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Bioorganic & Medicinal Chemistry

Kentaro Umei, Yosuke Nishigaya, Atsushi Kondo, Kazuya Tatani, Nobuyuki Tanaka, Yasushi Kohno, Shigeki Seto
Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4-6. Structure-activity relationships (SAR) studies of 4-6 were performed, leading to identification of the nanomolar-level EP1 antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats...
March 14, 2017: Bioorganic & Medicinal Chemistry
Grigoris Zoidis, Alice Sosic, Silvia Da Ros, Barbara Gatto, Claudia Sissi, Fausta Palluotto, Angelo Carotti, Marco Catto
DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2-c]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[h]indeno[1,2-c]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G-quadruplex sequences...
March 11, 2017: Bioorganic & Medicinal Chemistry
Kevin P Cole, Sarah J Ryan, Jennifer McClary Groh, Richard D Miller
Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120-240°C and 15-40min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation...
March 10, 2017: Bioorganic & Medicinal Chemistry
Lun K Tsou, Jacob S Yount, Howard C Hang
Increasing antibiotic resistance and beneficial effects of host microbiota has motivated the search for anti-infective agents that attenuate bacterial virulence rather than growth. For example, we discovered that specific flavonoids such as baicalein and quercetin from traditional medicinal plant extracts could attenuate Salmonella enterica serovar Typhimurium type III protein secretion and invasion of host cells. Here, we show epigallocatechin-3-gallate from green tea extracts also inhibits the activity of S...
March 10, 2017: Bioorganic & Medicinal Chemistry
Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi
Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro...
March 9, 2017: Bioorganic & Medicinal Chemistry
Simona Rubino, Rosalia Busà, Alessandro Attanzio, Rosa Alduina, Vita Di Stefano, Maria Assunta Girasolo, Santino Orecchio, Luisa Tesoriere
Mono- and binuclear Pt(II) and Pd(II) complexes with 2,2'-dithiobis(benzothiazole) (DTBTA) ligand are reported. [Pt(DTBTA)(DMSO)Cl]Cl∙CHCl3 (1) and [Pd2(µ-Cl)2(DTBTA)2]Cl2 (2) have been synthesized and structurally characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy, MS spectrometry and the content of platinum and palladium was determined using a flame atomic spectrometer. Two different coordination modes of 1 and 2 complexes were found; in both complexes, the coordination of Pt(II) and Pd(II) ions involves the N(3) atoms of the ligand but the binuclear complex 2, is a cis-chloro-bridged palladium complex...
March 9, 2017: Bioorganic & Medicinal Chemistry
Menshawy A Mohamed, Alaa A-M Abdel-Aziz, Helmy M Sakr, Adel S El-Azab, Silvia Bua, Claudiu T Supuran
A series of sulfonamides was obtained by reacting substituted-2-(1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxamido)benzoic acids with aromatic sulfonamides incorporating primary amino moieties. The new compounds were investigated as inhibitor of four carbonic anhydrase (CA, EC isoforms, the human (h) hCA I and II, and the α- and β-class CAs from the pathogenic bacterium Vibrio cholerae, VchCAα and VhcCAβ. hCA I was effectively inhibited by the new sulfonamides, with inhibition constants in the range of 4...
March 9, 2017: Bioorganic & Medicinal Chemistry
Qingxi Su, Seema Dalal, Michael Goetz, Maria B Cassera, David G I Kingston
No abstract text is available yet for this article.
March 9, 2017: Bioorganic & Medicinal Chemistry
Georgios Paraskevopoulos, Sara Monteiro, Rudolf Vosátka, Martin Krátký, Lucie Navrátilová, František Trejtnar, Jiřina Stolaříková, Jarmila Vinšová
No abstract text is available yet for this article.
March 9, 2017: Bioorganic & Medicinal Chemistry
Siyao Wang, Leo Corcilius, Phillip P Sharp, Richard J Payne
Herein we describe the synthesis of glycopeptide fragments from the death domains of TRADD and FADD bearing the recently discovered Nω-GlcNAc-β-arginine post-translational modification. TRADD and FADD glycopeptides were accessed through the use of a suitably protected synthetic glycosylamino acid 'cassette' that could be directly incorporated into conventional solid phase peptide synthesis (SPPS) protocols.
March 7, 2017: Bioorganic & Medicinal Chemistry
Samuel Asare-Nkansah, Dirk Schepmann, Bernhard Wünsch
The receptor binding profile of 2-phenyl-4-(aminoethyl)-1,3-dioxanes is dependent on the additional substituent in 2-position, the substituents at the amino moiety and the stereochemistry. Herein, conformationally restricted 1,3-dioxanes bearing an axially oriented phenyl moiety in 2-position were prepared and pharmacologically evaluated. Two subsequent intramolecular transacetalization reactions represent the key steps in the synthesis of the tricyclic system. The resulting alcohol 17 was transformed into amines 20-23 with axially (a-series) or equatorially oriented aminoethyl moiety (b-series)...
March 7, 2017: Bioorganic & Medicinal Chemistry
Leilei Zhao, Yifei Yang, Yahui Guo, Lingyun Yang, Jian Zhang, Jinpei Zhou, Huibin Zhang
BRD4 is an attractive target for antitumor due to its important role in regulation of gene transcription. In this paper, we synthesized a series of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD4 inhibitors and evaluated their BRD4 inhibitory activities in vitro and anti-proliferation effects on tumor cells. Gratifyingly, compound 10j exhibited robust potency of BRD4(1) and BRD4(2) inhibition with IC50 values of 130 and 76nM respectively. Docking studies were performed to explain the structure-activity relationship...
March 7, 2017: Bioorganic & Medicinal Chemistry
Xiaodong Qin, Gang Xu, Feihong Chen, Lei Fang, Shaohua Gou
Platinum-based complexes like cisplatin and oxaliplatin are well known the mainstay of chemotherapy regimens on clinic. Wogonin, a natural product that possesses wide biological activities, is now in phase I clinical test as an anticancer agent in China. Herein reported are a series of novel Pt(IV) complexes that conjugated a wogonin derivative (compound 3) to the axial position via a linker group. After being tethered to the platinum(IV) complexes, the wogonin derivative provided multiple anticancer effects, especially in compound 10, a fusion containing wogonin and cisplatin units...
March 7, 2017: Bioorganic & Medicinal Chemistry
Ryo Watanabe, Haruki Mizoguchi, Hideaki Oikawa, Hirofumi Ohashi, Koichi Watashi, Hiroki Oguri
Densely functionalized tetrahydropyridines were stereoselectively synthesized from 1,6-dihydropyridines. Exploiting a carbonyl group installed at the C3 position of the 1,6-dihydropyridine system, we devised a strategy for cyanomethylation at C2/C6 and subsequent divergent installation of an allyl group at C3/C5 in a highly regio- and stereo-controlled manner. This versatile protocol for programmable functionalization of the 1,6-dihydropyridine system allows the divergent and streamlined synthesis of multiply-substituted tetrahydropyridines as an important class of biologically and medicinally relevant scaffolds...
March 7, 2017: Bioorganic & Medicinal Chemistry
Xue Fei Tan, Zia Uddin, Chanin Park, Yeong Hun Song, Minky Son, Keun Woo Lee, Ki Hun Park
Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC50s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC50=70...
March 6, 2017: Bioorganic & Medicinal Chemistry
Huan-Huan Lu, Ping Xue, Yuan-Yuan Zhu, Xiu-Lian Ju, Xiao-Jiao Zheng, Xun Zhang, Ting Xiao, Christophe Pannecouque, Ting-Ting Li, Shuang-Xi Gu
30 new analogues of diarylpyrimidines were synthesized for further structural modifications, involving not only the linker but also the wing α of DAPYs. The anti-HIV-1 activities of all target molecules were evaluated, and most of them exhibited potent anti-HIV-1 (WT) activities and low cytotoxicities. Among which, compound 4g showed excellent activities against WT HIV-1 with an EC50 value of 5.8nM and SI of up to 26,034. Another compound 4ab bearing a novel pyridinyl Wing α also displayed attractive activities...
March 6, 2017: Bioorganic & Medicinal Chemistry
Sunho Lee, Dong Wook Kang, HyungChul Ryu, Changhoon Kim, Jihyae Ann, Hobin Lee, Eunhye Kim, Sunhye Hong, Sun Choi, Peter M Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee
A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki=0.1nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10mg/kg in the neuropathic pain model...
March 6, 2017: Bioorganic & Medicinal Chemistry
Zhikun Liu, Lei Fang, Huan Zhang, Shaohua Gou, Li Chen
Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies...
March 6, 2017: Bioorganic & Medicinal Chemistry
Huiqun Wang, Saheem A Zaidi, Yan Zhang
Mu opioid receptor selective antagonists are highly desirable because of their utility as pharmacological probes for receptor characterization and functional studies. Furthermore, the mu opioid receptors act as an important target in drug abuse and addiction treatment. Previously, we reported NAP as a novel lead compound with high selectivity and affinity towards the mu opioid receptor. Based on NAP, we have synthesized its derivatives and further characterized their binding affinities and selectivity towards the receptor...
March 6, 2017: Bioorganic & Medicinal Chemistry
Andrea Angeli, Damiano Tanini, Caterina Viglianisi, Lucia Panzella, Antonella Capperucci, Stefano Menichetti, Claudiu T Supuran
A series of selenides, diselenides and organoselenoheterocycles were evaluated as carbonic anhydrase (CA, EC inhibitors against the human (h) isoforms hCA I, II, IV, VII and IX, involved in a variety of diseases among which glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors etc. These investigated compounds showed inhibitory action against these isoforms and some of them were selective for inhibiting the cytosolic over the membrane-bound isoforms, thus making them interesting leads for the development of isoform-selective inhibitors...
March 6, 2017: Bioorganic & Medicinal Chemistry
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