1373443-30-1Relevant 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)
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.
ARYLOXY PHENOXY ACRYLIC COMPOUND HAVING HIF-1 INHIBITION ACTIVITY, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS AN ACTIVE INGREDIENT
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Paragraph 0134; 0135; 0136, (2013/09/26)
The present invention relates to a compound inhibiting HF-1 activity, a preparation method of the same, and a pharmaceutical composition comprising the same as an active ingredient. The compound of the present invention demonstrates anticancer activity no
