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      Synthesis and Anticancer Activity of Some New Pyrazolo[3,4- d]pyrimidin-4-one Derivatives

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          Abstract

          3,6-Dimethyl-1-phenyl-1 H-pyrazolo[3,4- d][1,3]oxazin-4-one ( 3) was prepared by hydrolysis of ethyl 5-amino-3-methyl-1-phenyl-1 H-pyrazole-4-carboxylate ( 1) to afford the corresponding carboxylic acid 2, which was reacted with acetic anhydride to give 3. The pyrazolo[3,4- d][1,3]oxazin-4-one 3 was reacted with hydroxylamine hydrochloride, urea, thiourea, thiosemicarbazide, phenylhydrazine and aromatic amines to afford the corresponding pyrazolo[3,4- d]pyrimidin-4-ones 4, 5a, b, 6, 7, 8ae, respectively. Condensation of pyrazoloxazine derivative 3 with 99% hydrazine hydrate afforded the 5-aminopyrazolo[3,4- d]pyrimidine derivative 9. Coupling of 9 with aromatic aldehydes yielded a series of 3,6-dimethyl-5-(4-substitutedbenzylideneamino)-1-phenyl-1,5-dihydropyrazolo[3,4- d]pyrimidin-4-ones 10ae. The new compounds were tested for their antitumor activity on the MCF-7 human breast adenocarcinoma cell line. Almost all the tested compounds revealed antitumor activity, especially 3,6-dimethyl-5-(4-nitrobenzylideneamino)-1-phenyl-1,5-dihydropyrazolo[3,4- d]pyrimidin-4-one ( 10e) which displayed the most potent inhibitory activity with a half maximal inhibitory concentration (IC 50) of 11 µM.

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          Most cited references19

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          Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy

          In recent years, tyrosine kinases (TKs) have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogenesis, and are therefore considered suitable potential targets for anti-cancer therapies. Several strategies for targeting TKs have been developed, the most successful being monoclonal antibodies and small molecule tyrosine kinase inhibitors. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity. This review intends to present the most recently identified molecular mechanisms that mediate acquired resistance to tyrosine kinase inhibitors, identified through the use of in vitro models or the analysis of patient samples. The knowledge obtained from these studies will help to design better therapies that prevent and overcome resistance to treatment in cancer patients.
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            Synthesis of some new pyrazolo[3,4-d]pyrimidine derivatives of expected anticancer and radioprotective activity.

            On the account of the reported anticancer activity of pyrazolo[3,4-d]pyrimidines, a new series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line. Moreover, one of the target products was evaluated for in-vivo radioprotective activity. The reaction of o-aminoester 1 with benzylamine in presence of triethylorthoformate yielded the corresponding 5-benzylpyrazolopyrimidine derivative 2. The N-amino derivative 3 was used to synthesize new derivatives of pyrazolopyrimidines 4-7. The corresponding 1,3,4-oxadiazolopyrazolopyrimidine derivatives 12 and 14 were obtained via reaction of compound 9 with reagent 10 and/or triethylorthoformate. Thiophosgenation of compound 1 furnished the corresponding 5-isothiocyanate derivative 15, which was reacted with o-phenylenediamine, thiosemicarbazide and anthranilic acid to give benzimidazolopyrazolopyrimidine, 17, pyrazolotriazolopyrimidine, 19 and pyrazolopyrimidobenzoxazine, 20 respectively. The structures of the synthesized compounds were confirmed by microanalyses, IR, NMR, and mass spectral data. Compounds 2 and 9 showed intermediate anticancer activity compared to doxorubicin as positive control with IC50 values of 90 and 100 microg/ml, respectively. On the other hand, compound 5 showed significant radioprotective effect. Copyright 2009 Elsevier Masson SAS. All rights reserved.
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              Synthesis and biological evaluations of pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors.

              A series of 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines 15-19, 30-38 capable of selectively inhibiting CDK2 activity were synthesized by derivatization at C-4, C-6 and N-1 with various amines and lower alkyl groups. For above synthetic compounds, biological evaluation was carried out and structure-activity relationship was examined. In our series, 4-anilino compounds exhibited better CDK2 inhibitory activity and antitumor activity compared to 4-benzyl compounds. The compounds 33a,b having a 3-fluoroaniline group at C-4 showed comparable or superior CDK2 inhibitory activity to those of olomoucine and roscovitine as reference compounds. In general, the unsubstituted compounds (30a,b, 33a,b, 36a,b) at N-1 possessed higher potency than the substituted compounds (32a,b, 34a,b) for the CDK2 inhibitory activity. As for EGFR inhibitory activity, most compounds didnot have a significant activity. The compounds 32a,b exhibited potent cell growth inhibitory activity against human cancer cell lines, but their CDK2 inhibitory activities were slightly poorer than olomoucine.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                18 March 2014
                March 2014
                : 19
                : 3
                : 3297-3309
                Affiliations
                [1 ]Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; E-Mails: khaled.ahmed@ 123456bsu.edu.eg (K.R.A.A.); Emansherif94@ 123456yahoo.com (E.K.A.A.); mhmdgwd@ 123456yahoo.com (M.A.A.)
                [2 ]Cell Biology and Histology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt; E-Mail: shorouk2002os@ 123456yahoo.com
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: raniabakr@ 123456ymail.com or rania.mohamed@ 123456pharm.bsu.edu.eg ; Fax: +2-082-231-7958.
                Article
                molecules-19-03297
                10.3390/molecules19033297
                6270843
                24647032
                6f60f96f-126f-4972-bf4f-f97dea98c7bf
                © 2014 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 31 December 2013
                : 27 February 2014
                : 05 March 2014
                Categories
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                pyrazolo[3,4-d]pyrimidin-4-one,anticancer activity,mcf7

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