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Design and synthesis of new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as VEGFR2 inhibitors affecting the Bax/Bcl-2 in the HepG2 cancer cells.

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Title: Design and synthesis of new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as VEGFR2 inhibitors affecting the Bax/Bcl-2 in the HepG2 cancer cells.
Authors: Youssef, Mohamed F.1 (AUTHOR) mohamed_gomma@science.suez.edu.eg, Eltamany, Elsayed H.1 (AUTHOR), Boraei, Ahmed T.A.1 (AUTHOR), Attia, Ahmed E.1 (AUTHOR), Nafie, Mohamed S.1,2 (AUTHOR) mohamed_nafie@science.suez.edu.eg
Source: Journal of Molecular Structure. Mar2026, Vol. 1355, pN.PAG-N.PAG. 1p.
Subjects: Vascular endothelial growth factor antagonists, Apoptosis, Antineoplastic agents, Hepatocellular carcinoma, Organonitrogen compounds, Cytotoxins, Chemical synthesis, Bcl-2 proteins
Abstract: • Novel substituted Thieno[2,3-d]Pyrimidine derivatives were synthesized and fully characterized. • Interestingly, compound 7 exhibited the most potent cytotoxicity against MCF-7 and HepG-2 cells, with IC 50 values of 0.09 µM. • Compound 7 exhibited promising VEGFR2 inhibition, with an IC 50 value of 0.098 µM. • Compound 7 induced apoptosis in the HepG2 cancer cells by 30.74-fold, arresting the cell cycle at the G1-phase. • Compound 7 treatment affected the Bax/Bcl-2 in gene expression analysis. There is a need to synthesize new bioactive compounds to fight cancer. As a result, ethyl 2-amino-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylate 1 used for the synthesis of 2-thioxo-thieno[2,3-d]pyrimidin-4-one 2 which benzylated to afford 2-(benzylthio)-thieno[2,3-d]pyrimidin-4-one 3. Chlorination of 3 yielded 2-(benzylthio)-4‑chloro-thieno[2,3- d ]pyrimidine 4 which thionated to furnish 2-(benzylthio)-thieno[2,3-d]pyrimidin-4-thione 5. Alkylation of 5 yielded the S-alkylated product 6 which on hydrazinolysis afforded 4-hydrazino-thienopyrimidine 7. Amination of 4‑chloro-thieno[2,3- d ]pyrimidine 4 yielded the 4-aminated products 8a-b. Reaction of 4-hydrazino-thienopyrimidine scaffold 7 with CS 2 , phthalic anhydride, succinic anhydride, acetyl acetone, chloroacetyl chloride, and benzoyl chloride, yielding products 10 – 17, respectively. The cytotoxicity of the synthesized compounds was assessed against MCF-7 and HepG2 cancer cell lines using the MTT assay. Approximately sixteen compounds showed promising antiproliferative potential with IC 50 in a range from 0.09 µM to 1.96 µM. Interestingly, compound 7 exhibited the most potent cytotoxicity against MCF-7 and HepG2 cells, with IC 50 values of 0.09 µM. Notably, compound 7 exhibited promising VEGFR2 inhibition, with an IC 50 value of 0.098 µM and an inhibition percentage of 86.8 %. Compound 7 treatment altered Bax/Bcl-2 gene expression in HepG2 cancer cells, inducing apoptosis by 30.74-fold and halting the cell cycle at the G1-phase. Accordingly, compound 7 can be further validated as a potent anticancer agent in an in vivo animal model. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract:• Novel substituted Thieno[2,3-d]Pyrimidine derivatives were synthesized and fully characterized. • Interestingly, compound 7 exhibited the most potent cytotoxicity against MCF-7 and HepG-2 cells, with IC 50 values of 0.09 µM. • Compound 7 exhibited promising VEGFR2 inhibition, with an IC 50 value of 0.098 µM. • Compound 7 induced apoptosis in the HepG2 cancer cells by 30.74-fold, arresting the cell cycle at the G1-phase. • Compound 7 treatment affected the Bax/Bcl-2 in gene expression analysis. There is a need to synthesize new bioactive compounds to fight cancer. As a result, ethyl 2-amino-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylate 1 used for the synthesis of 2-thioxo-thieno[2,3-d]pyrimidin-4-one 2 which benzylated to afford 2-(benzylthio)-thieno[2,3-d]pyrimidin-4-one 3. Chlorination of 3 yielded 2-(benzylthio)-4‑chloro-thieno[2,3- d ]pyrimidine 4 which thionated to furnish 2-(benzylthio)-thieno[2,3-d]pyrimidin-4-thione 5. Alkylation of 5 yielded the S-alkylated product 6 which on hydrazinolysis afforded 4-hydrazino-thienopyrimidine 7. Amination of 4‑chloro-thieno[2,3- d ]pyrimidine 4 yielded the 4-aminated products 8a-b. Reaction of 4-hydrazino-thienopyrimidine scaffold 7 with CS 2 , phthalic anhydride, succinic anhydride, acetyl acetone, chloroacetyl chloride, and benzoyl chloride, yielding products 10 – 17, respectively. The cytotoxicity of the synthesized compounds was assessed against MCF-7 and HepG2 cancer cell lines using the MTT assay. Approximately sixteen compounds showed promising antiproliferative potential with IC 50 in a range from 0.09 µM to 1.96 µM. Interestingly, compound 7 exhibited the most potent cytotoxicity against MCF-7 and HepG2 cells, with IC 50 values of 0.09 µM. Notably, compound 7 exhibited promising VEGFR2 inhibition, with an IC 50 value of 0.098 µM and an inhibition percentage of 86.8 %. Compound 7 treatment altered Bax/Bcl-2 gene expression in HepG2 cancer cells, inducing apoptosis by 30.74-fold and halting the cell cycle at the G1-phase. Accordingly, compound 7 can be further validated as a potent anticancer agent in an in vivo animal model. [ABSTRACT FROM AUTHOR]
ISSN:00222860
DOI:10.1016/j.molstruc.2025.144780