Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Jouanneau, Morgan¹  McClary, Brandon³  Reyes, Jeremy Chris P.^2,6  Chen, Rong⁴  Chen, Yuling⁴  Plunkett, William⁴  Cheng, Xin⁵  Milinichik, Andrew Z.⁵  Albone, Earl F.⁵  Liu, Jun O.³  Romo, Daniel¹ 

[1] Baylor Univ, Dept Chem & Biochem, Waco, TX 76798 USA

[2] Texas A&M Univ, Dept Chem, College Stn, TX 77842 USA

[3] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, 725 North Wolfe St, Baltimore, MD 21205 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77054 USA

[5] Morphotek Inc, Dept Biochem Discovery, 210 Welsh Pool Rd, Exton, PA 19341 USA

[6] Dow Chem Co USA, Freeport, TX USA

关键词: Agelastatin A;    Photoaffinity probe;    Diazirine;    Pyrrole-aminoimidazole alkaloid;    Structure-activity relationship;   

DOI  :  10.1016/j.bmcl.2016.02.051

来源: Elsevier

【 摘 要 】

(-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B-and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification. Published by Elsevier Ltd.

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