الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Cancer is still one of the major public health problems in the world. DHFR enzymatic pathway has been a significant goal in cancer therapy as it catalyzes the reduction of dihydrofolate into tetrahydrofolate and affords one-carbon moiety for de novo synthesis of thymidylate and purine nucleotides. Therefore, the inhibition of DHFR enzyme leads to cancer cell death. Non-classical antifolates have the ability to penetrate target cell membrane by passive diffusion due to their lipophilic nature rather than classical antifolates such as MTX which can enter cell only by active transport mechanism due to their hydrophilic nature. Several publications involved the synthesis and evaluation of the antitumor activity of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine containing drugs through inhibition of DHFR activity. Our present investigation involves the design and synthesis of new derivatives as candidates of DHFR inhibitors. The strategy for the rational design of the new inhibitors is based on the concept of biosiosterism. Computational exploring was performed for the final synthetized compounds to evaluate and compare the theoretical prediction and the experimental biological results aiming to get a promising lead that has optimal DHFR inhibitory effect with anticancer activity. In the present investigation, 37 novel compounds that are not mentioned in the available literatures were synthesized and purified by means of column chromatography and crystallization. The purity of compounds was assessed by TLC and detected by UV chamber. The structures of the new compounds were elucidated via 1H-NMR, 13C-NMR and Mass spectrometry. The new compounds were biologically evaluated for their in vitro antitumor activity. Compounds 53, 54, 66, 68, 70, 71, 72 and 74, in pyrido[2,3-d]pyrimidine series, which displayed the highest activity against the five tumor cell lines, in addition to compounds 95 and 98, in thieno[2,3-d]pyrimidine series, which showed the highest activity against complete NCI 60 cell line panels, were selected for human DHFR (hDHFR) inhibition assay relative to MTX as a reference drug. This work was supported by the docking studies using MOE software for the most active compounds at the active site of the DHFR enzyme. The docking results were in good accordance with the biological screening results.