Protein Structure-Based Design, Synthesis, and Biological Evaluation of 5-Thia-2,6-diamino-4(3H)-oxopyrimidines:  Potent Inhibitors of Glycinamide Ribonucleotide Transformylase with Potent Cell Growth Inhibition

Abstract

The design, synthesis, biochemical, and biological evaluation of a novel series of 5-thia-2,6-diamino-4(3H)-oxopyrimidine inhibitors of glycinamide ribonucleotide transformylase (GART) are described. The compounds were designed using the X-ray crystal structure of human GART. The monocyclic 5-thiapyrimidinones were synthesized by coupling an alkyl thiol with 5-bromo-2, 6-diamino-4(3H)-pyrimidinone, 20. The bicyclic compounds were prepared in both racemic and diastereomerically pure forms using two distinct synthetic routes. The compounds were found to have human GART KiS ranging from 30 microM to 2 nM. The compounds inhibited the growth of both L1210 and CCRF-CEM cells in culture with potencies down to the low nanomolar range and were found to be selective for the de novo purine biosynthesis pathway. The most potent inhibitors had 2,5-disubstituted thiophene rings attached to the glutamate moiety. Placement of a methyl substituent at the 4-position of the thiophene ring to give compounds 10, 18, and 19 resulted in inhibitors with significantly decreased mFBP affinity.

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

“…Among them, the thiomorpholin-3-one heterocycle is used in several therapeutic applications [178–179] and an Ugi-based MCR was reported by the group of Marcaccini (Scheme 68) [180]. In this work, monocyclic and bicyclic 5-oxothiomorpholine-3-carboxamides 228 were obtained in 76–85% yields (dr 1:1) by reacting bifunctional oxoacids 227 , benzylamines and cyclohexyl isocyanides in methanol.…”

Enantioselective synthesis of 6-substituted thiomorpholin-3-ones via asymmetric thia-Michael addition reactions using chiral bifunctional thiourea catalysts followed by intramolecular reductive cyclization

“…7 This nucleus is also present in 1,4-benzothiazine calcium antagonist Semotiadil, 8 as well as in a pyrimido [1,4]thiazine derivative 9 designed as an inhibitor of the glycinamide ribonucleotide transformylase with a potent cell growth inhibition. Numerous methods have been reported for the synthesis of such compounds; however, the synthesis of enantiomerically pure thiomorpholines in an efficient and straightforward manner is very rare 1 and is not trivial.…”

Application of LC-NMR to the identification of bulk drug impurities in GART inhibitor AG2034

“…We have recently applied this technique to the identification of bulk drug impurities present in manufactured lots of AG2034 (1), a potent glycinamide ribonucleotide transformylase (GART) inhibitor currently under clinical evaluation for antitumor activity. 5 Our studies focused on the identification of 2, the major unidentified impurity in 1. Our goal was to obtain as much information about the bulk drug impurity profile as possible from LC-NMR and LC-MS methodologies.…”