ina Yoon, Jayun Jang, Won Kyung Kim, Sangkook Lee, Jiyoun Lee, Sunghoon Kim, Jeewoo Lee
Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4-dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers...
June 2, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28619446/design-synthesis-and-evaluation-of-dna-topoisomerase-ii-targeted-nucleosides
#5
Hironobu Matsumoto, Mitsuaki Yamashita, Teruyuki Tahara, Shinya Hayakawa, Shun-Ichi Wada, Kiyoshi Tomioka, Akira Iida
We developed novel nucleoside-based topoisomerase II selective inhibitors and showed that small structural units, such as catechols, are essential for DNA topoisomerase II inhibitory activity. Moreover, nucleoside analogues containing TBS and 1,3-dithian moieties had potent and selective DNA topoisomerase II inhibitory activities. In further experiments, compound 25b having a beta configuration of the thymine moiety showed relatively strong growth inhibitory activity against cancer cell lines, and was more potent against all cancer cell lines than compound 26b, which carries a thymine moiety in the alpha configuration...
June 2, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28629630/design-synthesis-and-tumor-cell-growth-inhibitory-activity-of-3-nitro-2h-cheromene-derivatives-as-histone-deacetylaes-inhibitors
#6
Shuai Tan, Feng He, Tingting Kong, Jingde Wu, Zhaopeng Liu
As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275...
June 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28602669/the-selective-cytotoxicity-of-new-triazene-compounds-to-human-melanoma-cells
#7
Ana Sousa, Fábio Santos, Maria Manuela Gaspar, Susana Calado, João D Pereira, Eduarda Mendes, Ana Paula Francisco, Maria Jesus Perry
Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t½≥48h), and most of them showed to be slowly hydrolysed in human plasma (1...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28601509/olaparib-hydroxamic-acid-derivatives-as-dual-parp-and-hdac-inhibitors-for-cancer-therapy
#8
Zigao Yuan, Shaopeng Chen, Qinsheng Sun, Ning Wang, Dan Li, Shuangshuang Miao, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28601507/synthesis-and-pharmacological-evaluation-of-glycine-amide-derivatives-as-novel-vascular-adhesion-protein-1-inhibitors-without-cyp3a4-and-cyp2c19-inhibition
#9
Susumu Yamaki, Yuji Koga, Akira Nagashima, Mitsuhiro Kondo, Yoshiaki Shimada, Keitaro Kadono, Ayako Moritomo, Kosei Yoshihara
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28622907/synthesis-biological-evaluation-and-molecular-modeling-of-imidazo-1-2-a-pyridine-derivatives-as-potent-antitubulin-agents
#10
Jin Liu, Daiying Zuo, Tongfei Jing, Ming Guo, Lingyun Xing, Wenyu Zhang, Jianwen Zhao, Jiwei Shen, Ping Gong, Dajun Zhang, Xin Zhai
Two series of novel 5,7-diarylimidazo[1,2-a]pyridine-8-carbonitrile derivatives (3a-3q and 7a-7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h-7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC50 values in double-digit nanomolar degree...
May 30, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28601511/synthesis-molecular-modelling-and-cyp24a1-inhibitory-activity-of-novel-of-e-n-2-1h-imidazol-1-yl-2-phenylethyl-3-4-styrylbenzamides
#11
Ismail M Taban, Jinge Zhu, Hector F DeLuca, Claire Simons
CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC50 0.11-0.35μM) compared with the standard ketoconazole...
May 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28634040/1-2-4-triazole-and-1-3-4-oxadiazole-analogues-synthesis-mo-studies-in-silico-molecular-docking-studies-antimalarial-as-dhfr-inhibitor-and-antimicrobial-activities
#12
Sampark S Thakkar, Parth Thakor, Hiren Doshi, Arabinda Ray
1,2,4-Triazole and 1,3,4-oxadiazole analogues are of interest due to their potential activity against microbial and malarial infections. In search of suitable antimicrobial and antimalarial compounds, we report here the synthesis, characterization and biological activities of 1,2,4-triazole and 1,3,4-oxadiazole analogues (SS 1-SS 10). The molecules were characterized by IR, mass, (1)H NMR, (13)C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains, the results were explained with the help of DFT and PM6 molecular orbital calculations...
May 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28600079/synthesis-antiviral-evaluation-and-molecular-docking-studies-of-n-4-aryl-substituted-unsubstituted-thiosemicarbazones-derived-from-1-indanones-as-potent-anti-bovine-viral-diarrhea-virus-agents
#13
María C Soraires Santacruz, Matías Fabiani, Eliana F Castro, Lucía V Cavallaro, Liliana M Finkielsztein
A series of N(4)-arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N(4) position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC50=2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis...
May 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28622906/discovery-of-novel-quinazoline-2-4-1h-3h-dione-derivatives-as-potent-parp-2-selective-inhibitors
#14
Hailong Zhao, Ming Ji, Guonan Cui, Jie Zhou, Fangfang Lai, Xiaoguang Chen, Bailing Xu
The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program...
May 26, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28601510/synthesis-and-evaluation-of-symmetric-acyclic-nucleoside-bisphosphonates-as-inhibitors-of-the-plasmodium-falciparum-plasmodium-vivax-and-human-6-oxopurine-phosphoribosyltransferases-and-the-antimalarial-activity-of-their-prodrugs
#15
Petr Špaček, Dianne T Keough, Marina Chavchich, Martin Dračínský, Zlatko Janeba, Lieve Naesens, Michael D Edstein, Luke W Guddat, Dana Hocková
Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N(9) atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions...
May 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28583805/semisynthesis-of-autophagy-protein-lc3-conjugates
#16
Aimin Yang, Inken Hacheney, Yao-Wen Wu
Autophagy is a conserved catabolic process involved in the elimination of proteins, organelles and pathogens. Autophagosome formation is the key process in autophagy. Lipidated Atg8/LC3 proteins that are conjugated to phosphatidylethanolamine (PE) play a key role in autophagosome biogenesis. To understand the function of Atg8/LC3-PE in autophagosome formation and host-pathogen interaction requires preparation and structural manipulation of lipidated Atg8/LC3 proteins. Herein, we report the semisynthesis of LC3 proteins and mutants with modifications of different PE fragments or lipids using native chemical ligation and aminolysis approaches...
May 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28578993/a-statistical-view-of-protein-chemical-synthesis-using-ncl-and-extended-methodologies
#17
REVIEW
Vangelis Agouridas, Ouafâa El Mahdi, Marine Cargoët, Oleg Melnyk
Native chemical ligation and extended methodologies are the most popular chemoselective reactions for protein chemical synthesis. Their combination with desulfurization techniques can give access to small or challenging proteins that are exploited in a large variety of research areas. In this report, we have conducted a statistical review of their use for protein chemical synthesis in order to provide a flavor of the recent trends and identify the most popular chemical tools used by protein chemists. To this end, a protein chemical synthesis (PCS) database (http://pcs-db...
May 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28579308/a-dual-functional-peptide-auxiliary-conjugate-for-c-to-n-and-n-to-c-sequential-native-chemical-ligation-of-glycopeptides
#18
Claudia Bello, Christian F W Becker
Long, homogeneously glycosylated peptides and proteins can be assembled from multiple segments via sequential chemoselective reactions. The efficiency of the synthesis depends on the effectiveness and number of steps and on their compatibility with glycosylation methods. Here, we present how the combination of auxiliary-mediated native chemical ligation and thioester generation via hydrazinolysis from Wang-type resin enables multiple, sequential N-to-C and C-to-N ligations. The method can be applied to glycosylated peptides and peptide α-thioesters and has the potential to be further extended to sequential glycosylation, thus paving the way to the synthesis of complex homogeneous glycoproteins...
May 22, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28583806/the-tobacco-cembranoid-1s-2e-4s-7e-11e-2-7-11-cembratriene-4-6-diol-as-a-novel-angiogenesis-inhibitory-lead-for-the-control-of-breast-malignancies
#19
Mohammad M Hailat, Hassan Y Ebrahim, Mohamed M Mohyeldin, Amira A Goda, Abu Bakar Siddique, Khalid A El Sayed
(1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) and its 4-epi-analog (2) are diterpene precursors of the key flavor components in most Nicotiana (tobacco) species that purposely degraded during commercial tobacco fermentation. Angiogenesis, recruitment of new blood vessels, is important for tumor growth, survival and metastasis that can be targeted to control cancer. This study shows evidences and potential of the cembranoid 1 as a potent angiogenesis modulator through targeting VEGFR2. In silico study suggested favorable docking scores and binding affinity of 1 at the ATP binding pocket of VEGFR2...
May 20, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28578994/synthesis-molecular-docking-and-biological-activity-of-polyfluoroalkyl-dihydroazolo-5-1-c-1-2-4-triazines-as-selective-carboxylesterase-inhibitors
#20
Evgeny V Shchegol'kov, Galina F Makhaeva, Natalia P Boltneva, Sofya V Lushchekina, Olga G Serebryakova, Elena V Rudakova, Nadezhda V Kovaleva, Yanina V Burgart, Victor I Saloutin, Oleg N Chupakhin, Sergey O Bachurin, Rudy J Richardson
To search for effective and selective inhibitors of carboxylesterase (CaE), a series of 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo[5,1-c][1,2,4]triazines has been synthesized. Their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and CaE were investigated using the methods of enzyme kinetics and molecular docking. It was shown that the tested compounds are reversible selective CaE inhibitors of mixed type. Elongation of the polyfluoroalkyl substituent and the presence of an ester, preferably the ethoxycarbonyl group, enhance inhibitory activity toward CaE...
May 20, 2017: Bioorganic & Medicinal Chemistry
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