الفهرس 
Aim of the workOnly 14 pages are availabe for public view
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Abstract
The work presented in this thesis involves the synthesis of novel series of pyrimido[5,4-c]quinoline derivatives variously substituted at positions 2 and 5. The starting compound 2,4-dichloroquinoline-3-carbonitrile (141) was synthesized and reacted with guanidine hydrochloride (142a) in abs. EtOH under basic conditions to give the unexpected product 2-chloro-4-ethoxy-quinoline-3-carbonitrile 145 (Scheme 64). Similarly, in the absence of guanidine hydrochloride (142a), compound 141 afforded the product 145 under the same reaction conditions. When the same reaction mixture [compound 141, 142a-c, K2CO3, abs. EtOH] was refluxed for 3-6 h the desired 4-amino-5-chloro-2-substituted-pyrimido[5,4-c]quinolines 149a-c were obtained in one step (Scheme 65). It is notable that the activation energy was required to promote the reaction. Pyrimido[5,4-c]tetrazolo[1,5-a]quinolines 151a,b, as a new tetracyclic ring system, were prepared to chemically verify the structure of the novel polyfunctionally substituted pyrimido[5,4-c]quinoline 149. Thus, reaction of 149b,c, as example, with NaN3 in DMF at reflux temperature for 10 h did not give the corresponding azidopyrimido[4,5-b]-quinoline 150, but the isomeric ring-closed pyrimido[5,4-c]tetrazolo[1,5-a]quinolines 151a,b (Scheme 66). The IR spectrum of 151a,b have no azido bands. It is difficult to obtain these reaction products 151a,b if the nucleophilic substitution first take place at position 2. On the other hand, reacting 141 with guanidine hydrochlorides 142a,b (4 equivalents) in refluxing abs. methanol in the presence of sodium methoxide (5 equivalents) for 3 h gave the corresponding new 4-amino-5-methoxy-2-substituted-pyrimido[5,4-c]quinolines 153a,b in good yields (Scheme 67). However, in the case of the reaction of 141 with 142c, under entirely identical conditions as described above, the 4-amino-5-methoxy-2-phenyl-pyrimido[5,4-c]quinoline 153c was not observed and the corresponding product 149c was obtained instead (Scheme 67).
Due to our interest in developing synthetic approaches with the goal of synthesizing novel derivatives of pyrimido[5,4-c]quinolines with different substituents at positions 5, compound 149 was investigated for this purpose. Thus, Refluxing 149a-c with a mixture of acetic acid and water for 3h, resulting in the formation of the corresponding 4-amino-2-substituted-pyrimido[5,4-c]quinolin-5(6H)-ones 157a-c (Scheme 68). We next investigated the reaction of 149c with various types of amines (primary aliphatic amines, cyclic secondary amines, aromatic amines and heterocyclic amines). Heating compound 149c in an excess of butyl amine at reflux temperature for 45 h furnished the new 4-amino-5-butylamino-2-phenyl-pyrimido[5,4-c]quinoline (160) (Scheme 6). Meanwhile, heating 149c with appropriate cyclic secondary amines 161a-d [piperidine (161a), morpholine (161b), 1-methyl-piperazine (161c) and 4-methyl-piperidine (161d)] in refluxing DMF for 4 h gave the corresponding 4-amino-5-amino-substituted-2-phenyl-pyrimido[5,4-c]quinolines 162a-d (Scheme 69). However, the reaction of 149c with aromatic amines, in similar experimental conditions as above, afforded the previously unknown perianellated tricyclic4-amino-5-arylamino-2-phenyl-pyrimido[5,4-c]quinolines 163a-d (Scheme 70). On the other hand, refluxing 149c with 4-aminoantipyrine (164), as example for heterocyclic amines, in DMF for 1 h did not afford the 4-((4-amino-2-phenylpyrimido- [5,4-c]quinolin-5-yl)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (165A), but rather gave the unexpected isomeric structure 4-[(4-amino-2-phenylpyrimido[5,4-c]quinolin-5(6H)-ylidene)-amino]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (165B), as the sole isolable product (Scheme 70). The structure of product 165B has been confirmed unambiguously by single crystal X-ray crystallographic analysis (Fig.2).
All the synthesized compounds were screened for their in vitro antiproliferative activity. The most active hybrids 162a-d, 163a-d, and 165B were assessed against topoisomerase (topo) I, topo IIα, CDK2, and EGFR. The majority of the tested compounds exhibited selective topo I inhibitory activity while had weak topo IIα inhibitory action with compounds 165B and 163d, showed better topo I inhibitory activity than the reference camptothecin. Compound 165B, the most potent derivative as antiproliferative agent, exhibited moderate activity against CDK2 (IC50 = 1.60 µM). The results of this assay show that CDK2 is not a potential target for these compounds, implying that the observed cytotoxicity of these compounds is due to a different mechanism. Compounds 165B, 163d, and 163c were found to be the most potent against EGFR and their EGFR inhibitory activities (IC50 = 0.40±0.2, 0.49±0.2, and 0.64±0.3, respectively) relative to the positive control erlotinib (IC50 = 0.07 ± 0.03 µM). These results revealed that topo I and EGFR are attractive targets for this class of chemical compounds.