الفهرس 
AbstractOnly 14 pages are availabe for public view
 |  | from | 144 |  |  |
| | | from | 144 | | |
Abstract
An introductory part describing the chemistry of quinazoline, different
approaches for its synthesis and tyrosine kinase inhibitors as targeted
chemotherapeutic agents such as gefitinib, erlotinib, lapatinib and caneratinib.
An introductory part describing the ATP-binding pocket of TK domain of
EGFR.
Chapter II (Research Objectives):
The aim of this research is to synthesize structural analogues of gefitinib
(Iressa®) and its congeners: erlotinib (Tarceva®), lapatinib (Tykerb®) and
caneratinib (CI 1033®).
Our strategy is directed toward the design of a variety of ligands by
attaching new moieties at C-6 of the quinazoline ring of substituted 4-
anilinoquinazoline derivatives and/or by varying the aniline substitution pattern
in the hope of discovering more active ATP site inhibitors.
Chapter III (Theoretical Discussion):
A theoretical discussion of synthetic pathways that have been followed to
obtain final new compounds and their mechanisms and spectral data.
Eight cell lines were used to measure cytotoxic sensitivity of the proposed
quinazoline derivatives. Most of tested compounds showed good activity
against breast cancer (MCF-7) with IC50 range of 5.52-34.91 µg/ml.
Molecular docking was performed into EGFR-TK active site and some
compounds showed comparable binding mode to lapatinib. Molecular docking
studies supported the strong inhibitory activity of our newly synthesized
compounds and help to design novel potent inhibitors.
5
Chapter IV (Experimental):
The starting materials, quinazolin-4(3H)-one (I) was prepared according to
Niementowski reaction. The reaction involved the condensation of anthranilic
acid with formamide at 120 °C.
Scheme 1 involved the chlorination of quinazolin-4(3H)-one (I), with
phosphorus oxychloride (POCl3). The next step involved a nucleophilic attack
of p-pheneylene diamine on the carbon atom at the position-4 of the
quinazoline ring to produce 4-(4-aminoanilino)quinazoline (III).
Scheme 2 involved the reaction of 4-(4-aminoanilino)quinazoline (III)
with phenyl isocyanate, phenyl isothiocyanate, glyoxalic acid, acrylic acid and
succinic anhydride to produce 1-phenyl-3-(4-(quinazolin-4-ylamino) phenyl)-
urea (IV), 1-phenyl-3-(4-(quinazolin-4-ylamino) phenyl)thiourea (V), 2-(4-
(quinazolin-4-ylamino)phenylimino)acetic acid (VI), 3-(4-(quinazolin-4-
ylamino)phenylamino)propanoic acid (VII) and 4-oxo-4-(4-(quinazolin-4-
ylamino)phenylamino)butanoic acid (VIII) respectively.
Scheme 3 involved the chlorosulfonation of quinazolin-4(3H)-one (I) at
position-6 followed by a nucleophilic attack of a variety of substituted
piperazines, piperdine and cyclohexyl amine on the sulfur atom to produce
compounds (Xa-g). Compounds (Xa-g) were treated with phosphorus
oxychloride (POCl3) to afford the desired derivatives (XIa-g).
Scheme 4 and 5, compounds (XIa-g) were undergone a nucleophilic
substitution reaction in the prescence of substituted aniline derivatives to give
the final products (XIIb,c,d,g & XIIIa-g).
The structures of the newly synthesized compounds were confirmed by
both analytical and spectral data (IR, 1H-NMR, MS).
The present investigation involves the synthesis of the following
intermediates:-
1] Quinazolin-4(3H)-one (I).
2] 4-Chloroquinazoline (II).
3] 4-(4-Aminoanilino)quinazoline (III).
6
4] 6-Chlorosulfonylquinazolin-4(3H)-one (IX).
5] N-Cyclohexyl-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (Xa).
6] 6-(Piperidin-1-ylsulfonyl)quinazolin-4(3H)-one (Xb).
7] 6-(Piperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xc).
8] 6-(4-Methylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xd).
9] 6-(4-Ethylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xe).
10] 6-(4-Phenylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xf).
11] 6-(4-Benzylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xg).
12] 4-Chloro-N-cyclohexylquinazoline-6-sulfonamide (XIa).
13] 4-Chloro-6-(piperidin-1-ylsulfonyl)quinazoline (XIb).
14] 4-Chloro-6-(piperazin-1-ylsulfonyl)quinazoline (XIc).
15] 4-Chloro-6-(4-methylpiperazin-1-ylsulfonyl)quinazoline (XId).
16] 4-Chloro-6-(4-ethylpiperazin-1-ylsulfonyl)quinazoline (XIe).
17] 4-Chloro-6-(4-phenylpiperazin-1-ylsulfonyl)quinazoline (XIf).
18] 6-(4-Benzylpiperazin-1-ylsulfonyl)-4-chloro-quinazoline (XIg).
In addition to, the synthesis of the following final new compounds:
1] 1-Phenyl-3-(4-(quinazolin-4-ylamino)phenyl)urea (IV).
2] 1-Phenyl-3-(4-(quinazolin-4-ylamino)phenyl)thiourea (V).
3] 2-(4-(Quinazolin-4-ylamino)phenylimino)acetic acid (VI).
4] 3-(4-(Quinazolin-4-ylamino)phenylamino)propanoic acid (VII).
5] 4-Oxo-4-(4-(quinazolin-4-ylamino)phenylamino)butanoic acid (VIII).
6] 4-(4-Bromoanilino)-6-(piperidin-1-ylsulfonyl)quinazoline (XIIb).
7] 4-(4-Bromoanilino)-6-(piperazin-1-ylsulfonyl)quinazoline (XIIc).
8] 4-(4-Bromoanilino)-6-(4-methylpiperazin-1-ylsulfonyl)quinazoline (XIId).
9] 6-(4-Benzylpiperazin-1-ylsulfonyl)-4-(4-bromoanilino)quinazoline (XIIg).
7
10] N-Cyclohexyl-4-(phenylamino)quinazoline-6-sulfonamide (XIIIa).
11] 4-Anilino-6-(piperidin-1-ylsulfonyl)quinazoline (XIIIb).
12] 4-Anilino-6-(piperazin-1-ylsulfonyl)quinazoline (XIIIc).
13] 4-Anilino-6-(4-methylpiperazin-1-ylsulfonyl)quinazoline (XIIId).
14] 4-Anilino-6-(4-ethylpiperazin-1-ylsulfonyl)quinazoline (XIIIe).
15] 4-Anilino-6-(4-phenylpiperazin-1-ylsulfonyl)quinazoline (XIIIf).
16] 4-Anilino-6-(4-benzylpiperazin-1-ylsulfonyl)quinazoline (XIIIg).
Lead compounds were evaluated for their ability to inhibit the growth of
human breast carcinoma (MCF-7) in which tyrosine kinase activity is over
expressed.
Docking study for the most active compounds was carried out on the
crystal structure of EGFR- lapatinib complex (PDB code: 2J5F).
Chapter V (Conclusion):
A summary of the present study, conclusions and the future work.
Chapter VI (References):
A list of references which were used and their arrangement according to
their order in the thesis.