Amine Containing Analogs of Sulindac for Cancer Prevention

TY - JOUR

T1 - Amine Containing Analogs of Sulindac for Cancer Prevention

AU - Mathew, Bini

AU - Hobrath, Judith V.

AU - Connelly, Michele C.

AU - Guy, R. Kiplin

AU - Reynolds, Robert C.

N1 - 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. We thank both Lucile White and Lynn Rasmussen for HTS support services. We also thank the contributions by the High Throughput Biology Center in the Department of Chemical Biology and Therapeutics at St. Jude Children’s Research Hospital in Memphis, TN for BJ cell line data and additional anticancer cell line screens (included in Supplementary Materials: Appendix A). The work at St. Jude was supported by American Lebanese Syrian AssociatedCharities (ALSAC)

PY - 2018/1/31

Y1 - 2018/1/31

N2 - 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 activityin vitroand demonstratingin vivoxenograft 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 identifiedviain vitrocancer cell line screening with the most potent compound (26) in the nanomolar range.Conclusion: Compound26and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.

AB - 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 activityin vitroand demonstratingin vivoxenograft 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 identifiedviain vitrocancer cell line screening with the most potent compound (26) in the nanomolar range.Conclusion: Compound26and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.

KW - Anticancer

KW - Cancer

KW - COX-independent

KW - NSAIDs

KW - Reverse amide

KW - Sulfonamide

KW - Sulindac

U2 - 10.2174/1874104501812010001

DO - 10.2174/1874104501812010001

M3 - Article

C2 - 29492166

SN - 1874-1045

VL - 12

SP - 1

EP - 12

JO - Open Medicinal Chemistry Journal

JF - Open Medicinal Chemistry Journal

ER -