Paclitaxel and the vinca alkaloids represent important chemotherapeutics in the treatment of cancer. These drugs, however, exhibit undesirable side effects and have limiting physicochemical properties. This project will discover potential drug leads that overcome these limitations. The approaches to be used are synthesis, computational screening, high- throughput assays for biological effects, and nude mouse xenograft antitumor studies. The lead compounds are 1) structurally simple, low toxicity dichlorocyclopropanes, and 2) (+)-discodermolide. The dichlorocyclopropanes are essentially non-toxic to rodents (LD50's of > 3 g/kg), yet active against human breast, ovarian and prostate tumor cells in vitro, and rat mammary carcinomas in vivo. Computationally designed derivatives (32) will be synthesized and tested for improved potency. Using this group's extensive computational chemistry capabilities, QSAR models for microtubule perturbation have been validated. In this way the action of (+)-discodermolide was discovered. It has subsequently been found to be the most potent microtubule stabilizing agent known to date. In this project, not only will sufficient quantities of (+)-discodermolide for animal testing be prepared, but also a series of 18 simplified analogs, based on the QSAR analyses, will be synthesized. Finally, a virtual screening effort with the QSAR systems has identified 200 novel chemicals within the untested portion of the NCI DTP repository predicted to have paclitaxel-like properties. These will be obtained and screened in the in vitro assays. In the end, the two most effective agents discovered from the above approaches will then be screened for in vivo antitumor activity.
This project will discover potential drug leads that overcome undesirable side effects and costly methods of administration which afflict current therapies against breast and prostate cancers. Moreover, it will validate the computational chemistry approach to drug discovery.
| Balachandran, R; Grant, S G; Welsh, M J et al. (2000) Z-1,1-Dichloro-2,3-diphenylcyclopropanes block human prostate carcinoma cell proliferation, inhibit prostate-specific antigen expression, and initiate apoptosis. Prostate 45:277-88 |
