Amine Containing Analogs of Sulindac for Cancer Prevention



Bini Mathew1, Judith V. Hobrath2, Michele C. Connelly3, R. Kiplin Guy4, Robert C. Reynolds5, *
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, TN38105-3678, USA
4 The University of Kentucky College of Pharmacy, 214H BioPharm Complex, Lexington, KY40536-0596, USA
5 Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, Alabama35294, USA


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© 2018 Mathew et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4. 0 International Public License (CC-BY 4. 0), a copy of which is available at: https://creativecommons. org/licenses/by/4. 0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this authors at the Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA, Tel: +1-(205) 934-8276; Fax: +1-(205) 934-2543; E-mail: rcr12lkt@uab.edu


Abstract

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 activity in vitro and demonstrating in vivo xenograft 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 identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range.

Conclusion:

Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.

Keywords: NSAIDs, Sulindac, COX-independent, Reverse amide, Sulfonamide, Cancer, Anticancer.