Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers

Heba K Abd El-Mawgoud; Asmaa M AboulMagd; Mohamed T M Nemr; Magdy M Hemdan; Aya I Hassaballah; Paula S Farag

doi:10.1016/j.bioorg.2024.107622

Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers

Bioorg Chem. 2024 Sep:150:107622. doi: 10.1016/j.bioorg.2024.107622. Epub 2024 Jul 9.

Authors

Heba K Abd El-Mawgoud¹, Asmaa M AboulMagd², Mohamed T M Nemr³, Magdy M Hemdan⁴, Aya I Hassaballah⁴, Paula S Farag⁴

Affiliations

¹ Chemistry Department, Faculty of Women for Arts, Science and Education, Ain Shams University, Heliopolis, 11767 Cairo, Egypt. Electronic address: [email protected].
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef, Egypt. Electronic address: [email protected].
³ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street 11562, Cairo, Egypt.
⁴ Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, 11566 Cairo, Egypt.

PMID: 38996545
DOI: 10.1016/j.bioorg.2024.107622

Abstract

Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC₅₀ = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC₅₀ = 14.86 μM HePG-2, 8.04 μM PC-3 and 12.90 μM MCF-7) and 17 (IC₅₀ = 9.98 μM HePG-2, 33.66 μM PC-3 and 14.62 μM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC₅₀ = 0.161 and 1.06 μM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC₅₀ = 0.487 and 0.364 μM, respectively, while compound 17 showed IC₅₀ = 0.164 and 0.452 μM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands.

Keywords: AKT-1; Anticancer; Apoptosis; Autophagy; Thienopyrimidine; VEGFR-2.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis* / drug effects
Autophagy* / drug effects
Cell Line, Tumor
Cell Proliferation* / drug effects
Dose-Response Relationship, Drug*
Drug Design*
Drug Screening Assays, Antitumor*
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Proto-Oncogene Proteins c-akt* / antagonists & inhibitors
Proto-Oncogene Proteins c-akt* / metabolism
Pyrimidines* / chemical synthesis
Pyrimidines* / chemistry
Pyrimidines* / pharmacology
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2* / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2* / metabolism

Substances

Vascular Endothelial Growth Factor Receptor-2
Pyrimidines
Antineoplastic Agents
Protein Kinase Inhibitors
KDR protein, human
Proto-Oncogene Proteins c-akt
thieno(2,3-d)pyrimidine