3NU0

Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors

Summary for 3NU0

• Entry DOI: 10.2210/pdb3nu0/pdb
• Related: 3GHC 3NTZ
• Descriptor: Dihydrofolate reducatase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2S)-2-(5-{[(2-amino-4-oxo-3,4-dihydro[1]benzothieno[2,3-d]pyrimidin-5-yl)methyl]amino}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioic acid, ... (5 entities in total)
• Functional Keywords: dihydrofolate reductase, cyclized inhibitors, oxidoreductase hdhfr-264-nadph, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion : P00374
• Total number of polymer chains: 1
• Total formula weight: 22890.65

Authors

Cody, V. (deposition date: 2010-07-06, release date: 2011-05-25, Last modification date: 2024-04-03)

Primary citation

Zhang, X.,Zhou, X.,Kisliuk, R.L.,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., 19:3585-3594, 2011

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-CH₃ substituents inhibited human (h) TS (IC₅₀ =0.26-0.8 μM), but not hDHFR. Substitution of the 2-CH₃ 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.

PubMed: 21550809
DOI: 10.1016/j.bmc.2011.03.067

Experimental method

X-RAY DIFFRACTION (1.35 Å)