Newly Developed Piperidinyl Sulfamides as Tyrosyl-DNA Phosphodiesterase 1 (Tdp 1) Inhibitors, and Study of Anticancer Activity of Piperidinyl Sulfamides Derivatives and Seven-Membered Cyclic Sulfamide Analogs Using the National Cancer Institute 60 Human Cancer Cell Line (NCI 60) Screen

Abstract

Sulfur containing compounds have become increasingly important in the development of biological agents for pharmaceutical and industrial use. Cyclic sulfamides, in particular, have been found to be useful as cancer, HIV protease inhibitors and other therapeutic treatments. As the need for new and improved inhibitors is warranted by the serious cancer disease, the search for new synthetic pathways to access novel sulfamides is ongoing. To this end, the work discussed herein focuses on the synthesis of newly developed sulfamides utilizing the reductive amination and Mitsunobu reaction to generate novel chiral amino ester containing sulfamide compounds. These compounds are being screened for their biological activities as Tyrosyl-DNA phosphodiesterase 1 (Tdp 1) inhibitors and anti-cancer drugs. Initially, reductive amination, CSI coupling, and Mitsunobu reaction were employed to generate piperidinyl sulfamides, and these compounds were screened for Tdp1 inhibition. These compounds were submitted to Dr. Pomier's group at NIH to carry out the gel study to select active compounds. We also checked the binding effect through the protein docking study. In addition, these sulfamide compounds were screened from NCI 60-cancer cell lines to check the bioactivity and in vitro cytotoxicity evaluation. To understand anti-cancer activity of cyclic sulfamides, symmetric and unsymmetric seven-membered sulfamides compounds were tested in 60 cancer cell line from the National Cancer Institute. These compounds were made when I studied for the Master degree at the University of Kansas. RCM was employed to generate symmetric seven-membered cyclic sulfamides similar in structure to known active HIV protease inhibitor DMP 323. Functionalization of these compounds employing "robust S-linchpins" in conjunction with RCM yields an array of new S-heterocycles. Further work in sulfamides employed a combination of RCM with different coupling routes to generate unsymmetric seven-membered cyclic sulfamides with varied substitution in their P1/P1' and P2/P2' periphery in attempts to broaden the scope of this chemistry and to generate new biologically active compounds.