Evolution of uracil based thymidine phosphorylase inhibitors, SAR and electronic correlation: revisit

Thymidine phosphorylase (TPase), a dimeric proteinaceous enzyme is responsible for elevation of drug resistance and cell apoptosis. Increased TPase levels lead to angiogenesis which is a major culprit for the metastasis and cancer in the body. Hence, an efficient approach for anticancer drug discovery is based up on inhibition of thymidine phosphorylase enzyme. Solving of the crystal structure of TPase made the drug discovery easier. Legion of drugs was designed and synthesized having a wide variety of structural moieties and different functionalities such as phosphonic acid, amines, arylamines, acetamides, benzoyl, esters, amides, and so forth. Among the structural designs and models engineered, uracil is one of the structural motifs utilized for drug design. In this review, uracil is chosen where in structural unit with its structural modifications were summarized. Uracil unit could be structurally modified at its N1, N3, C5, and C6 positions to afford innumerable uracil derivatives. In general consensus, N1‐ and N3‐substituted uracil derivatives resulted in diminished/lower inhibitory activities which might be attributed to reduced acidic character. Whereas, substitution at 5‐ and 6‐positions have yielded fruitful results and excellent thymidine phosphorylase inhibitors prevailed. Furthermore, uracil possessing nucleoside uridine/deoxyuridine was also derivatized to afford potential TPase inhibitors. 3′‐ & 5′‐Hydroxyl groups of uridine/deoxyuridine were also exploited for derivative preparation and some of them were found to be potent TPase inhibitors.