New cytotoxic benzosuberene analogs. Synthesis, molecular modeling and biological evaluation

• Published in: Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6688-6694
• Main Authors: Chen, Zecheng, Maderna, Andreas, Sukuru, Sai Chetan K., Wagenaar, Melissa, O’Donnell, Christopher J., Lam, My-Hanh, Musto, Sylvia, Loganzo, Frank
• Format: Article
• Language: English
• Subjects: Animals; Benzene Derivatives - chemistry; Benzene Derivatives - metabolism; Benzene Derivatives - toxicity; Benzosuberenes; Binding Sites; Cell Line; cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; colchicine; Colchicine - analogs & derivatives; Colchicines mimetics; crystal structure; cytotoxicity; derivatization; Dogs; Humans; Microsomes, Liver - metabolism; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Tubulin - chemistry; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - metabolism; Tubulin Modulators - toxicity; Tubulin polymerization inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.10.039

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.