Development of Laulimalide-Based Microtubule-Stabilizing Agents: New Chemistry for the Treatment of Breast Cancer

摘要

Through a collaborative research program involving Utah State University and the Cancer Research Center of Hawaii, we have discovered that the sponge-derived macrolides laulimalide and isolaulimalide are potent cytotoxins with paclitaxel-like antimicronibule-stabilizing activity. Laulimalide is a potent inhibitor of cellular proliferation with an IC50 in the low nanomolar range and it maintains activity against a drug resistant, P-glycoprotein over- expressing ovarian cancer cell line. Laulimalide represents a lead compound for new class of microtubule-stabilizing agents with activities that may prove therapeutically useful for the treatment of breast cancer. The aim of this project is to utilize a combinatorial solid-phase synthetic approach for the construction of a library of laulimalide analogs for structure activity relationship (SAR) studies. In an effort to discover a new chemotherapeutic agent for the treatment of breast cancer we propose to do the following: (1) transfer our current solution-phase synthetic approach to solid phase, (2) using a split and pool strategy, prepare 260 laulimalide analogs, (3) test laulimalide analogs for microtubule-stabilizing activity, cytotoxicity against both drug-sensitive and drug-resistant breast cell lines, and (4) submit active analogs to the NCI for screening in the 60-cell line. Work to-date has been concentrated on the adaptation of our solution phase laulimalide synthetic methods for efficient conversion to the solid phase. Because of difficulties adding fragment C, a new retrosynthetic approach has been developed and is now being explored. It has the advantage that the coupling of fragment C to the resin-bound material will not involve the formation of a new asymmetric center, thus simplifying the reaction. Fragment B analogs have been prepared and coupled using a Juliea-Kocienski type reaction to an appropriate aldehyde and the first two laulimalide analogs have been screened for biological activity.