Diverse amide analogs of sulindac for cancer treatment and prevention

TY - JOUR

T1 - Diverse amide analogs of sulindac for cancer treatment and prevention

AU - Mathew, Bini

AU - Hobrath, Judith V.

AU - Connelly, Michele C.

AU - Kiplin Guy, R.

AU - Reynolds, Robert C.

N1 - This work was supported by grants from the National Institutes of Health NCI 1R01CA131378 (RCR PI) and DOD Era of Hope awardW81XWH-07-1-0463 (RCR PI). We thank Lucile White, Lynn Rasmussen and Melinda Ingram for HTS support services. We would also like to acknowledge 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. The work at St. Jude was supported by American Lebanese Syrian Associated Charities (ALSAC).

PY - 2017/10/15

Y1 - 2017/10/15

N2 - Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development.

AB - Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development.

KW - NSAIDs

KW - Sulindac

KW - Amides

KW - Cancer

U2 - 10.1016/j.bmcl.2017.09.022

DO - 10.1016/j.bmcl.2017.09.022

M3 - Article

C2 - 28935266

SN - 0960-894X

VL - 27

SP - 4614

EP - 4621

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 20

ER -