الفهرس 
CancerOnly 14 pages are availabe for public view
 |  | from | 184 |  |  |
| | | from | 184 | | |
Abstract
Cancer, also known as a malignant tumor, is a group of diseases involving abnormal cell
growth with the potential to invade or spread to other parts of the body. A major problem
in treating cancer is the fact that it is not a single disease. There are more than 200
different cancers resulting from different cellular defects. 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 VEGFR-2, angiogenesis is greatly inhibited leading to the death
of the tumor cells.
In this study, thienopyrimidine derivatives have been designed and synthesized as targeted
angiogenesis inhibitors. 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 in silico.
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-Nitrophenyl)-3-phenylurea (Ia)
2) 1-(3-Methoxyphenyl)-3-(4-nitrophenyl)urea (Ib)
3) 1-(4-Nitrophenyl)-3-(m-tolyl)urea (Ic)
4) 1-(4-Acetylphenyl)-3-(4-nitrophenyl)urea (Ie)
5) 1-(4-Chlorophenyl)-3-(4-nitrophenyl)urea (Ig)
6) N1-(3-Bromophenyl)-3-(4-nitrophenyl)urea (Ih)
7) 1-(4-Ethylphenyl)-3-(4-nitrophenyl)urea (Ii)
8) 1-(3,4-diChlorophenyl)-3-(4-nitrophenyl)urea (Ij)
9) 1-(3-trifluoromethyl-4-chlorophenyl)-3-(4-nitrophenyl)urea (Ik)
10)1-(4-Aminophenyl)-3-phenylurea (IIa)
11)1-(4-Aminophenyl)-3-(3-methoxyphenyl)urea (IIb)
12)1-(4-Aminophenyl)-3-(m-tolyl)urea (IIc)
13)1-(4-Aminophenyl)-3-(4-chlorophenyl)urea (IIg)
14)1-(4-Aminophenyl)-3-(3-bromophenyl)urea (IIh)
15)1-(4-aminophenyl)-3-(3,4-diChlorophenyl) urea (IIj) 16)1-(4-aminophenyl)-3-(3-trifluoromethyl-4-chlorophenyl) urea (IIk)
17)1-(4-Hydroxyphenyl)-3-phenylurea (IIIa)
18)1-(3-Bromophenyl)-3-(4-hydroxyphenyl)urea (IIIb)
19)1-(4-Hydroxyphenyl)-3-(3-methoxyphenyl)urea (IIIc)
20)1-(4-Chlorophenyl)-3-(4-hydroxyphenyl)urea (IIId)
21)11-(3,4-Dichlorophenyl)-3-(4-hydroxyphenyl)urea (IIIf)
22)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (IIIg)
23)5-Nitroindazole (IV)
24)5-Aminoindazole (V)
25)5-Amino benzimidazole (VI)
26)N-(4-Nitrophenyl)-2-phenylacetamide (VII)
27)N-(4-aminophenyl)-2-phenylacetamide (VIII)
28)N-(4-Hydroxyphenyl)-2-phenylacetamide (IX)
29)Diethyl (5-amino-3-methylthiophene)-2,4-dicarboxylate (X)
30)Ethyl (5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine)-6-carboxylate (XI)
31)Ethyl (4-chloro-5-methylthieno[2,3-d]pyrimidine)-6-carboxylate (XII)
32)3-((6-(Ethoxycarbonyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)amino)benzoic acid
(XXII)
Also, it comprised the following new intermediates:
1) 1-(3-Acetylphenyl)-3-(4-nitrophenyl)urea (Id)
2) 1-(3-Chloro-4-methylphenyl)-3-(4-nitrophenyl)urea (If)
3) 1-(3-Acetylphenyl)-3-(4-aminophenyl)urea (IId)
4) 1-(4-Acetylphenyl)-3-(4-aminophenyl)urea (IIe)
5) 1-(4-Aminophenyl)-3-(3-chloro-4-methylphenyl)urea (IIf)
6) 1-(4-Aminophenyl)-3-(4-ethylphenyl)urea (IIi)
7) 1-(3-Chloro-4-methylphenyl)-3-(4-hydroxyphenyl)urea (IIIe)
8) 5-Methyl-4-((4-(3-phenylureido)phenyl)amino)thieno[2,3-d]pyrimidine-6-carboxylic
acid (XIVa)
9) 4-((4-(3-(3-methoxyphenyl)ureido)phenyl)amino)-5-methylthieno[2,3-d]pyrimidine-6-
carboxylic acid (XIVb)Also, the study involved the synthesis and the characterization of the following newtargeted compounds:
1) Ethyl 5-methyl-4-((4-(3-phenylureido)phenyl)amino)thieno[2,3-d]pyrimidine-6-
carboxylate (XIIIa)
2) Ethyl 4-((4-(3-(3-methoxyphenyl)ureido)phenyl)amino)-5-methylthieno[2,3-d]
pyrimidine-6-carboxylate (XIIIb)
3) Ethyl 5-methyl-4-((4-(3-(m-tolyl)ureido)phenyl)amino)thieno[2,3-d]pyrimidine-6-
carboxylate (XIIIc)
4) Ethyl 4-((4-(3-(3-acetylphenyl)ureido)phenyl)amino)-5-methylthieno[2,3-d]
pyrimidine-6-carboxylate (XIIId)
5) Ethyl 4-((4-(3-(4-acetylphenyl)ureido)phenyl)amino)-5-methylthieno[2,3-d]
pyrimidine-6-carboxylate (XIIIe)
6) Ethyl 4-((4-(3-(3-chloro-4-methylphenyl)ureido)phenyl)amino)-5-methylthieno [2,3-
d]pyrimidine-6-carboxylate (XIIIf)
7) Ethyl 4-((4-(3-(4-chlorophenyl)ureido)phenyl)amino)-5-methylthieno[2,3-d]
pyrimidine-6-carboxylate (XIIIg)
8) Ethyl4-((4-(3-(3-bromophenyl)ureido)phenyl)amino)-5-methylthieno [2,3d]
pyrimidine -6-carboxylate (XIIIh)
9) Ethyl4-((4-(3-(4-ethylphenyl)ureido)phenyl)amino)-5-methylthieno[2,3-d]pyrimidine-
6-carboxylate (XIIIi)
10)Ethyl4-((4-(3-(3,4-dichlorophenyl)ureido)phenyl)amino)-5-methylthieno[2,3-
d]pyrimidine-6-carboxylate (XIIIj)
11)Ethyl4-((4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)amino)-5-
methylthieno[2,3-d]pyrimidine-6-carboxylate (XIIIk)
12)5-Methyl-4-((4-(3-phenylureido)phenyl)amino)-N-propylthieno[2,3-d]pyrimidine-6-
carboxamide (XVa)
13)4-((4-(3-(3-Methoxyphenyl)ureido)phenyl)amino)-5-methyl-N-propylthieno[2,3-
d]pyrimidine-6-carboxamide (XVb)
14)Ethyl 5-methyl-4-(4-(3-phenylureido)phenoxy)thieno[2,3-d]pyrimidine-6-carboxylate
(XVIa)
15)Ethyl 4-(4-(3-(3-bromophenyl)ureido)phenoxy)-5-methylthieno[2,3-d] pyrimidine-6-
carboxylate (XVIb)
16)Ethyl 4-(4-(3-(3-methoxyphenyl)ureido)phenoxy)-5-methylthieno[2,3-d] pyrimidine-6-
carboxylate (XVIc) 17)Ethyl 4-(4-(3-(4-chlorophenyl)ureido)phenoxy)-5-methylthieno[2,3-d] pyrimidine-6-
carboxylate (XVId)
18)Ethyl 4-(4-(3-(3-chloro-4-methylphenyl)ureido)phenoxy)-5-methylthieno [2,3-
d]pyrimidine-6-carboxylate (XVIe)
19)Ethyl 4-(4-(3-(3,4-dichlorophenyl)ureido)phenoxy)-5-methylthieno[2,3-d] pyrimidine-
6-carboxylate (XVIf)
20)Ethyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-5-
methylthieno[2,3-d] pyrimidine-6-carboxylate (XVIg)
21)4-(4-(3-(3-chloro-4-methylphenyl)ureido)phenoxy)-5-methyl-N-propylthieno[2,3-
d]pyrimidine-6-carboxamide (XVIIa)
22)4-(4-(3-(3,4-dichlorophenyl)ureido)phenoxy)-5-methyl-N-propylthieno[2,3-
d]pyrimidine-6-carboxamide (XVIIb)
23) Ethyl4-((1H-indazol-5-yl)amino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate
(XVIII)
24)Ethyl 5-methyl-4-((1-(phenylcarbamoyl)-1H-indazol-5-yl)amino)thieno[2,3-
d]pyrimidine-6-carboxylate (XIXa)
25)Ethyl 4-((1-((3-chloro-4-methylphenyl)carbamoyl)-1H-indazol-5-yl)amino)-5-
methylthieno[2,3-d]pyrimidine-6-carboxylate (XIXb)
26)Ethyl 4-((1-((3-methoxyphenyl)carbamoyl)-1H-indazol-5-yl)amino)-5-
methylthieno[2,3-d]pyrimidine-6-carboxylate (XIXc)
27)Ethyl4-((1H-benzo[d]imidazol-5-yl)amino)-5-methylthieno[2,3-d]pyrimidine-6-
carboxylate (XX)
28)Ethyl5-methyl-4-((4-(2-phenylacetamido)phenyl)amino)thieno[2,3-d]pyrimidine-6-
carboxylate (XXIa)
29)Ethyl5-methyl-4-(4-(2-phenylacetamido)phenoxy)thieno[2,3-d]pyrimidine-6-
carboxylate (XXIb)
30)Ethyl4-((3-(cyclopropylcarbamoyl)phenyl)amino)-5-methylthieno[2,3-d]pyrimidine-6-
carboxylate (XXIII)
In vitro biological evaluation was accomplished through testing both anticancer activity
and VEGF enzyme inhibition activity of the newly synthesized compounds. Most of the
synthesized compounds showed good to potent VEGFR-2 inhibitory potency. Most of the tested urea compounds demonstrated highly potent dose-related VEGFR-2 inhibition with
IC50 values in nanomolar range. Incorporation of a diphenylurea moiety at the C4-position
of the thieno[2,3-d]pyrimidin core via an oxygen linker gave the highest potency. The
thieno[2,3-d]pyrimidine based-derivatives (XVIb and XVIe) resulted in compounds that
showed highest potent single-digit nanomolar VEGFR-2 inhibition (IC50 of 3.9 nM and 5.0
nM respectively). Seven of the final Compounds (XIIIg, XVb, XVId , XVIe, XVIIa, XIXa,
XIXb) were selected by the National Cancer Institute “NCI” for single dose screening
program at 10 μM in the full NCI 60 cell panel. The thieno[2,3-d]pyrimidine-based
derivative (XIIIg) showed remarkably the lowest cell growth promotion, hence good antiproliferative activity against different cell lines.
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.
The thesis involves 268 references showing the literature survey for this research.