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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.

Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A
Bioorg Med Chem 19 3585-94 (2011)
Cited: 13 times
EuropePMC logo PMID: 21550809

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.

Reviews - 3ntz mentioned but not cited (1)

  1. DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents. Raimondi MV, Randazzo O, La Franca M, Barone G, Vignoni E, Rossi D, Collina S. Molecules 24 E1140 (2019)

Articles - 3ntz mentioned but not cited (4)

  1. Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan. Bilsland E, van Vliet L, Williams K, Feltham J, Carrasco MP, Fotoran WL, Cubillos EFG, Wunderlich G, Grøtli M, Hollfelder F, Jackson V, King RD, Oliver SG. Sci Rep 8 1038 (2018)
  2. 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. Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A. Bioorg Med Chem 19 3585-3594 (2011)
  3. Identification of novel potential antibiotics against Staphylococcus using structure-based drug screening targeting dihydrofolate reductase. Kobayashi M, Kinjo T, Koseki Y, Bourne CR, Barrow WW, Aoki S. J Chem Inf Model 54 1242-1253 (2014)
  4. Selective Targeting of Lung Cancer Cells with Methylparaben-Tethered-Quinidine Cocrystals in 3D Spheroid Models. Krishnamoorthi S, Kasinathan GN, Paramasivam G, Rath SN, Prakash J. ACS Omega 8 46628-46639 (2023)


Articles citing this publication (8)

  1. An innovative strategy for dual inhibitor design and its application in dual inhibition of human thymidylate synthase and dihydrofolate reductase enzymes. Arooj M, Sakkiah S, Cao Gp, Lee KW. PLoS One 8 e60470 (2013)
  2. The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents. Zhang X, Raghavan S, Ihnat M, Hamel E, Zammiello C, Bastian A, Mooberry SL, Gangjee A. Bioorg Med Chem 23 2408-2423 (2015)
  3. Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication. Bassetto M, Leyssen P, Neyts J, Yerukhimovich MM, Frick DN, Brancale A. Eur J Med Chem 123 31-47 (2016)
  4. Investigation of Classical Organic and Ionic Liquid Cosolvents for Early-Stage Screening in Fragment-Based Inhibitor Design with Unrelated Bacterial and Human Dihydrofolate Reductases. Toulouse JL, Abraham SMJ, Kadnikova N, Bastien D, Gauchot V, Schmitzer AR, Pelletier JN. Assay Drug Dev Technol 15 141-153 (2017)
  5. Synthesis, Antitumor Activity, and In Silico Drug Design of New Thieno[2,3-d]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors. Abdelaziz OA, El Husseiny WM, Selim KB, Eisa HM. ACS Omega 7 45455-45468 (2022)
  6. Effect of pyrimethamine treatment on male rat testicular cell population development. Gutiérrez-Pérez O, Durand-Montaño C, Rojas-Castañeda JC, Chavez-Saldaña M, Vigueras-Villaseñor RM. Andrology 2 780-786 (2014)
  7. Identification of Active Compounds against Melanoma Growth by Virtual Screening for Non-Classical Human DHFR Inhibitors. Vásquez AF, Gómez LA, González Barrios A, Riaño-Pachón DM. Int J Mol Sci 23 13946 (2022)
  8. The Complementarity Principle-One More Step towards Analytical Docking on the Example of Dihydrofolate Reductase Complexes. Potemkin V, Grishina M. Life (Basel) 11 983 (2021)


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