Design, synthesis, and biological evaluation of pyrazolo3,4d. Experimental section and copies of 1 h and c nmr spectra of compounds. No appreciable activity was observed, except for compounds 1e, 2b, and 3e. When 2 was reacted with phenylhydrazine derivatives under reflux, rather than yielding. Note that from the first issue of 2016, mdpi journals use article numbers instead of page numbers. In this work we can synthesize a novel pyrimidine, pyyrazolo 3,4 d pyrimidine and 1,8 naphthyridine derivatives from n,n dimethyl n 1,1,3 tricyano 4 4 dimethylaminophenyl buta 1,3 dien 2ylformimidamide and n 4 cyano 3. Regioselective multicomponent synthesis of 1 h pyrazolo3,4. The reaction of the pyrazolo3,4bpyridine derivative 11 with acetylacetone 12a or ethyl acetoacetate 12b in glacial acetic acid gave, in both cases, a single product. Synthesis of 4 aminopyrazolo3,4dpyrimidine derivatives from.
Compound 6e and 10c exhibited inhibition of src kinase with an ic50 value of 5. The ic 50 values of the target compounds ranged from 1. This substance has been found in the following regulatory activities directly, or inheriting the regulatory context of a parent substance. This is a pdf file of an unedited manuscript that has been accepted for publication. The synthesis of pyrazolo 3, 4 d pyrimidine derivatives has also received significant attention in recent years because of their wide range of biological and pharmaceutical properties such as antitumor and antileukemia activity, antimycobacterial 14. Pyrazolo3,4dpyrimidines as sigma1 receptor ligands for. Herein, starting from the knowledge that kinases are implicated in gbm, we evaluated three inhouse pyrazolo 3, 4 d pyrimidines active as src, fyn, and sgk1 kinase inhibitors against patient derived cell lines from either the invasive region or contrastenhanced core of gbm. Interestingly, the results indicated intermediate 4 showed good to excellent activity in three models curative, protection, and inactivation. A convenient fourcomponent onepot strategy toward the synthesis. One isomer of pyrazolopyrimidines, known as pyrazolo 1,5 a pyrimidine, is the basis for a class of sedative and anxiolytic drugs related in terms of their effect to benzodiazepines. It is also know by registry numbers zinc000004353300, zinc0000518512, mfcd00005687. Synthesis of new pyrazolo3,4bpyridines and pyrazolo1,5. These pyrazolo3,4dpyrimidines were further tested at a wide range of concentrations in order to determine its ic 50 values table 1. A new series of pyrazolo3,4dpyrimidines has been synthesized.
Compound iii31, 6d commercial ningnanmycin and ribavirin were selected as the positive controls. Pyrazolo3,4 dpyrimidines are bicyclic heteroaromatic organic compounds in which the pyrazole ring is fused to the pyrimidine ring. The lack of vcn in the ir spectrum of the isolated product supported the formation of structure 22 scheme 3. Starting from the final pyrazolo3,4dpyrimidine compounds 1 and 2, a classical carbamate synthesis was performed using triphosgene and sodium bicarbonate in ch 2 cl 2. The interaction of 6allylthio 4 imino1methyl 3 methylthio5phenyl1,5dihydro4h pyrazolo 3, 4 d pyrimidine with bromine leads to the formation of 8bromomethyl 4 imino1methyl 3 methylthio5phenyl 4,5,7,8tetrahydro1h pyrazolo 4, 3 e1, 3 thiazolo 3,2a pyrimidinium tribromide. Generally pyrazolopyrimidine and its derivatives are found to possess a wide range of important pharmacophores and are privileged structures in medicinal chemistry. Study of novel pyrazolo3,4dpyrimidine derivatives as selective tgcdpk1 inhibitors. Synthesis and halogenation of allylthioethers of pyrazolo. We report herein the successful application of this strategy with two representative pyrazolo3,4dpyrimidine derivatives 1 and 2, which led to the development of the corresponding and highly water. An efficient onepot synthesis of pyrazolo3,4dpyrimidine derivatives by the four component. Synthesis and halogenation of allylthioethers of pyrazolo3,4. Pdf a pyrazolo3,4dpyrimidine compound reduces cell. The ir spectrum of 17 showed bands due to nh 2 and nh functionalities in the region 33403150 cm. Pyrazolo 3, 4 d pyrimidine is an isomer of imidazolo 3, 4 d pyrimidine purine, the central core of adenine, cytosine, xanthine alkaloids, and other important biomolecules.
In fact, the antitumor effect of these novel pyrazolo 3, 4 d pyrimidine compounds is partly through augmenting ros stress by production of h 2 o 2. Methods for preparing pyrazolo3,4dpyrimidine compounds of the invention are illustrated in scheme i. Therefore, chemistry of pyrazolo 3, 4 d pyrimidines has received significant attention, particularly for the development of new biologically active substances caravatti et al. Starting from our inhouse library of pyrazolo3,4dpyrimidines, a crossdocking simulation was. Pyrazolo3,4dpyrimidine derivatives hoffmanla roche inc. Studies on pyrazolo 3,4 d pyrimidine nucleosides a dissertation submitted to the aligarh muslim university, aligarh for the degree of master of philosophy in chemistry by. Pyrazolo 3,4d thiazolo3,2apyrimidine ring is isomeric with the purine and thiazol ring and therefore, is of interest as a model for biologically active compounds. S1 discovery of a potent protein kinase d inhibitor. Predicted data is generated using the us environmental protection agencys episuite. Regioselective multicomponent synthesis of 1 h pyrazolo. These compounds and their pharmaceuticallyacceptable salts and esters are antiproliferative agents useful in the treatment or control of proliferative disorders such as solid tumors, in particular breast tumor, colon tumor, lung tumor, prostate tumor.
We synthesized a novel radiofluorinated 4 anilinopyrido 3, 4 d pyrimidine derivative 18fapp1 and evaluated its potential as a positron emission tomography pet imaging probe to discriminate the difference in mutations of tumors. Sds of 1hpyrazolo3,4dpyrimidine4thiol, safety data. This is a pdf file of an unedited manuscript that has been accepted for. Disclosed are novel pyrazolo3,4 dpyrimidine derivatives that are inhibitors of raf kinase. Aug 29, 2012 a variety of pyrazolo 3, 4 d pyrimidine 67hthione derivatives were easily synthesized with a novel, simple, efficient, and regioselective method via threecomponent condensation reaction of 5methyl1hpyrazol 3 amine, arylisothiocyanates, and aldehydes in the presence of catalytic amount of ptoluenesulfonic acid ptsa in 1butyl 3 methylimidazolium bromide ionic liquid with excellent. Diacetyl ketene n, sacetal was used for the synthesis of. Pdf pyrazolo3,4dpyrimidine based scaffold derivatives targeting. A series of pyrazolo3,4dpyrimidine derivatives was synthesized and evaluated for the src kinase inhibitory activities. Pyrazolo3,4dpyrimidine derivatives containing a schiff. This shows that the catalytic properties of sodium hydroxide have some limitations. Synthesis and antimicrobial activity of some new pyrazoles.
The new compounds were tested for their antitumor activity on 60 different. Pyrazolo3,4 dpyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Page 240 synthesis of new pyrazolo3,4bpyridin3ones and pyrazolo1,5 apyrimidin21hone and study of the pyrazolic nitrogen reactivity salah fadel,a salha hamri,a youssef hajbi,a,b franck suzenet,b abderrafia hafid,a elmostapha rakib,a mostafa khouili,a maria d. The interaction of 6allylthio4imino1methyl3methylthio5phenyl1,5dihydro4hpyrazolo3,4dpyrimidine with bromine leads to the formation of 8bromomethyl4imino1methyl3methylthio5phenyl4,5,7,8tetrahydro1hpyrazolo4,3e1,3thiazolo3,2a pyrimidinium tribromide. A solution of sodium 3 5methyl1phenyl1hpyrazol 4 yl 3 oxoprop1en1olate 2 2. In the title compound, c 19 h 16 n 4 s, the pyrazolo3,4 d pyrimidine ring is close to being planar, with the greatest deviation from the mean plane being 0. These compounds and their pharmaceuticallyacceptable salts and esters are antiproliferative agents useful in the treatment or control of proliferative disorders such as solid tumors, in particular breast tumor, colon tumor, lung tumor, prostate tumor, and melanoma. Study of novel pyrazolo3,4dpyrimidine derivatives as. The pyrazolo1,5apyrimidine ldn193189 is a potent inhibitor of activin receptorlike kinase 2 alk2 but is nonselective for highly homologous alk3 and shows only modest kinome selectivity. Synthesis of new pyrazolo1,5apyrimidine, triazolo4,3a.
Pyrazolo 3,4d pyrimidines were identified as a general class of adenosine receptors20,21. Design of pyrazolo3,4 dpyrimidine derivatives containing a schiff base moiety. High purity, submicron and nanopowder forms may be considered. Therefore, chemistry of pyrazolo3,4dpyrimidines has received significant attention, particularly for the development of new biologically active substances caravatti et al. Reaction of 2 with hydrazine hydrate was known to produce 4iminopyrazolo3,4dpyrimidines10 3 with mp 236238. A variety of pyrazolo3,4dpyrimidine67hthione derivatives were easily synthesized with a novel, simple, efficient, and regioselective method via threecomponent condensation reaction of 5methyl1hpyrazol3amine, arylisothiocyanates, and aldehydes in the presence of catalytic amount of ptoluenesulfonic acid ptsa in 1butyl3methylimidazolium bromide ionic liquid with excellent. In this work we can synthesize a novel pyrimidine, pyyrazolo 3,4 d pyrimidine and 1,8 naphthyridine derivatives from n,n dimethyl n 1,1,3 tricyano 4 4 dimethylaminophenyl buta 1,3. The synthesis protocol of pyrazolo3,4 d pyrimidines 5 is depicted in scheme 1. The reaction of compound 11 with ethyl cyanoacetate 2a gave the pyrido2. Specifically, pyrazolo3,4 dpyrimidines are considered to be chemically and pharmaceutically more. Crystal structure of s6k1 kinase domain in complex with a pyrazolopyrimidine derivative 441hbenzimidazol2ylpiperidin1yl1hpyrazolo3,4dpyrimidine. Nov 07, 2010 comprehensive coverage of both the preparation and biologic activity of all pyrazolo3,4 dpyrimidines reported in the literature to show such activity would lead to a truly enormous treatise. Pdf in a cellbased screen of novel anticancer agents, the hit compound 1a which bears a.
Verschueren klaasa, mathias cobbautb, joachim demaerela, lina saadahb, arnout r. The reactivity of 2hydrazino4,4diphenyl1himidazol54hone 2 towards active methylene reagents. Study of novel pyrazolo 3, 4 d pyrimidine derivatives as selective tgcdpk1 inhibitors. The pyrazolo 3, 4 d pyrimidine derivative, sco201, reverses multidrug resistance mediated by abcg2bcrp. Discovery of 34sulfamoylnaphthylpyrazolo1,5apyrimidines as potent and selective alk2 inhibitors.
Us8377946b1 pyrazolo3,4dpyrimidine and pyrrolo2,3d. In general, the acyclic nucleoside of pyrazolo 3, 4 d pyrimidine derivative 42 revealed the highest anticancer activity among the other tested compounds. Files available from the acs website may be downloaded for personal use only. Jul 11, 20 pyrazolo 3, 4 d pyrimidines represent a promising class of compounds capable of inhibiting several oncogenic tyrosine kinases, which represent an attractive target for the development of new therapeutic agents against cancer. We identified our src inhibitor, si306, as a promising lead compound. M showing 56fold selectivity over src kinase inhibition. Molport offers 1h pyrazolo3,4 dpyrimidine 4thiol for your scientific research needs. Volume 32, issue 46, 11 november 1991, pages 67876788. Ma, shaojie, zhou, shengfu, lin, weicong, zhang, rong, wu, wenjuan, zheng, kangcheng source. Fortunately, some strong bases could promote the reaction to produce 5a. American elements produces to many standard grades when applicable, including mil spec military grade. Jun 28, 2011 disclosed are novel pyrazolo3,4 dpyrimidine derivatives that are inhibitors of raf kinase. A convenient fourcomponent onepot strategy toward the. The synthetic details is shown in supplementary data file.
Pyrazolo3,4dpyrimidine is an isomer of imidazolo3,4dpyrimidine purine, the central core of adenine, cytosine, xanthine alkaloids, and other important biomolecules. Pdf novel pyrazolo3,4d pyrimidine derivatives as potential. Therefore, the ability to predict whether egfr will undergo secondary mutation is extremely important. Cells free fulltext the pyrazolo 3, 4 d pyrimidine. Tachykinins are peptide neurotransmitters interacting with a class of gproteincoupled receptors 214. Two step reaction in which compound i is reacted with n,n. Pyrazolo1,5apyrimidine3carboxylic acid 95% sigmaaldrich. Synthesis of 4aminopyrazolo 3, 4d pyrimidine derivatives from 5. Condensation of pyrazoloxazine derivative 3 with 99% hydrazine hydrate afforded the 5aminopyrazolo3,4dpyrimidine derivative 9. Design, synthesis, and antitumor evaluation of novel pyrazolo3,4d. Herein, we present the onepot twostep procedure for the synthesis of a set of pyrazolo3,4dpyrimidine prodrugs 1a. This compound is available from 10 suppliers, including chemdiv, inc.
Synthesis and anticancer activity of some new pyrazolo 3, 4d. Herein, we report the crystal structure of 4hydrazino1. A solution of sodium 35methyl1phenyl1hpyrazol4yl3oxoprop1en1olate 2 2. The antiviral activity of pyrazolo3,4dpyrimidine derivatives against tmv was evaluated using the halfleaf spot method 10. We report herein the successful application of this strategy with two representative pyrazolo 3, 4 d pyrimidine derivatives 1 and 2, which led to the development of the corresponding and highly water. Comprehensive coverage of both the preparation and biologic activity of all pyrazolo3,4 dpyrimidines reported in the literature to show such activity would lead to a truly enormous treatise. Development of pyrazolo3,4dpyrimidine kinase inhibitors. Pyrazolo3,4dpyrimidine ribonucleosides related to 2aminoadenosine and isoguanosine. Pyrazolo3,4dpyrimidine ribonucleosides related to 2. A plenty of synthetic methods have been outlined for the synthesis of pyrazolo3,4dpyrimidines. Pdf molecular targeted therapies are based upon drugs acting on tumors by interfering with specific targets involved in growth and spread of cancer find, read and cite all the research you. Also, a book was then extend to explain a new methods for synthesis and biological activity of some new heterocyclic systems containing pyrazolo3,4d. Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable adme properties, in particular aqueous solubility and bioavailability.
Hydroxamate derivative 15a was found to be a metalmediated inhibitor for human csk with an ic50 value of 2. All intermediates 1 4 can be easily synthesized according to references, 7, 8, 9 and compound 5 was prepared by the reaction of intermediate 4 with different aromatic. Pyrazolo3,4dpyrimidines are potent protein kinase inhibitors with promising antitumor activity but. Optical grade, usp and epbp european pharmacopoeia. Synthesis of pyrazolo3,4dpyrimidine derivatives and. Use of the information, documents and data from the echa website is subject to the terms and conditions of this legal notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the echa website may be reproduced, distributed andor used, totally or in part, for noncommercial purposes provided that echa is. Here you can find all of the regulations and regulatory lists in which this substance appears, according to the data available to echa. Most of the drugs from this class marketed to date are intended to induce sleep, and are prescribed for people suffering insomnia, however some newer. Pyrazolo3,4dpyrimidines derivatives have been explored for their. Synthesis of some novel pyrazolo3,4dpyrimidine derivatives. The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo3,4dpyrimidine scaffold, led to highly active sigma1 receptor. Pyrazolo 3, 4 d pyrimidine analogues of isoguanine. The pyrazolo3,4dpyrimidine heterocyclic system is known to be a bioisoster of purine. Phenyl or pyrazolyl groups were the best in terms of affinity for the.
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