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

Abstract

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 GI 50 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 IC 50 s 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.

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

“…[14] The phthalazine ring is a vital pharmacophoric scaffold present in the core structures of many anticancer molecules [11,[15][16][17][18][19] with potent activity against hepatocellular carcinoma, [18] colon cancer, [11] and breast cancer, [19] and as degraders of VEGFR-2. [15,20] Many phthalazine derivatives were reported to have VEGFR-2 and EGFR kinase inhibitory activities, with IC 50 values in the nanomolar range; however, compounds were more selective and better inhibitors of VEGFR-2 compared with EGFR. [21,22] Other pharmacophoric heterocycles have been implanted in the structures of recently reported anticancer agents with a VEGFR-2 inhibitory effect, for example, pyrazole [23,24] and pyrimidine.…”

“…[15,20] Many phthalazine derivatives were reported to have VEGFR-2 and EGFR kinase inhibitory activities, with IC 50 values in the nanomolar range; however, compounds were more selective and better inhibitors of VEGFR-2 compared with EGFR. [21,22] Other pharmacophoric heterocycles have been implanted in the structures of recently reported anticancer agents with a VEGFR-2 inhibitory effect, for example, pyrazole [23,24] and pyrimidine. [25,26] The latter were reported to have spatial configurations that enable both to interact with the VEGFR-2 binding site.…”

Synthesis of Fluorinated 2-Benzylphthalazin-1(2H)-one, 1-Phthalazinamine, and 1-Alkoxy/Benzyloxyphthalazine Derivatives by an Ultrasonication Method

“…Because, phthalazine-1(2H)-one is an N-containing benzo-fused heterocyclic compound also called 2H-benzo [d]pyridazine-1-one which contains a 1,2-diazine ring with two adjacent nitrogen atoms, 13 and they show numerous biological activities such as anticancer (I), 14 antidiabetic zopolrestat (II, IV), 15 ponalrestat (III), 16 and antiasthmatic agents: azelastine, flezelastine (V-VI) 17 (Figure 1A). Whereas, 1-phthalazinamine derivatives exhibited UT-B inhibitor activity (VII), 18 anti-inflammatory activity (VIII-IX), 19 trypanosomicidal activity (X-XI), 20 anti-cancer activity by an investigational drug, vatalanib/PTK787 (XII), 21 (XIII) 22 , etc. (Figure 1B).…”

“…24 These existing methods often require harsh conditions and high temperatures. 21 Therefore, syntheses of various fluorinated phthalazinone and phthalazine compounds under mild conditions, such as those provided by ultrasonication, would be superior to the conventional methods. 3 Here, we report syntheses of phthalazinones, aminophthalazines, and alkoxyphthalazines by using an ultrasonication method.…”

A green microwave method for synthesizing a more stable phthalazin-1-ol isomer as a good anticancer reagent using chemical plasma organic reactions

“…Phthalazin-1-ol and its substituted derivatives in position 1 were reported to possess anticancer [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ], anticonvulsant [ 9 ], cardiotonic [ 10 ], vasorelaxant activities [ 11 ] and the canonical Gibbs entropy of residual mass is achieved. Our proposed novel dual system which merges both microscopic (DFT simulation) and macroscopic (kinetic Arrhenius Model) show that phthalazin-1-ol ( 5 ) is more stable than phthalzin-1-one ( 4 ).…”