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.
Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities.
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).
Several active compounds were identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range.
Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.
Digital Object Identifier (DOI)
This work was supported by a grant from the National Institutes of Health NCI 1R01CA131378 (RCR PI). We also acknowledge DOD Era of Hope award W81XWH-07-1-0463 (RCR PI) for supporting HTS cancer cell activity profiling.
Supplementary material is available on the publishers Website along with the published article. https://benthamopen.com/contents/supplementary-material/TOMCJ-12-1_Sp.pdf
Screening against HT29 colorectal carcinoma, PC3 prostate and MDA-MB-231 breast cancer cell lines are described. Results of additional cancer cell line screens and cytotoxicity data is summarized in Table S1. Computed physicochemical properties of compounds 7-33 are listed in Table S2.
General experimental methods, synthetic procedures and analytical data are provided.
Mathew, Bini; Hobrath, Judith V.; Connelly, Michele C.; Guy, R. Kiplin; and Reynolds, Robert C., "Amine Containing Analogs of Sulindac for Cancer Prevention" (2018). Pharmaceutical Sciences Faculty Publications. 102.