186521-22-2Relevant academic research and scientific papers
Syntheses of optically pure compounds useful as GARFT inhibitors and their intermediates
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, (2008/06/13)
The invention relates to methods of making compounds of the formula VII STR1 and their enantiomers, where Ar is a substituted or unsubstituted five- or six-membered aromatic group and B is either an amino acid linked through the amino portion to form an a
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
Varney, Michael D.,Palmer, Cindy L.,Romines III, William H.,Boritzki, Theodore,Margosiak, Stephen A.,Almassy, Robert,Janson, Cheryl A.,Bartlett, Charlotte,Howland, Eleanor J.,Ferre, Rosanne
, p. 2502 - 2524 (2007/10/03)
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 K(i)s ranging from 30 μM 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 hove 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.
