Development of Laulimalide-Based Microtubule-Stabilzing Agents: New Chemistry for the Treatment of Breast Cancer
Abstract
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 antimicrotubule 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: I) 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA410243
Entities
People
- Bradley S. Davidson
Organizations
- Utah State University