52804-25-8Relevant articles and documents
Synthesis, biological evaluation and molecular docking studies of indeno [1, 2-c] pyrazol derivatives as inhibitors of mitochondrial malate dehydrogenase 2 (MDH2)
Ahmadi, Farzaneh,Engel, Matthias,Baradarani, Mehdi M.
, (2021/03/15)
Hypoxia inducible factor-1 (HIF-1) is a pivotal transcription factor, which is strongly correlated with the induction of angiogenesis, tumor survival, metastasis, and cell proliferation, making it a pivotal therapeutic target for solid tumor therapeutic agents. Herein, a new series of multi-functional chemical probes were designed including principal groups, viz. adamantyl and indene, at various locations of the parent compound LW6. Molecular docking studies were performed on the designed compounds and their relationship with HIF-1α and malate dehydrogenase 2 (MDH2). Inhibition of MDH2 by our compounds was expected to decrease the NADH level. Indeed, treatment of the breast cancer cell line 4T1 led to a strong reduction of the NADH concentration. The greatest reduction in NADH production in mitochondria was observed with (E)-3-(4-((3r, 5r, 7r)-adamantan-1-yl) phenoxy)-N-(5-(piperidine-1-carbonyl)-1, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) acrylamide (18: IC50 = 59 nM), and has the best inhibitory potential under hypoxic conditions (MCF-7: IC50 = 57 nM). This compound also gave one of the highest docking “higher than the score obtained with LW6 in parallel (?31.63 kcal/mol) in the initial docking runs (PDB Code: 4WLO). Other related compounds with good yields were also synthesized from docking results, and all the synthesized compounds (14, 18, 22, 26, 29, 30) were evaluated in vitro on human adenocarcinoma cell lines.
Methyl 3-(3-(4-(2,4,4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1/2 Inhibitor Targeting Cancer Metabolism
Naik, Ravi,Ban, Hyun Seung,Jang, Kyusic,Kim, Inhyub,Xu, Xuezhen,Harmalkar, Dipesh,Shin, Seong-Ah,Kim, Minkyoung,Kim, Bo-Kyung,Park, Jaehyung,Ku, Bonsu,Oh, Sujin,Won, Misun,Lee, Kyeong
, p. 8631 - 8646 (2017/11/03)
Previously, we reported a hypoxia-inducible factor (HIF)-1 inhibitor LW6 containing an (aryloxyacetylamino)benzoic acid moiety inhibits malate dehydrogenase 2 (MDH2) using a chemical biology approach. Structure-activity relationship studies on a series of (aryloxyacetylamino)benzoic acids identified selective MDH1, MDH2, and dual inhibitors, which were used to study the relationship between MDH enzyme activity and HIF-1 inhibition. We hypothesized that dual inhibition of MDH1 and MDH2 might be a powerful approach to target cancer metabolism and selected methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)-benzoate (16c) as the most potent dual inhibitor. Kinetic studies revealed that compound 16c competitively inhibited MDH1 and MDH2. Compound 16c inhibited mitochondrial respiration and hypoxia-induced HIF-1α accumulation. In xenograft assays using HCT116 cells, compound 16c demonstrated significant in vivo antitumor efficacy. This finding provides concrete evidence that inhibition of both MDH1 and MDH2 may provide a valuable platform for developing novel therapeutics that target cancer metabolism and tumor growth.
Synthesis and biological evaluation of ortho-carborane containing benzoxazole as an inhibitor of hypoxia inducible factor (HIF)-1 transcriptional activity
Nakamura, Hiroyuki,Yasui, Yuka,Ban, Hyun Seung
, p. 189 - 194 (2013/11/19)
ortho-Carborane and adamantane containing benzoxazoles were synthesized by intramolecular dehydration of the corresponding phenoxyacetanilides. Among the compounds synthesized, ortho-carborane containing benzoxazole 2b which has a carboxylic group on the benzoxazole ring, exhibited significant inhibition of hypoxia-induced HIF-1 transcriptional activity with the IC50 value of 14.4 μM toward HeLa cell-based reporter gene assay.
Discovery of a novel series of benzimidazole derivatives as diacylglycerol acyltransferase inhibitors
Lee, Kyeong,Goo, Ja-Il,Jung, Hwa Young,Kim, Minkyoung,Boovanahalli, Shanthaveerappa K.,Park, Hye Ran,Kim, Mun-Ock,Kim, Dong-Hyun,Lee, Hyun Sun,Choi, Yongseok
supporting information, p. 7456 - 7460 (2013/02/22)
A novel series of benzimidazole derivatives was prepared and evaluated for their diacylglycerol acyltransferase (DGAT) inhibitory activity using microsome from rat liver. Among the newly synthesized compounds, furfurylamine containing benzimidazole carboxamide 10j showed the most potent DGAT inhibitory effect (IC50= 4.4 μM) and inhibited triglyceride formation in HepG2 cells. Furthermore, compound 10j reduced body weight gain of Institute of Cancer Research mice on a high-fat diet and decreased levels of total triglyceride, total cholesterol, and LDL-cholesterol in the blood accompanied with a significant increase in HDL-cholesterol level.
Boron-containing phenoxyacetanilide derivatives as hypoxia-inducible factor (HIF)-1α inhibitors
Shimizu, Kazuki,Maruyama, Minako,Yasui, Yuka,Minegishi, Hidemitsu,Ban, Hyun Seung,Nakamura, Hiroyuki
scheme or table, p. 1453 - 1456 (2010/07/06)
A series of boron-containing phenoxyacetanilide derivatives 8a-f, 9a-f, 15, and 16 were synthesized as hypoxia-inducible factor (HIF)-1α inhibitors. Among the compounds synthesized, carboranylphenoxyacetanilide 16 (GN26361) was found to be a potent inhibitor against HIF-1α accumulation under hypoxic conditions and inhibited the hypoxia-induced HIF-1 transcriptional activity in HeLa cells (IC50 = 0.74 μM). Compound 16 suppressed hypoxia-induced HIF-1α accumulation and vascular endothelial growth factor mRNA expression in a concentration-dependent manner without affecting the expression of HIF-1α mRNA.
Synthesis of (aryloxyacetylamino)-isonicotinic/nicotinic acid analogues as potent hypoxia-inducible factor (HIF)-1α inhibitors
Boovanahalli, Shanthaveerappa K.,Jin, Xuejun,Jin, Yinglan,Kim, Jin Hwan,Dat, Nguyen Tien,Hong, Young-Soo,Lee, Jeong Hyung,Jung, Sang-Hun,Lee, Kyeong,Lee, Jung Joon
, p. 6305 - 6310 (2008/09/17)
We report a new series of HIF-1α inhibitors which were obtained through structural modifications of previously reported lead 1. The in vitro inhibitory potencies of newly synthesized compounds were evaluated against hypoxia-induced HIF-1 activation using
(Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors
Lee, Kyeong,Lee, Jeong Hyung,Boovanahalli, Shanthaveerappa K.,Jin, Yinglan,Lee, Mijeoung,Jin, Xuejun,Kim, Jin Hwan,Hong, Young-Soo,Lee, Jung Joon
, p. 1675 - 1684 (2008/02/01)
Structural modification of a compound discovered during screening using an HRE-dependent reporter assay has revealed a novel class of HIF-1 inhibitors, which potently inhibit the HIF-1α protein accumulation and its target gene expression under hypoxic conditions in human hepatocellular carcinoma Hep3B cells.
New aliphatically substituted aryl-chalcogeno-hydrocarbon derivatives
-
, (2008/06/13)
Compounds of the formula I wherein R1 is adamantyl, Ph is phenylene which is optionally substituted by amino, nitro, lower alkyl, lower alkoxy, halogen or trifluoromethyl, X is oxy or thio, alk is alkylene with 1 to 20 C atoms or alkenylene with 2 to 20 C atoms and R2 is free, esterfied or amidised carboxyl, sulpho or sulphonamido and therapeutically acceptable salts thereof are useful as anti-allergic and hypolipidaemic agents.
