title: Structure-activity studies on gossypol in tumor cell lines.
abstract: Gossypol [(2,2'-binaphthalene)-8,8'-dicarboxaldehyde-1,1',6,6',7,7'-hexahydroxy-5,5'-diisopropyl-3,3'-dimethyl] 1a is a naturally occurring compound extracted from the cotton plant and has been extensively studied as an oral male contraceptive. Its favorable toxicity profile, and the more recent demonstration of anti-tumor activity in animals and humans, prompted us to investigate the role of the aldehyde groups in a structure-activity study in cultured tumor cells. Four racemic compounds were evaluated: gossypol 1a, gossypolone 2, the bis Schiff's base of L-phenylalanine methyl ester with gossypol (bis Schiff's base) 1c and apogossypol 1b. The former two compounds both retain the aldehyde functional groups at positions 8 and 8' of the molecule whilst in the latter two compounds the aldehydes are blocked or absent, respectively. In addition, the l- and d-isomers of gossypol 1a, the bis Schiff's base 1c and the half Schiff's base 1d (one aldehyde blocked) were tested. The cell lines studied included melanoma (SK-mel-19), cervix (Sihas), small cell lung (H69) and myelogenous leukemia (K562). Cytotoxicity was measured using the MTT and flow cytometric viability assays. Racemic gossypol 1a and gossypolone 2 induced similar dose-dependent decreases in cell viability in all the cell lines with IC50 values of 23-46 and 28-50 microM, respectively. In contrast, the racemic bis Schiff's base derivative of gossypol 1c and apogossypol 1b showed minimal activity in any cell line up to 50 microM. The l-enantiomer of gossypol 1a was significantly more active than the d-enantiomer (IC50 of 20 versus > 50 microM, respectively). When one aldehyde of either enantiomer was blocked 1d cytoxicity was comparable to the l-enantiomer of gossypol. The data suggest that only one aldehyde group is required for the cytotoxicity of gossypol 1a, irrespective of the stereoconfiguration.
authors.affiliation: Research Laboratories, Velindre NHS Trust, Whitchurch, Cardiff, UK. mike.shelley@velindre.tr.wales.nhs.uk
authors.forename: M D
authors.initials: MD
authors.lastname: Shelley
authors.forename: L
authors.initials: L
authors.lastname: Hartley
authors.forename: P W
authors.initials: PW
authors.lastname: Groundwater
authors.forename: R G
authors.initials: RG
authors.lastname: Fish
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006072:Gossypol / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006072:Gossypol