Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent

Junseong Ahn,Ho Yoo,Seyoung Yang,Kyung-T Lee,Jae Y Lee,Jiwon Woo,Kwang H Moon,Kyung S Chung,Joohoon Ahn,Dohyeong Ko,Jeong H Lee,Joaquin Campos

doi:10.1155/2021/6169055

Abstract

If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy. Our group has recently reported that KCP-10043F (OZ-001) as a racemate (±)-3,4-dihydroquinazoline derivative strongly represses the proliferation of human A549 lung cancer cells by caspase-mediated apoptosis via STAT3 inactivation. To investigate the possible teratological effects of the two enantiomers of a racemic KCP-10043F, therefore chiral resolution of (±)-KCP-10043F was performed and subsequently followed by a series of chemical processes to afford the corresponding chiral diastereomers. By using 1H NMR anisotropy method, the absolute configuration (+)-KCP-10043F and (−)-KCP-10043F could be assigned as S and R configuration, respectively. The bacterial reverse mutation test (Ames test) for racemate (±)-KCP-10043F and its two enantiomers exhibited that all three stereoisomers were found to be nongenotoxic against five bacterial strains with/without metabolic activation. In addition, (R)-(−)-KCP-10043F displayed almost equal anticancer activity to (S)-(+)-KCP-10043F against three cancer cell lines. Based on these overall results, racemate KCP-10043F (OZ-001) could be used for our ongoing preclinical and clinical studies without the expensive asymmetric process and/or chiral separation.

Highlights

If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy
Our group has recently reported that KCP-10043F (OZ-001) as a racemate (±)-3,4-dihydroquinazoline derivative strongly represses the proliferation of human A549 lung cancer cells by caspasemediated apoptosis via STAT3 inactivation
During the late 1950s and early 1960s, thalidomide produced birth defects in children born to women who took the racemic mixture during pregnancy [5]

Summary

Introduction

If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy. We separated the racemate (±)-KCP-10043F into two optically pure enantiomers (+)-KCP-10043F and (−)-KCP-10043F, which were assigned for their absolute configuration by the formation of chiral diastereomers and 1H NMR anisotropy method.

Results

Conclusion