Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition

Journal of Enzyme Inhibition and Medicinal Chemistry

Sohair M. Khojah¹  Deena S. Lasheen²  Khaled A. M. Abouzid³  Tamer M. Ibrahim⁴  Asmaa M. Aboul-Magd⁵  Salwa Elmeligie⁶  Tamer M. Abdelghany⁷ 

[1] Biochemistry Department, Faculty of science, King Abdulaziz University, Jedda, Kingdom of Saudi Arabia;Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt;Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt;Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egyp;Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, Egypt;Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University, Beni Suef, Egypt;Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt;Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;

关键词: Substituted phthalazines;    VEGFR-2 kinase inhibitors;    anti-proliferative;    apoptosis;   

DOI  :  10.1080/14756366.2019.1642883

来源: publisher

【 摘 要 】

In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.

【 授权许可】

CC BY