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 |
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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. |
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ISSN: | 2046-2069 2046-2069 |
DOI: | 10.1039/d4ra02103g |