In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

Rana M Abdelnaby; Afaf A El-Malah; Rasha R FakhrEldeen; Marwa M Saeed; Rania I Nadeem; Nancy S Younis; Hanaa M Abdel-Rahman; Nehad M El-Dydamony

doi:10.3390/ph15060700

In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

Pharmaceuticals (Basel). 2022 Jun 2;15(6):700. doi: 10.3390/ph15060700.

Authors

Rana M Abdelnaby¹, Afaf A El-Malah^{2

3}, Rasha R FakhrEldeen⁴, Marwa M Saeed⁵, Rania I Nadeem⁶, Nancy S Younis⁷, Hanaa M Abdel-Rahman^{8

9}, Nehad M El-Dydamony¹⁰

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
³ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
⁴ Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12585, Egypt.
⁵ Pharmacology and Toxicology Lecturer, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
⁶ Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
⁷ Pharmaceutical Sciences Department, Faculty of Clinical Pharmacy, King Faisal University, Al-Ahsa, Al-Hofuf 31982, Saudi Arabia.
⁸ Pharmacy Practice Department, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt.
⁹ Department of Forensic Medicine and Toxicology, Faculty of Medicine, Ain Shams University, Cairo 11562, Egypt.
¹⁰ Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City 12585, Egypt.

Abstract

Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC₅₀ = 3.105 and 2.15 μM) and 4c (IC₅₀ = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC₅₀ = 0.075 and 4.60 μM, respectively, while 3b showed IC₅₀ = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma.

Keywords: AKT; VEGFR-2; anticancer; apoptosis; thienopyrimidine; thiophene.

Grants and funding

This work was supported by the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia, [Project No. GRANT618].