Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors
DOI
10.1016/j.bmc.2011.03.067
Document Type
Journal Article
Publication Date
6-1-2011
Publication Title
Bioorganic and Medicinal Chemistry
Volume
19
Issue
11
First Page
3585
Last Page
3594
ISSN
9680896
Keywords
DHFR, Dual, Inhibitor, TS
Abstract
Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d] pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1- benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH3 substituents inhibited human (h) TS (IC 50 = 0.26-0.8 μM), but not hDHFR. Substitution of the 2-CH 3 with a 2-NH2 increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC50 = 0.09-0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate. © 2011 Elsevier Ltd. All rights reserved.
Open Access
Green Accepted
Preprint
Repository Citation
Zhang, X., Zhou, X., Kisliuk, R., Piraino, J., Cody, V., & Gangjee, A. (2011). Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. Bioorganic and Medicinal Chemistry, 19 (11), 3585-3594. https://doi.org/10.1016/j.bmc.2011.03.067