Targeting VEGFR-2 signaling pathway is well-established as an important approach for the treatment of solid tumors, particularly renal cancer. Herein, novel indolyl-1,2,4-triazole hybrids were designed and synthesized as VEGFR-2 kinase inhibitors with potential anti-renal cancer activity. The structures of the newly synthesized compounds were confirmed based on their spectral and elemental analyses. The results of in vitro kinase assay indicated that all target compounds revealed submicromolar inhibition of VEGFR-2 kinase enzyme. Analogs 5c, 5d and 9b emerged as the most active compounds (IC50 = 0.034-0.064 µM), showing VEGFR-2 inhibitory activity much superior to that of sunitinib reference drug (IC50 = 0.075 µM). Moreover, compounds 5a, 8c, 9d, 12c were equipotent to sunitinib against VEGFR-2 kinase. Additionally, the most potent compounds were further examined for their anticancer activity against two human renal cancer cell lines. All screened compounds effectively inhibited the growth of the two tested cell lines with IC50 values spanning from sub-micromolar to low micromolar levels. Compounds 5b, 5d, 11c and 12c were three to five-fold more potent than sunitinib against CAKI-1 cell line. Analogue 8c was superior/comparable to sunitinib against CAKI-1/A498 cell lines. Moreover, compound 9d showed double potency of sunitinib against A498 cell line. Besides, compounds 8c and 12c demonstrated a safety profile much better than that of sunitinib against non-cancer human renal cells. As well, the docked models of title compounds revealed strong interactions with key residues within the active site of VEGFR-2 kinase.
Bioorganic chemistry. 2020 Oct 01 [Epub ahead of print]
Sami A Al-Hussain, Thoraya A Farghaly, Magdi E A Zaki, Hanan G Abdulwahab, Nadia T Al-Qurashi, Zeinab A Muhammad
Department of Chemistry, Faculty of Science, Al-Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia., Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt; Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah, Saudi Arabia. Electronic address: ., Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt., Department of Basic Science, University College in Adam, Umm Al-Qura University, Makkah, Saudi Arabia., Department of Organic Chemistry, National Organization for Drug Control and Research (NODCAR), Giza 12311, Egypt.