Abstract
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 vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft 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.
Document Type
Article
Publication Date
10-15-2017
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.bmcl.2017.09.022
Funding Information
This work was supported by grants from the National Institutes of HealthNCI 1R01CA131378 (RCR PI) and DOD Era of Hope award W81XWH-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).
Related Content
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2017.09. 022.
Repository Citation
Mathew, Bini; Hobrath, Judith V.; Connelly, Michele C.; Guy, R. Kiplin; and Reynolds, Robert C., "Diverse Amide Analogs of Sulindac for Cancer Treatment and Prevention" (2017). Pharmaceutical Sciences Faculty Publications. 86.
https://uknowledge.uky.edu/ps_facpub/86
Supplementary data 1. Biological studies: experimental methods, computed physicochemical properties and metabolic stability predictions.
1-s2.0-S0960894X17309186-mmc2.docx (65 kB)
Supplementary data 2. Synthetic experimental methods and analytical data.
Notes/Citation Information
Published in Bioorganic & Medicinal Chemistry Letters, v. 27, issue 20, p. 4614-4621.
© 2017 The Author(s). Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).