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.

Article Details

Citation

Copy to clipboard

Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A

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.

Bioorg Med Chem. 2011 Jun 1;19(11):3585-94. doi: 10.1016/j.bmc.2011.03.067. Epub 2011 Apr 9.

PubMed ID

21550809 [ View in PubMed

]

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-CH(3) substituents inhibited human (h) TS (IC(5)(0) =0.26-0.8 muM), but not hDHFR. Substitution of the 2-CH(3) with a 2-NH(2) increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC(5)(0) = 0.09-0.1 muM). 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methotrexate	Dihydrofolate reductase	IC 50 (nM)	22	N/A	N/A	Details
Methotrexate	Thymidylate synthase	IC 50 (nM)	>18000	N/A	N/A	Details