POSTER 8
Structure-activity relationships in a series of anit-tumour arylheterocycles
Dawen Rong,a Li Li,b Roger M. Phillipsb and Richard T. Wheelhousea
aSchool of Pharmacy & bInstitute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK
Biarylheterocycles have been discovered with exquisite and potent activity against colon carcinoma (IC50 16-640 nM), prostate carcinoma and leukaemia cell lines, although no correlation with binding to duplex DNA was apparent (∆Tm < 2.1 °C). COMPARE analysis of the NCI 60 cell line data showed a strong correlation with aplidine, a marine natural product currently in clinical trials for colon cancer (P = 0.748) and with the expression of gene-like sequences of unknown function; however, no correlation with any standard agent (P < 0.365) was apparent.
Analysis of these biarylheterocycles allowed identification of a minimum, active, core structure, DW37 (IC50 0.9 μM in A2780 cell lines). Discernment of a SAR and optimisation of the pharmacophore with application of Lipinski’s rules has been undertaken, with variation of structural and electronic properties of the molecules. In vitro chemosensitivity demonstrated notable activity and selectivity (IC50 150 nM – greater than 100 μM) in a panel of colon, ovarian and prostate cancer cell lines, that were independent of duplex DNA binding affinity. The identity and function of the molecular target involved in the mechanism of action of these new compounds are being probed using an innovative proteomics–mass spectrometry strategy.