期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 7, 页码 2725-2736出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01312
关键词
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资金
- French National Research Agency (ANR) through the EPINE Grant [ANR-12-JSV1-0004-01]
- LabEx LERMIT [ANR-10-LABX-0033-LERMIT]
- French Fonds de Dotation Recherche en Sante Respiratoire Fondation du Souffle
- Agence Nationale de la Recherche (ANR) [ANR-12-JSV1-0004] Funding Source: Agence Nationale de la Recherche (ANR)
Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5-32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure-activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent. Molecular docking studies helped to interpret initial SAR related to MIF tautomerase inhibition and propose preferred binding mode for 31 within the MIF tautomerase active site. Interestingly, daily treatment with 31 started 2 weeks after a subcutaneous monocrotaline injection regressed established pulmonary hypertension in rats.
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