Diverse amide analogs of sulindac for cancer treatment and prevention

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4614-4621. doi: 10.1016/j.bmcl.2017.09.022.

Bini Mathew ¹, Judith V Hobrath ², Michele C Connelly ³, R Kiplin Guy ⁴, Robert C Reynolds ⁵

Affiliations

1 Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.
2 Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
3 Department of Chemical Biology & Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Mailstop 1000, Memphis, TN 38105-3678, USA.
4 The University of Kentucky College of Pharmacy, 214H BioPharm Complex, Lexington, KY 40536-0596, USA.
5 Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: [email protected].

PMID: 28935266 DOI: 10.1016/j.bmcl.2017.09.022

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 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.

Keywords

Amides; Cancer; NSAIDs; Sulindac.

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