title: Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe.
abstract: (-)-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.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Jouanneau
authors.affiliation: Department of Pharmacology and Molecular Sciences, John Hopkins School of Medicine, 725 North Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: McClary
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77842-3012, USA.
authors.forename: Jeremy Chris P
authors.initials: JC
authors.lastname: Reyes
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.affiliation: Department of Biochemistry Discovery, Morphotek, Inc, 210 Welsh Pool Road, Exton, PA 19341, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry Discovery, Morphotek, Inc, 210 Welsh Pool Road, Exton, PA 19341, USA.
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Milinichik
authors.affiliation: Department of Biochemistry Discovery, Morphotek, Inc, 210 Welsh Pool Road, Exton, PA 19341, USA.
authors.forename: Earl F
authors.initials: EF
authors.lastname: Albone
authors.affiliation: Department of Pharmacology and Molecular Sciences, John Hopkins School of Medicine, 725 North Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Romo
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D015335:Molecular Probes; D023303:Oxazolidinones; C464968:agelastatin A
keywords: Agelastatin A; Diazirine; Photoaffinity probe; Pyrrole-aminoimidazole alkaloid; Structure–activity relationship