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Bioorganic & Medicinal Chemistry

Dhimant Desai, Matthew Lauver, Alexandria Ostman, Linda Cruz, Kevin Ferguson, Ge Jin, Brianne Roper, Daniel Brosius, Aron Lukacher, Shantu Amin, Nick Buchkovich
Opportunistic viruses are a major problem for immunosuppressed individuals, particularly following organ or stem cell transplantation. Current treatments are non-existent or suffer from problems such as high toxicity or development of resistant strains. We previously published that a trafficking inhibitor that targets a host protein greatly reduces the replication of human cytomegalovirus. This inhibitor was also shown to be moderately effective against polyomaviruses, another family of opportunistic viruses...
March 13, 2019: Bioorganic & Medicinal Chemistry
Charlotte Baker, Tiago Rodrigues, Bernardo P de Almeida, Nuno L Barbosa-Morais, Gonçalo J L Bernardes
We report the design, synthesis and biological evaluation of natural product-drug conjugates for treatment of prostate cancers over-expressing the transient receptor potential vanilloid 1 (TRPV1) channel. We validate the relevance of TRPV1 as a target in prostate cancer patients by using a bioinformatics approach and provide proof-of-concept for the drug delivery strategy through bioorthogonal chemistry and stability assays under simulated physiological conditions. In cell-based assays, the constructs displayed modest activity...
March 13, 2019: Bioorganic & Medicinal Chemistry
Lichao Zhang, Sibo Wang, Mingzheng Yang, Ailong Shi, He Wang, Qi Guan, Kai Bao, Weige Zhang
In view of expanding the structure activity relationship of xanthine oxidase inhibitors, a series of 3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide/carboxylic acid derivatives were designed by molecular docking and synthesized. All the target compounds were evaluated for their in vitro XO inhibition by using febuxostat and allopurinol as the standard controls. Most of the hydrazide derivatives exhibited potency levels in the micromolar range. From the view of docking study, hydrazide derivatives bind to the active site of XO through a novel interaction mode, which is different from that of febuxostat bearing a carboxyl group...
March 13, 2019: Bioorganic & Medicinal Chemistry
Ryo Mizojiri, Noriyuki Nii, Moriteru Asano, Masako Sasaki, Yoshihiko Satoh, Yukiko Yamamoto, Hiroyuki Sumi, Hironobu Maezaki
We initiated our structure-activity relationship (SAR) studies for novel ACC1 inhibitors from 1a as a lead compound. Our initial SAR studies of 1H-Pyrrolo[3,2-b]pyridine-3-carboxamide scaffold revealed the participation of HBD and HBA for ACC1 inhibitory potency and identified 1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1c as a potent ACC1 inhibitor. Although compound 1c had physicochemical and pharmacokinetic (PK) issues, we investigated the 1H-pyrrolo[3,2-b]pyridine core scaffold to address these issues...
March 12, 2019: Bioorganic & Medicinal Chemistry
Marco Lelle, Maik Otte, Susanne Thon, Daniela Bertinetti, Friedrich W Herberg, Klaus Benndorf
Synthetic derivatives of cyclic adenosine monophosphate, such as halogenated or other more hydrophobic analogs, are widely used compounds, to investigate diverse signal transduction pathways of eukaryotic cells. This inspired us to develop cyclic nucleotides, which exhibit chemical structures composed of brominated 7-deazaadenines and the phosphorylated ribosugar. The synthesized 8-bromo- and 7-bromo-7-deazaadenosine-3',5'-cyclic monophosphates rank among the most potent activators of cyclic nucleotide-regulated ion channels as well as cAMP-dependent protein kinase...
March 12, 2019: Bioorganic & Medicinal Chemistry
Katerina Otrubova, Shreyosree Chatterjee, Srijana Ghimire, Benjamin F Cravatt, Dale L Boger
A series of N-acyl pyrazoles was examined as candidate serine hydrolase inhibitors in which the active site acylating reactivity and the leaving group ability of the pyrazole could be tuned not only through the nature of the acyl group (reactivity: amide > carbamate > urea), but also through pyrazole C4 substitution with electron-withdrawing or electron-donating substituents. Their impact on enzyme inhibitory activity displayed pronounced effects with the activity improving substantially as one alters both the nature of the reacting carbonyl group (urea > carbamate > amide) and the pyrazole C4 substituent (CN > H > Me)...
March 11, 2019: Bioorganic & Medicinal Chemistry
Tatsuru Hayashi, Hiroshi Tsuchikawa, Yuichi Umegawa, Michio Murata
Molecular behavior under bilayer membrane environments is one of the important research topics concerning how organic molecules exert their biological activities when interacting with cellular membranes. However, chemistry-based approaches to this property have not been successful when compared with the structural biological strategy on ligand-receptor interactions. Here, we investigated the molecular behavior of the lipophilic ATPase inhibitor bafilomycin A1 and its derivatives under a lipid environment from a chemical point of view...
March 8, 2019: Bioorganic & Medicinal Chemistry
Yumin Dai, Ashley N Peralta, Jessica E Wynn, Chringma Sherpa, Hao Li, Astha Verma, Stuart F J Le Grice, Webster L Santos
Interaction of HIV-1 rev response element (RRE) RNA with its cognate protein, Rev, is critical for HIV-1 replication. Understanding the mode of interaction between RRE RNA and ligands at the binding site can facilitate RNA molecular recognition as well as provide a strategy for developing anti-HIV therapeutics. Our approach utilizes branched peptides as a scaffold for multivalent binding to RRE IIB (high affinity rev binding site) with incorporation of unnatural amino acids to increase affinity via non-canonical interactions with the RNA...
March 7, 2019: Bioorganic & Medicinal Chemistry
Kazuhiko Iikubo, Kazuo Kurosawa, Takahiro Matsuya, Yutaka Kondoh, Akio Kamikawa, Ayako Moritomo, Yoshinori Iwai, Hiroshi Tomiyama, Itsuro Shimada
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4-ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4-ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4-ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure-activity relationship (SAR) using computational modeling...
March 7, 2019: Bioorganic & Medicinal Chemistry
Leyao Li, Lingling Wu, Xia E, Wenru Yan, Xingguang Cai, Jing Han, Lidan Sun
Glucagon-like peptide-1 (GLP-1) has emerged as a major therapeutic target for the treatment of type 2 diabetes. The nonapeptide GLP-1 (28-36) amide is one of the biological C-terminal products of GLP-1 modified by the neutral endopeptidase (NEP) 24.11 with limited hypoglycemic activity. In this study, we focused on the modification of GLP-1 (28-36) amide for the first time and synthesized a series of GLP-1 (28-36) amide analogues. Results of biological activity evaluation in INS-1 cell, STZ-induced diabetic and diet induced obesity (DIO) mice indicated that S3 as a promising candidate to treat type 2 diabetes and obesity...
March 7, 2019: Bioorganic & Medicinal Chemistry
Ji Yeong Kim, Jeong Yoon Kim, Janar Jenis, Zuo Peng Li, Yeong Jun Ban, Aizhamal Baiseitova, Ki Hun Park
Anti-melanogenesis effects of silymarin from milk thistle have been reported recently, but detailed tyrosinase inhibition properties of individual components have not been investigated. This study purported to substantiate tyrosinase inhibition and its mechanism based on a single metabolite. The responsible components for tyrosinase inhibition of target source were found out as flavonolignans which consist of isosilybin A (1), isosilybin B (2), silydianin (3), 2,3-dihydrosilychristin (4), silychristin A (5), silychristin B (6) and silybin (7), respectively...
March 7, 2019: Bioorganic & Medicinal Chemistry
Kamila B Muchowska, Elodie Chevallot-Beroux, Joseph Moran
The biochemistry of all living organisms uses complex, enzyme-catalyzed metabolic reaction networks. Yet, at life's origins, enzymes had not yet evolved. Therefore, it has been postulated that non-enzymatic metabolic pathways predated their enzymatic counterparts. In this account article, we describe our recent work to evaluate whether two ancient carbon fixation pathways, the rTCA (reductive tricarboxylic acid) cycle and the reductive AcCoA (Wood-Ljungdahl) pathway, could have operated without enzymes and therefore have originated as prebiotic chemistry...
March 7, 2019: Bioorganic & Medicinal Chemistry
Yunpeng Ji, Xin Chen, Huan Chen, Xin Zhang, Zhenya Fan, Lina Xie, Bing Ma, Changjin Zhu
A series of quinoxalinone scaffold-based acyl sulfonamides were designed as aldose reductase inhibitors and evaluated for aldose reductase (ALR2)/aldehyde reductase (ALR1) inhibition and antioxidation. Compounds 9b-g containing styryl side chains at C3-side exhibited good ALR2 inhibitory activity and selectivity. Of them, 9g demonstrated the most potent inhibitory activity with an IC50 value of 0.100 μM, and also exhibited excellent antioxidant activity, even comparable to the typical antioxidant Trolox...
March 7, 2019: Bioorganic & Medicinal Chemistry
Naoshi Yamamoto, Sayaka Ohrui, Takahiro Okada, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase
Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX1 R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1 R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1 R, but these changes did not affect the 6α-derivatives...
March 5, 2019: Bioorganic & Medicinal Chemistry
Xiaojun Yang, Shi Cai, Xueting Liu, Pan Chen, Jinpei Zhou, Huibin Zhang
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of 2,5-dimethylfuran-3-carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among these, compound 19a exhibited excellent IDO1 inhibitory activity (HeLa cellular IC50  = 4.0 nM, THP-1 cellular IC50  = 4.6 nM). Further molecular docking studies revealed that the compound 19a formed a coordinate bond with the heme iron through the carboxylic acid moiety...
March 5, 2019: Bioorganic & Medicinal Chemistry
Ru-Nan Yu, Cheng-Juan Chen, Lei Shu, Yuan Yin, Zhi-Jian Wang, Tian-Tai Zhang, Da-Yong Zhang
Janus kinases (JAKs) play a key role in the proliferation, apoptosis and differentiation of immune cells, and JAKs are considered as an attractive target for the treatment of inflammatory and autoimmune diseases. Here we show the design and optimization of pyrimidine-4,6-diamine derivatives as selectivity JAK3 inhibitors. Compound 11e, which might interact with unique cysteine (Cys909) residue in JAK3, exhibited excellent JAK3 inhibitory activity (IC50  = 2.1 nM) and high JAK kinase selectivity. In cellular assay, 11e showed moderate potency inhibiting IL-2-stimulated T cell proliferation...
March 5, 2019: Bioorganic & Medicinal Chemistry
Raju Suresh Kumar, Abdulrahman I Almansour, Natarajan Arumugam, Faruq Mohammad, D Kotresha, J Carlos Menéndez
A small library of spirooxindole-pyrrolidine hybrids have been synthesized for the first time in an ionic liquid, [bmim]Br in good to excellent yields employing a new class of non-stabilized azomethine ylides derived from isatin and tyrosine, a combination that has been rarely employed for the in situ generation of azomethine ylides using [3+2] cycloaddition strategy. Following the synthesis and characterization of the spirooxindole-pyrrolidine heterocyclic hybrids, they were tested for their anticancer activity as against the changes in the concentrations and time periods with different in vitro cell cultures containing cancer and non-cancer cells, where the results revealed for a potential therapeutic activity...
March 5, 2019: Bioorganic & Medicinal Chemistry
Fahad M Almutairi, Ahmed A Abd-Rabou, Mervat S Mohamed
Non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are leading causes of cancer mortality and morbidity around the world. Despite the recent advances in their diagnosis and therapy, their prognosis remains poor owing to the development of drug resistance and metastasis. Raloxifene (RX), a drug first used in the treatment of osteoporosis, was recently approved for NSCLC and HCC prevention. Unfortunately, many of the therapies that use RX are likely to become ineffective due to drug resistance...
March 4, 2019: Bioorganic & Medicinal Chemistry
Qiuqiong Zhang, Jiahui Lv, Feng He, Chenggong Yu, Ying Qu, Xiangna Zhang, Ana Xu, Jingde Wu
Histone deacetylases inhibitors (HDACIs) represents effective treatments for cancer. In continuing our efforts to develop novel and potent HDACIs, a series of N-hydroxycinnamamide-based HDACIs with aromatic ring and various aliphatic linker have been successfully designed and synthesized. Biological evaluations established that compounds 4h, 4i, 4j, 4l, 4r showed superior inhibition on histone deacetylase and antiproliferative activity in some solid tumor cell lines [HeLa, SK-N-BE(2), PC-3] compared to the known inhibitor SAHA...
March 4, 2019: Bioorganic & Medicinal Chemistry
Taha F S Ali, Halil I Ciftci, Mohamed O Radwan, Ryoko Koga, Takeo Ohsugi, Yoshio Okiyama, Teruki Honma, Akiko Nakata, Akihiro Ito, Minoru Yoshida, Mikako Fujita, Masami Otsuka
Bleomycin is considered to exert its antitumor activity via DNA cleavage mediated by activated oxygen generated from the iron complex in its chelator moiety. Spin-offs from this moiety, HPH-1Trt and HPH-2Trt, with anti-cancer activities were recently synthesized. In this paper, we developed inhibitors of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of Sirtuin protein (SIRT2), based on HPH-1Trt/HPH-2Trt, and aimed to generate new anti-cancer drugs. HPH-1Trt and HPH-2Trt had in vitro anti-SIRT2 inhibitory activity with 50% inhibitory concentration (IC50 ) values of 5...
March 2, 2019: Bioorganic & Medicinal Chemistry
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