Amine Containing Analogs of Sulindac for Cancer Prevention.

ABSTRACT

BACKGROUND: Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity. OBJECTIVE: Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities. METHOD: A series of sulindac amine analogs were designed and synthesized and then further modified in a "libraries from libraries" approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast). RESULTS: Several active compounds were identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range. CONCLUSION: Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.