Identification, Biological Evaluation & Retrometabolic Drug Designing of Active Metabolites of 5-Amino-4-(3, 4-Dimethoxy Phenyl Sulfonamido)-5-Oxopentanoic Acid (SM-1) As Antimultiple Myeloma and Antiangiogenic Agents

Abstract

A candidate drug, SM-1, with promising anticancer and antiangiogenic activity, was subjected to in vivo metabolite study in rabbits to identify if any of its metabolites is more active andless toxic than the parent candidate drug. The probable metabolites were predicted using MetaSite software. SM-1 and the predicted metabolites were docked,in-silico,at the active site of VEGFR-2 using the LibDock protocol of Discovery studio. VEGFR-2 is a well-known pro-angiogenic molecular target. Predicted metabolites having comparable binding affinity to the receptor with that of SM-1 were chosen for identification. Following oral administration of SM-1 to the rabbits, the collected blood samples were analyzed using RP-HPLC, and three metabolites, M-1, M-3 & M-4, were identified with the help of synthetic standards. The anticancer and antiangiogenic properties of the metabolites were evaluated on RPMI-8226 (Multiple Myeloma) and HUVEC cell lines, respectively. The cytotoxic effect on VERO cells was checked to study their toxic effect on normal epithelial cells. M-3 exhibited more activity than SM-1 and was found to be less toxic than SM-1. The structure of M-3 was explored as a lead for further drug design, suggesting six new molecules which could be more active than M-3.