الفهرس 
Synthesis of certain pyrazolo [ 3,4-d ] pyrimidine derivatives of expected anticancer activity
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Abstract
The chemistry of pyrazolo[3,4-d]pyrimidine derivatives has received great attention due to their structural similarity with purines. Many 5-substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ones were reported to possess antiproliferative activity against different cancer cell lines.
The current study involves the design and synthesis of six novel series of pyrazolo[3,4-d]pyrimidine-based compounds. The anticancer activity of all synthesized compounds was screened at the National Cancer Institute (NCI), USA for anticancer activity against 60 human cancer cell lines. Compounds Vd, Ve, and XIVa showed significant antiproliferative activity at 10 μM dose and were accordingly evaluated at five dose concentrations. In addition, this thesis involves the evaluation of novel target compounds Vd and Ve as anticancer agents by CDK-2 enzyme pathway inhibition and the evaluation of compounds XIVa and XXa as anticancer agents by VEGFR-2 pathway inhibition.
Scheme 1 includes the preparation of starting compound 3,6-dimethyl-1-phenylpyrazolo[3,4-d][1,3]oxazin-4(1H)-one (IV) via the cyclization of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (III) with acetic anhydride. The corresponding compounds (Va-e) were obtained through the reaction of IV with substituted amines. Furthermore, compound IV was reacted with hydrazine hydrate to yield 5-amino-3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (VI). Compounds (VIIa-d) containing azomethine linker were prepared via the reaction of compound VI with different aromatic aldehydes.
Scheme 2 includes the preparation of 2-amino-5-substituted phenyl-1,3,4-oxadiazole derivatives (IXa-c) via the reaction of semicarbazone (VIIIa-c) with a solution of bromine/ glacial acetic acid in presence of sodium acetate. Nucleophilic displacement of the oxygen atom of compound IV with oxadiazole derivatives IXa-c afforded compounds (Xa-c) containing hydrazone linker.
Scheme 3 involves reacting compound IV as a starting material with formamide to give the corresponding pyrazolo[3,4-d]pyrimidinone XI. Acetylation with ethyl chloroacetate yielded the corresponding ester XII, then reacting this ester with hydrazine hydrate yielded the corresponding acetohydrazide derivative XIII. Furthermore, condensing compound XIII with the respective aromatic aldehydes afforded the corresponding Schiff’s bases XIVa-d.
Abstract
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Scheme 4 involves the reaction of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (XVI) with formic acid to yield pyrazolo[3,4-d]pyrimidinone XVII, acetylation of XVII with ethyl chloroacetate yielded derivative XVIII. Furthermore reacting XVIII with hydrazine hydrate 99% gave the corresponding acetohydrazide XIX. Finally, condensing compound XIX with different aromatic aldehydes or phthalic anhydride yielded the new series of N’-(substituted benzylidene)-2-(3-methyl-4-oxo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetohydrazide (XXa-d) and 2-(3,6-dimethyl-4-oxo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)-N-(1,3-dioxoisoindolin-2-yl)acetamide (XXI), respectively.
Finally, Scheme 5 involves the reaction of compound XVI with triethyl orthoformate to yield ethyl N-(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)formimidate (XXII). The reaction of XXII with hydrazine hydrate in dry benzene afforded the desired key compound 4-imino-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-amine (XXIII). Treatment of XXIII with different aromatic aldehyde derivatives gave the desired compounds XXIVa-d.
The structural identification of all the newly synthesized compounds was supported by elemental analyses, IR, 1H NMR, D2O 1H NMR, and 13C NMR.