الفهرس 
Cancer TherapyOnly 14 pages are availabe for public view
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Abstract
Cancer is a leading cause of death worldwide. Epidemiological studies revealed that
cancer accounts for one of every five deaths. Moreover, it is estimated that the annual
number of deaths due to cancers will increase from 7.6 million in 2008 to 13 million in
2030. Despite improved imaging and molecular diagnostic techniques, and advances in
prevention and chemotherapeutic management, the disease still affects many millions of
patients worldwide. The growth of new blood vessels (angiogenesis) is one of the well
established hallmarks in the process of carcinogenesis. Vascular endothelial growth factor
receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. By targeting vascular
endothelial growth factor receptor (VEGFR), angiogenesis is greatly inhibited leading to the
death of the tumor cells. from another point of view, apoptosis, or programmed cell death,
plays a crucial role in maintaining the normal body health. In its simplest model, the stages
of apoptosis may be regarded as initiation, genetic regulation, and effector
mechanisms. Initiators of apoptosis include anticancer drugs, gamma and ultraviolet
irradiation, deprivation of survival factors such as interleukin-1, or other cytokines that
activate “death receptors”. Hence, the identification of apoptosis inducers has evolved as an
attractive approach for development of potential anticancer agents.
In this study, new series of phthalazine based compounds have been designed and
synthesized as targeted VEGFR-2 inhibitors and apoptosis inducers. The design focused on
exploration of the previous revealed SAR studies, bioisosteric modifications of the lead
compounds both in market and in clinical studies, and identification of the key interactions
with the binding site.
Synthesis of the designed compounds was then accomplished & their structures were
confirmed by various spectral and microanalytical data.
This study involved the synthesis of the following unavailable reported intermediates:
1) 1-(4-Hydroxyphenyl)-3-phenylurea (Ia)
2) 1-(4-Chlorophenyl)-3-(4-hydroxyphenyl)urea (Ib)
3) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (Ic)
4) Phthalazin-1(2H)-one (IIa)
5) 4-Methylphthalazine-1(2H)-one (IIb) 6) 1-Chlorophthalazine (IIIa)
7) 1-Chloro-4-methylphthalazine (IIIb)
8) 2,3-Dihydrophthalazine-1,4-dione (IX)
9) 1,4-Dichlorophthalazine (X)
Also, it comprised the following new intermediates:
1) N1-(Phthalazin-1-yl)benzene-1,4-diamine (IVa)
2) N1-(4-Methylphthalazin-1-yl)benzene-1,4-diamine (IVb)
3) N1-(4-Arylphthalazin-1-yl)benzene-1,4-diamine (XI)
4) N-(4-Chlorophenyl)-4-methylphthalazin-1-amine (XIVb)
5) 4-(Bromomethyl)-N-(chlorophenyl)phthalazin-1-amine (XV)
Also, the study involved the synthesis and the characterization of the following newtargeted compounds:
1) N-(4-(Phthalazin-1-ylamino)phenyl)benzamide (Va)
2) 4-Chloro-N-(4-(phthalazin-1-ylamino)phenyl)benzamide (Vb)
3) N-(4-(4-Methylphthalazin-1-ylamino)phenyl)benzamide (Vc)
4) 4-Chloro-N-(4-(4-methylphthalazin-1-ylamino)phenyl)benzamide (Vd)
5) 1-Phenyl-3-(4-(phthalazin-1-ylamino)phenyl)urea (VIa)
6) 1-(4-Chlorophenyl)-3-(4-(phthalazin-1-ylamino)phenyl)urea (VIb)
7) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(phthalazin-1-ylamino)phenyl)urea (VIc)
8) 1-(4-(4-Metyhlphthalazin-1-ylamino)phenyl)3-phenylurea (VId)
9) 1-(4-Chlorophenyl)-3-(4-(4-methylphthalazin-1-ylamino)phenyl)urea (VIe)
10)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-methylphthalazin-1-
ylamino)phenyl)urea (VIf)
11)1-Phenyl-3-(4-(phthalazin-1-yloxy)phenyl)urea (VIIa)
12)1-(4-Chlorophenyl)-3-(4-(phthalazin-1-yloxy)phenyl)urea (VIIb)13)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(phthalazin-1-yloxy)phenyl)urea (VIIc)
14)1-(4-(4-Methylphthalazin-1-yloxy)-3-phenyl)urea (VIId)
15)1-(4-Chlorophenyl)-3-(4-(4-methylphthalazin-1-yloxy)phenyl)urea (VIIe)
16)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-metyhlphthalazin-1-yloxy)phenyl)urea
(VIIf)
17)Ethyl 4-(phthalazin-1-yl)piperazine-1-carboxylate (VIIIa)
18)1-(4-Phenylpiperazin-1-yl)phthalazine (VIIIb)
19)1-(4-(2-Fluorophenyl)piperazin-1-yl)phthalazine (VIIIc)
20)1-(4-(Pyridin-2-yl)piperazin-1-yl)phthalazine (VIIId)
21)Furan-2-yl(4-(phthalazin-1-yl)piperazin-1-yl)methanone (VIIIe)
22)Ethyl 4-(4-methylphthalazin-1-yl)piperazine-1-carboxylate (VIIIf)
23)1-Methyl-4-(4-phenylpiperazin-1-yl)phthalazine (VIIIg)
24)1-(4-(2-Fluorophenyl)piperazin-1-yl)-4-methylphthalazine (VIIIh)
25)1-Methyl-4-(4-(pyridin-2-yl)piperazin-1-yl)phthalazine (VIIIi)
26)Furan-2-yl(4-(4-methylphthalazin-1-yl)piperazin-1-yl)methanone (VIIIj)
27)1-(4-(4-Chlorophthalazin-1-ylamino)phenyl)-3-phenylurea (XIIa)
28)1-(4-Chlorophenyl)-3-(4-(4-chlorophthalazin-1-ylamino)phenyl)urea (XIIb)
29)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(4-chlorophthalazin-1
ylamino)phenyl)urea (XIIc)
30)1-(4-(4-Chlorophthalazin-1-yloxy)phenyl)-3-phenylurea (XIIIa)
31)1-(4-Chlorophenyl)-3-(4-(4-chlorophthalazin-1-yloxy)phenyl)urea (XIIIb)
32)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(phthalazin-1-yloxy)phenyl)urea (XIIIc)
33)N-(4-Chlorophenyl)-4-((phenylamino)methyl)phthalazin-1-amine(XVIa)
34)N-(4-Chlorophenyl)-4-((3-chlorophenylamino)methyl)phthalazin-1-amine (XVIb)
35)N-(4-Chlorophenyl)-4-((m-tolylamino)methyl)phthalazin-1-amine (XVIc)
36)N-(4-Chlorophenyl)-4-((3-methoxyphenylamino)methyl)phthalazin-1-amine(XVId) 37)N-(4-Chlorophenyl)-4-(phenoxymethyl)phthalazin-1-amine (XVIIa)
38)N-(4-Chlorophenyl)-4-(m-tolyloxymethyl)phthalazin-1-amine (XVIIb)
The biological evaluation was accomplished to test both the enzyme inhibitory activity
of the synthesized compounds. The enzymatic assay was performed in BPS Bioscience
Corporation, USA. The enzymatic assessment of the synthesized compounds against
VEGFR-2 tyrosine kinase revealed the significant inhibitory activities of the biarylureas
(XIIb, XIIc, and XIIIc) with IC50 of 4.4, 2.7 & 2.5 μM respectively. In addition, these
compounds displayed remarkable inhibition of VEGF-stimulated proliferation of human
umbilical vein endothelial cells (HUVEC) with 79.83, 72.58 & 71.6 % inhibition respectively
at 10 μM.
Additionally, eighteen of the final compounds (Vb, Vd, VIb, VIe, VIIb, VIIe, VIIIa,
VIIId, VIIIf-i, XIIIa-c, XVIa, XVId, and XVIIa) were selected by the National Cancer
Institute “NCI” for single dose screening program at 10 μM in the full NCI 60 cell panel.
Eight compounds (VIb, VIe, VIIb, XIIIa, XIIIc, XVIa, XVId, and XVIIa) exhibited excellent
broad spectrum anti-proliferative activity in NCI 5-log dose assays against the full 60 cell
panel with GI50 values ranging from 0.15 to 8.41 μM. GI50 values ranging from 0.15 to 8 μM.
Furthermore, three compounds (VIIb, XIIIc, and XVIa) were found to induce cell cycle
arrest at S phase boundary with subsequent increase in pre-G cell population in MCF-7 and
HCT-116 cell lines and increased the percentage of apoptotic cells in a time dependent
manner. Compound VIIb caused a concurrent increase in cleaved caspase-3 expression
level, indicating the potential involvement of these compounds in apoptotic-induced cell
death. Finally, a thorough Molecular docking, using C-DOCKER protocol in Discovery Studio
2.5 Software, was attempted to investigate the binding mode of the targeted compounds
and interpret their variable inhibitory activity.