ChemInform Abstract: 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.
✍ Scribed by M. D. VARNEY; C. L. PALMER; W. H. III ROMINES; T. BORITZKI; S. A. MARGOSIAK; R. ALMASSY; C. A. JANSON; C. BARTLETT; E. J. HOWLAND; R. FERRE
- Publisher
- John Wiley and Sons
- Year
- 2010
- Weight
- 32 KB
- Volume
- 28
- Category
- Article
- ISSN
- 0931-7597
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✦ Synopsis
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. -A novel series of inhibitors such as (I) and (II) are prepared and designed using the X-ray crystal structure of human glycinamide ribonucleotide transformylase. The most potent compounds have inhibition constants in the low nanomolar range. The most potent inhibitors have 2,5-disubstituted thiophene rings attached to the glutamate moiety. Placement of a methyl substituent at the 4-position of the thiophene ring gives inhibitors with significantly decreased mFBP affinity. Compound (IIa) shows excellent in vivo antitumor activity and is chosen for clinical evaluation. -(VARNEY,