title: New cytotoxic benzosuberene analogs. Synthesis, molecular modeling and biological evaluation.
abstract: In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results.
authors.affiliation: Pfizer World Wide Research and Development, World Wide Medicinal Chemistry, Oncology Eastern Point Road, Groton, CT 06340, United States.
authors.forename: Zecheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Andreas
authors.initials: A
authors.lastname: Maderna
authors.forename: Sai Chetan K
authors.initials: SC
authors.lastname: Sukuru
authors.forename: Melissa
authors.initials: M
authors.lastname: Wagenaar
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: My-Hanh
authors.initials: MH
authors.lastname: Lam
authors.forename: Sylvia
authors.initials: S
authors.lastname: Musto
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives; D004285:Dogs; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*
chemical_list: D001555:Benzene Derivatives; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine
keywords: Benzosuberenes; Chemotherapy; Colchicines mimetics; Tubulin polymerization inhibitors