Exploration of novel VEGFR2 tyrosine kinase inhibitors via design and synthesis of new alkylated indolyl-triazole Schiff bases for targeting breast cancer

According to the World Health Organization (WHO) statistics: In 2020, there were 2.3 million women diagnosed with breast cancer and 685,000 deaths globally. Therefore, searching for new leads for fighting this type of cancer is necessary. VEGFR-2 kinase plays a crucial role in the proliferation, migration, and survival of breast cancer cells so, identifying novel inhibitors for VEGFR-2 could be effective in breast cancer treatment. Accordingly, novel heterocyclic compounds containing indole, 1,2,4-triazole, and glycosyl or allyl moieties were synthesized. The synthesized compounds were evaluated for their cytotoxic and apoptotic activities towards breast cancer cell lines (MCF7). In this regard, compounds 6, 17, and 18 exhibited promising cytotoxic activity against MCF-7 cells with IC50 values of 3.06, 1.18, and 3.02 mu M compared to Sorafenib (IC50 = 2.13 mu M). Interestingly, among the identified lead molecules, compound 17 displayed remarkable VEGFR2 inhibition activity with IC50 value of 19.8 nM compared to Sunitinib (IC50 = 75 nM) and Sorafenib (IC50 = 30 nM). Moreover, it is significantly stimulated apoptotic breast cancer cell death; it induced apoptosis by 17.4 %, arresting the cell cycle phases at G1 and S-phases. Additionally, in vivo (Xenograft model) study validated the anticancer activity of the hit compound 17, which showed a tumor inhibition ratio of 54.2 % compared to 5-FU (49.5%) with an improvement of hematological and biochemical parameters. The results disclosed that the identified hit com-pound 17 is validated for impeding cell proliferation and migration through apoptosis activation and VEGFR2 inhibition.

Automated summary

Compound 17 has shown significant anti-breast cancer activity by inhibiting cell proliferation and migration, and exerting its effects through apoptosis activation and VEGFR2 inhibition.