- Novel pyrazolo[3,4-d]pyrimidine derivatives inhibit human cancer cell proliferation and induce apoptosis by ROS generation
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The paucity of effective anticancer drugs for successful treatment is a major concern, indicating the strong need for novel therapeutic compounds. In the quest of new molecules, the present study aimed to explore the potential of pyrazolo[3,4-d]pyrimidine derivatives as antiproliferative agents. In vitro anticancer screening of selected compounds was done by the National Cancer Institute's Developmental Therapeutics Programme against a panel of 60 cancer cell lines. The lead compound PP-31d considerably inhibited the growth of cancer cells, such as NCI-H460 (non-small-cell lung cancer), OVCAR-4 (ovarian cancer), 786-0 (renal cancer), A549 (non-small-cell lung cancer), and ACHN (renal cancer), showing strong anticancer potential, among other derivatives. Kinetic studies of PP-31d on NCI-H460 cells revealed a dose-dependent effect with an IC50 of 2 μM. The observed inhibition by PP-31d is attributed to the generation of reactive oxygen species and the subsequent induction of cellular apoptosis, as evidenced by the increase in the hypodiploid (subG1) population, the early apoptotic cell population, and caspase-3/7 activity, the loss of the mitochondrial membrane potential, and the degradation of nuclear DNA. Collectively, our results demonstrated that pyrazolo[3,4-d]pyrimidine derivatives inhibit cancer cell proliferation by inducing apoptosis and, thus, have the potential to be further explored for anticancer properties.
- Gaonkar, Supreet,Garbhagudi, Manjunatha,Khazi, Imtiyaz Ahmed M.,Mantur, Shivaraj,Mulla, Sikandar I.,Nadaf, AfraQuasar A.,Najare, Mahesh S.,Savanur, Mohammed Azharuddin
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Read Online
- Design, Synthesis, and Antifungal Activity of 2,6-Dimethyl-4-aminopyrimidine Hydrazones as PDHc-E1 Inhibitors with a Novel Binding Mode
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A series of novel 2,6-dimethyl-4-aminopyrimidine hydrazones 5 were rationally designed and synthesized as pyruvate dehydrogenase complex E1 (PDHc-E1) inhibitors. Compounds 5 strongly inhibited Escherichia coli (E. coli) PDHc-E1 (IC50 values 0.94-15.80 μM). As revealed by molecular docking, site-directed mutagenesis, enzymatic, and inhibition kinetic analyses, compounds 5 competitively inhibited PDHc-E1 and bound in a "straight"pattern at the E. coli PDHc-E1 active site, which is a new binding mode. In in vitro antifungal assays, most compounds 5 at 50 μg/mL showed more than 80% inhibition against the mycelial growth of six tested phytopathogenic fungi, including Botrytis cinerea, Monilia fructigena, Colletotrichum gloeosporioides, andBotryosphaeria dothidea. Notably, 5f and 5i were 1.8-380 fold more potent against M. fructigena than the commercial fungicides captan and chlorothalonil. In vivo, 5f and 5i controlled the growth of M. fructigena comparably to the commercial fungicide tebuconazole. Thus, 5f and 5i have potential commercial value for the control of peach brown rot caused by M. fructigena.
- Zhou, Yuan,Zhang, Shasha,Cai, Meng,Wang, Kaixing,Feng, Jiangtao,Xie, Dan,Feng, Lingling,Peng, Hao,He, Hongwu
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p. 5804 - 5817
(2021/06/25)
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- An efficient and practical synthesis of 2,4-substituted pyrido[4,3-d]pyrimidin-5(6H)-ones
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We describe an efficient synthesis of 2,4-substituted pyrido[4,3-d]pyrimidin-5(6H)-ones, which involves the acid-promoted cyclization of cyano enamine 15 to afford 2,4-bis(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one 17 as a key intermediate. Selective displacement of the 4-methylthio group by a wide range of anilines followed by oxidation of the 2-methylthio group and subsequent substitution by amines enabled the synthesis of a variety of 2,4-disubstituted pyrido[4,3-d]pyrimidin-5(6H)-ones.
- Tian, Xinrong,Suarez, Dominic P.,Li, William Hoi Hong,McSherry, Allison K.,Sanchez, Robert M.,Moore, Michael L.,Axten, Jeffrey M.
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supporting information
(2019/11/13)
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- Novel pyrazolo[3,4-d]pyrimidines: design, synthesis, anticancer activity, dual EGFR/ErbB2 receptor tyrosine kinases inhibitory activity, effects on cell cycle profile and caspase-3-mediated apoptosis
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A series of novel pyrazolo[3,4-d]pyrimidines was synthesised. Twelve synthesised compounds were evaluated for their anticancer activity against 60 human tumour cell lines by NCI (USA). Compound 7d proved prominent anticancer activity. It showed 1.6-fold more potent anti-proliferative activity against OVCAR-4 cell line with IC50 = 1.74 μM. It also exhibited promising potent anticancer activity against ACHN cell line with IC50 value 5.53 μM, representing 2.2-fold more potency than Erlotinib. Regarding NCI-H460 cell line, compound 7d (IC50 = 4.44 μM) was 1.9-fold more potent than Erlotinib. It inhibited EGFR and ErbB2 kinases at sub-micromolar level (IC50 = 0.18 and 0.25 μM, respectively). Dual inhibition of EGFR and ErbB2 caused induction of apoptosis which was confirmed by a significant increase in the level of active caspase-3 (11-fold). It showed accumulation of cells in pre-G1 phase and cell cycle arrest at G2/M phase.
- Maher, Mai,Kassab, Asmaa E.,Zaher, Ashraf F.,Mahmoud, Zeinab
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p. 532 - 546
(2019/02/03)
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- KINASE INHIBITORS AND USES THEREOF
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The present disclosure relates generally to compounds and compositions, intermediates, processes for their preparation, and their use as kinase inhibitors.
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Paragraph 0256; 0315
(2018/12/13)
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- Fused-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient
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The present invention relates to a conjugated pyrimidine derivative, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating Bruton′s tyrosine kinase activity-related diseases containing the same as an active ingredient. The conjugated pyrimidine derivative according to the present invention is excellent in the ability to inhibit the activity of Bruton′s tyrosine kinase or TMD80, and thus can be usefully used for prevention or treatment of diseases related to Bruton′s tyrosine kinase activity, particularly cancer or autoimmune diseases.COPYRIGHT KIPO 2019
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Paragraph 0492-0496
(2019/02/02)
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- Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors
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Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0.41?±?0.03?μM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies.
- Fang, Zhen,Wang, Tian-qi,Li, Hui,Zhang, Guo,Wu, Xiao-ai,Yang, Li,Peng, Yu-lan,Zou, Jun,Li, Lin-li,Xiang, Rong,Yang, Sheng-yong
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supporting information
p. 3201 - 3204
(2017/06/13)
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- Simple access to highly functional bicyclic γ- and δ-lactams: Origins of chirality transfer to contiguous tertiary/quaternary stereocenters assessed by DFT
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This paper describes the synthesis of both polysubstituted oxazolo-pyrrolidinones and -piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron-withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)-phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereo-selectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation.
- Le Goff, Ronan,Martel, Arnaud,Sanselme, Morgane,Lawson, Ata Martin,Dach, Adam,Comesse, Sbastien
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supporting information
p. 2966 - 2979
(2015/02/19)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Paragraph 0175
(2014/05/24)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, Formula (1) wherein R1, R2, R3, X, Y, Z, A, B, G1, m, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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Paragraph 0347
(2014/06/25)
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- Transesterification of trimethyl orthoacetate: An efficient protocol for the synthesis of 4-alkoxy-2-aminothiophene-3-carbonitriles
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A facile one-pot method is reported for the synthesis of 4-alkoxy-2-aminothiophene-3-carbonitriles. Transesterification of trimethylorthoacetate technique allowed introducing alkoxy substituents into 2-aminothiophene ring system. Diverse alkoxy substituents could be introduced efficiently by using this methodology. Further the synthesis of some of new 4-alkylamino-2-aminothiophenes is also reported.
- Venkata Rao,Balakumar,Lakshmi Narayana,Pran Kishore,Rajwinder,Raghuram Rao
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supporting information
p. 1274 - 1278
(2013/03/13)
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- HETEROCYCLIC COMPOUNDS AND METHODS OF USE
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Formula I compounds, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological disorders, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 258-259
(2012/08/27)
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- SUBSTITUTED PYRAZOLES AS ESTROGEN RECEPTOR LIGANDS
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The invention provides a compound of formula (I) wherein G is a pyrazole ring as defined in the specification and R4, R5, R6 and R7 are as defined in the specification; or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt. The invention also provides the use of such compounds in the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.
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Paragraph 0140; 0141
(2013/03/26)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, Formula (1) wherein R1, R2, R3, X, Y, Z, A, B, G1, m, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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Page/Page column 83
(2012/08/07)
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- Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2] thiazolo[5,4- d ]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent
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Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)- N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl) -2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.
- Theoclitou, Maria-Elena,Aquila, Brian,Block, Michael H.,Brassil, Patrick J.,Castriotta, Lillian,Code, Erin,Collins, Michael P.,Davies, Audrey M.,Deegan, Tracy,Ezhuthachan, Jayachandran,Filla, Sandra,Freed, Ellen,Hu, Haiqing,Huszar, Dennis,Jayaraman, Muthusamy,Lawson, Deborah,Lewis, Paula M,Nadella, Murali V. P.,Oza, Vibha,Padmanilayam, Maniyan,Pontz, Timothy,Ronco, Lucienne,Russell, Daniel,Whitston, David,Zheng, Xiaolan
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supporting information; experimental part
p. 6734 - 6750
(2011/12/04)
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- SUBSTITUTED PYRAZOLES AS ESTROGEN RECEPTOR LIGANDS
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The invention provides a compound of formula (I) wherein G is a pyrazole ring as defined in the specification and R4, R5, R6 and R7 are as defined in the specification; or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt. The invention also provides the use of such compounds in the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.
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Page/Page column 31-32
(2011/04/26)
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- INDAZOLE COMPOUNDS USEFUL AS KETOHEXOKINASE INHIBITORS
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The present invention is directed to substituted indazole compounds, pharmaceutical compositions of these compounds and methods of use thereof. The compounds of the present invention are ketohexokinase (KHK) inhibitors, useful for treating or ameliorating a KHK mediated metabolic disorders and/or diseases such as obesity, Type II diabetes mellitus and Metabolic Syndrome X.
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Page/Page column 45
(2011/11/06)
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- INDOLE AND BENZOXAZINE DERIVATIVES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
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The present invention relates to novel indole and benzoxazine derivatives which are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 ("mGluR2") and which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.
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Page/Page column 28
(2010/06/17)
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- IMIDAZO[1,2-A]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
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The present invention relates to novel compounds, in particular novel imidazo[1,2-a]piridine derivatives according to Formula (I) wherein all radicals are as defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic receptors - subtype 2 ("mGluR2") which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.
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Page/Page column 46-47
(2009/06/27)
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- THIENOPYRIDINE DERIVATIVES
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The present invention provides a compound promoting osteogenesis. The present invention provides a compound having the following general formula (I) wherein R 1 is H or alkyl, R 2 is R a S-, R a O-, R a NH-, R a (R b )N- or cyclic amino, and R a and R b are alkyl which may be substituted, cycloalkyl which may be substituted, or the like, or a pharmacologically acceptable salt thereof.
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Page/Page column 113
(2010/11/26)
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- Synthesis of 1,4-dihydro-2-methyl-4-oxo-nicotinic acid: Ochiai's route failed
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The synthesis of 1,4-dihydro-2-methyl- and 1,4-dihydro-1,2-dimethyl-4-oxo-nicotinic acids was accomplished following a route other than Ochiai's procedure, which yielded the isomer 1,6-dihydro-2-methyl-6-oxo-nicotinic acid ethyl ester, and not the 4-oxo-derivative, as reported. Analytical data confirmed the identity of the two isomer oxo-nicotinic acids. UV-vis and potentiometric preliminary data showed that Al(III) does not form complexes with 1,6-dihydro-2-methyl-6-oxo-nicotinic acid ethyl ester in solution, as expected, but with 1,4-dihydro-2-methyl-4-oxo-nicotinic acid.
- Ferlin, Maria Grazia,Di Marco, Valerio B.,Dean, Annalisa
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p. 6222 - 6227
(2007/10/03)
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- Selected fused heterocyclics and uses thereof
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This invention relates to novel compounds having the structural formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment or prophylaxis of cancer.
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Page/Page column 13; 20
(2008/06/13)
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- Microwave-assisted synthesis of substituted pyrazoles and pyrazolo [3,4-d]thiopyrimidines
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Ethyl(ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile were synthesized from the reaction of malononitrile or ethylcyanoacetate with triethyl orthoformate or orthoacetate in N, N-dimethylacetamide under microwave irradiation. In a similar manner, substituted pyrazoles were synthesized from the reaction of ethyl (ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile with phenylhydrazine. These pyrazoles were converted to pyrazolo[3,4-d]thiopyrimidines upon treatment with arylisothiocyanate and thiourea under microwave irradiation. Copyright Taylor & Francis Group, LLC.
- Heravi, Majid M.,Nami, Navabeh,Seifi, Nasim,Oskooie, Hossein A.,Hekmatshoar, Rahim
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p. 591 - 599
(2007/10/03)
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- Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors
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Several different heterocyclic systems were compared as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5,1-f][1,2,4]triazin-4-ones and pyrazolopyrimidinones, isomeric imidazo[1,5-a][1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity. SAR trends were elucidated for sulfonamide derivatives with generality across different scaffolds.
- Haning, Helmut,Niewoehner, Ulrich,Schenke, Thomas,Lampe, Thomas,Hillisch, Alexander,Bischoff, Erwin
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p. 3900 - 3907
(2007/10/03)
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- PYRROLE AND PYRAZOLE DERIVATIVES AS POTENTIATORS OF GLUTAMATE RECEPTORS
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The present invention relates to pyrrole and pyrazole compounds of formula (I) and their pharmaceutically acceptable salts, and further relates to their use in treating schizophrenia, cognitive deficits associated with schizophrenia, Alzheimer's disease, dementia of the Alzheimer's type, mild cognitive impairment, or depression. The compounds act as potentiators on glutamate receptors, in particular AMPA and the GluR family.
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Page/Page column 80
(2008/06/13)
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- NOVEL FUSED HETEROCYCLES AND USES THEREOF
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This invention relates to novel compounds having the formula (I) (a chemical formula should be inserted here - please see paper copy enclosed herewith) m = 0, 1, 2 n = 0, 1 (I) wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in the specification and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment or prophylaxis of cancer.
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Page 32; 63; 65; 70; 74; 79
(2008/06/13)
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- Ink compositions
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An ink comprising water, a water-dissipatable polymer and one or more dyes of Formula (1): wherein:R1 is H or a substituent;R2 and R3 are each independently optionally substituted alkyl, aryl or aralkyl, or R2 andR3 together with the carbon atom to which they are attached form an optionally substituted ring;R4 is H or optionally substituted alkyl, aryl or aralkyl; andD is an optionally substituted arylene group. Also claimed are the dyes of Formula (1), ink jet printing processes and cartridges containing the inks.
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