title: Inhibition of tubulin polymerization by select alkenyldiarylmethanes.
abstract: During studies on the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), analogues were discovered that exhibit low micromolar and submicromolar cytotoxicities. Since the ADAMs are structurally related to the tubulin polymerization inhibitor CC-5079, a set of 14 ADAMs were tested for inhibition of tubulin polymerization in an attempt to identify the biological target responsible for their cytotoxicity. The results indicate that, overall, the ADAMs are poor inhibitors of tubulin polymerization. However, the two most cytotoxic compounds, 15 and 16, are in fact active as inhibitors of tubulin assembly with IC(50) values of 3.7+/-0.3 and 2.8+/-0.2 microM, respectively, and they both inhibit the binding of colchicine to tubulin. Both compounds were investigated for anticancer activity in the National Cancer Institute's panel of 60 human cancer cell lines, and both compounds consistently displayed submicromolar cytotoxicities with mean-graph midpoint (MGM) values of 0.31+/-0.08 and 0.47+/-0.09 microM, respectively.
authors: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
authors: Matthew D
authors: MD
authors: Cullen
authors: Taradas
authors: T
authors: Sarkar
authors: Ernest
authors: E
authors: Hamel
authors: Tracy L
authors: TL
authors: Hartman
authors: Karen M
authors: KM
authors: Watson
authors: Robert W
authors: RW
authors: Buckheit
authors: Christophe
authors: C
authors: Pannecouque
authors: Erik
authors: E
authors: De Clercq
authors: Mark
authors: M
authors: Cushman
mesh_terms: D001704:Biopolymers / Q000737:chemistry*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D008697:Methane / Q000031:analogs & derivatives* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry*
chemical_list: D001704:Biopolymers; D018894:Reverse Transcriptase Inhibitors; D014404:Tubulin; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D008697:Methane