Synthesis of novel phthalazine-based derivatives with potent cytotoxicity against HCT-116 cells through apoptosis and VEGFR2 inhibition

The parent ethyl 3-(4-benzyl-1-oxophthalazin-2(1 H )-yl) propanoate ( 3 ) has 25 compounds. Their respective mono, dipeptides and hydrazones derivatives were produced by chemoselective N -alkylation via addition reaction of 4-benzylphthalazin-1(2 H )-one ( 2 ) with ethyl acrylate and anhydrous potas...

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Veröffentlicht in:RSC advances 2024-04, Vol.14 (19), p.1327-1343
Hauptverfasser: El Sayed, Donia, El Rayes, Samir M, Soliman, Hamdy A, AlBalaa, Imad Eddin, Alturki, Mansour S, Al Khzem, Abdulaziz Hassan, Alsharif, Mohammed Abdullah, Nafie, Mohamed S
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Sprache:eng
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Zusammenfassung:The parent ethyl 3-(4-benzyl-1-oxophthalazin-2(1 H )-yl) propanoate ( 3 ) has 25 compounds. Their respective mono, dipeptides and hydrazones derivatives were produced by chemoselective N -alkylation via addition reaction of 4-benzylphthalazin-1(2 H )-one ( 2 ) with ethyl acrylate and anhydrous potassium carbonate to give ethyl 3-(4-benzyl-1-oxophthalazin-2(1 H )-yl) propanoate ( 3 ). The ester 3 was hydrazinolyzed to give the corresponding hydrazide 3-(4-benzyl-1-oxophthalazin-2(1 H )-yl) propanehydrazide ( 5 ), then azide 6 coupled with amino acid ester hydrochloride and/or amines to afford several parent esters 8a-c , then a series of hydrazinolyzed reactions occurred to give corresponding hydrazides 9a-c . The hydrazide 9a was subjected to the azide coupling procedure, which resulted in the formation of various dipeptides. Subsequently, it was condensed with various aldehydes to yield hydrazone derivatives 13a-d . Interestingly, compounds 9c , 12b , and 13c exhibited potent cytotoxicity with IC 50 values of 1.58, 0.32 and 0.64 μM compared to sorafenib (IC 50 = 2.93 μM). Compound 12b exhibited potent VEGFR2 inhibition by 95.2% with an IC 50 value of 17.8 μM compared to sorafenib (94.7% and IC 50 of 32.1 μM). For apoptosis activity, 12b -treatment induced apoptosis in HCT-116 cells by 21.7-fold, arresting the cell proliferation at S-phase. Finally, it formed a good binding affinity towards VEGFR2 protein with a binding energy of −10.66 kcal mol −1 , and it formed binding interactions with the key interactive amino acids. A novel phthalazine derivative exhibited potent cytotoxicity against HCT-116 cells as VEGFR2 inhibitor and apoptosis cell death.
ISSN:2046-2069
2046-2069
DOI:10.1039/d4ra02103g