Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and Kinase Inhibitory Potencies of Pyrazolo[3,4-g]isoquinolines.

ABSTRACT: A new series of pyrazolo[3,4-g]isoquinoline derivatives, diversely substituted at the 4- or 8-position, were synthesized. The results of the kinase inhibitory potency study demonstrated that the introduction of a bromine atom at the 8-position was detrimental to Haspin inhibition, while the introduction of an alkyl group at the 4-position led to a modification of the kinase inhibition profiles. Altogether, the results obtained demonstrated that new pyrazolo[3,4-g]isoquinolines represent a novel family of kinase inhibitors with various selectivity profiles.

SUBMITTER: Defois M

PROVIDER: S-EPMC9457941 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and Kinase Inhibitory Potencies of Pyrazolo[3,4-g]isoquinolines.

Defois Mathilde M Rémondin Chloé C Josselin Béatrice B Nauton Lionel L Théry Vincent V Anizon Fabrice F Ruchaud Sandrine S Giraud Francis F Moreau Pascale P

Molecules (Basel, Switzerland) 20220830 17

A new series of pyrazolo[3,4-g]isoquinoline derivatives, diversely substituted at the 4- or 8-position, were synthesized. The results of the kinase inhibitory potency study demonstrated that the introduction of a bromine atom at the 8-position was detrimental to Haspin inhibition, while the introduction of an alkyl group at the 4-position led to a modification of the kinase inhibition profiles. Altogether, the results obtained demonstrated that new pyrazolo[3,4-g]isoquinolines repr ...[more]

PMID: 36080340

Similar Datasets

Synthesis and Antibacterial Evaluation of New Pyrazolo[3,4-d]pyrimidines Kinase Inhibitors.

Project description:Pyrazolo[3,4-d]pyrimidines represent an important class of heterocyclic compounds well-known for their anticancer activity exerted by the inhibition of eukaryotic protein kinases. Recently, pyrazolo[3,4-d]pyrimidines have become increasingly attractive for their potential antimicrobial properties. Here, we explored the activity of a library of in-house pyrazolo[3,4-d]pyrimidines, targeting human protein kinases, against Staphylococcus aureus and Escherichia coli and their interaction with ampicillin and kanamycin, representing important classes of clinically used antibiotics. Our results represent a first step towards the potential application of dual active pyrazolo[3,4-d]pyrimidine kinase inhibitors in the prevention and treatment of bacterial infections in cancer patients.

| S-EPMC7696985 | biostudies-literature

First synthesis of thiazepino[3,4-a]isoquinolines, a facile new synthetic route to diazepino[3,4-a]isoquinolines and assessment of their dopamine and σ receptor affinities.

Project description:Heterocycles that bear the novel 5,6,14,14a-tetrahydro-8H-benzo[6,7][1,4] thiazepino[3,4-a]isoquinoline and the 5,6,14,14a-tetrahydro-8H-13l2-benzo [6,7][1,4]diazepino[3,4-a]isoquinoline frameworks were synthesized in a facile manner. These tetrahydroprotoberberine (THPB)-inspired scaffolds demonstrate selective affinity for the σ1R in contrast to the naturally occurring THPB congeners that show D1R and σ2R selectivity.

| S-EPMC8460126 | biostudies-literature

Synthesis and Characterization of Novel Functionally Substituted Planar Pyrimidothienoisoquinolines and Nonplanar (3aR, 4S, 9aS)-pyrazolo[3,4-g]isoquinolines.

Project description:7-Acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-5,6,7,8-tetrahydroisoquinolin-3(2H)-thiones 2a,b are prepared and dehydrated to give 7-acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-7,8-dihydrodroisoquinolin-3(2H)-thiones 6a,b via a novel method by heating with acetyl chloride in acetic acid. The reaction of both compounds 2a,b and 6a,b with N-aryl-2-chloroacetamides 7a-c under two different conditions gave the same corresponding products, 7-acetyl-8-aryl-3-(N-aryl)carbamoylmethylsulfanyl-4-cyano-1,6-dimethyl-7,8-dihydroisoquinolines 8a-e, in high yields. On treatment of compounds 8a,b,e in methanol with a slightly excess molar amount of sodium methoxide, they underwent intramolecular Thorpe-Ziegler cyclization followed by spontaneous aromatization, providing the planar 7-acetyl-1-amino-6-aryl-2-(N-aryl)carbamoyl-5,8-dimethyl-8,9-dihydrothieno[2,3-c] isoquinolines 9a,b,e in good yield. Cyclocondensation reactions of 6a,b with phenyl hydrazine, thiosemicarbazide, or hydrazine hydrate led to the formation of nonplanar (3aR, 4S, 9aS)-pyrazolo[3,4-g]isoquinolines 11a, 11b, and 13, respectively. The reaction of compound 13 with 2-chloromethylquinazolin-4(3H)-one in the presence of anhydrous sodium acetate gave the expected thienopyrazoloisoquinolone 14. Heating the latter compound (14) with triethyl orthoformate in glacial acetic acid afforded the fused heptacyclic compound 15. All of the synthesized compounds were characterized based on their full spectral analyses such as IR, 1H nuclear magnetic resonance (NMR), and mass spectrometry (MS). Moreover, the crystal structure of compound 6a was elucidated by X-ray diffraction analysis.

| S-EPMC8015098 | biostudies-literature

Facile Synthesis of Tricyclic 1,2,4-Oxadiazolines-Fused Tetrahydro-Isoquinolines from Oxime Chlorides with 3,4-Dihydroisoquinoline Imines.

Project description:A mild and efficient strategy for the synthesis of tricyclic 1,2,4-oxadiazolines-fused tetrahydro-isoquinolines derivatives via [3 + 2] cycloaddition reaction is reported. The reactions provided the functionalized tricyclic 1,2,4-oxadiazolines in high yields (up to 96%). This protocol is simple and easy to handle. Moreover, a gram-scale experiment further highlights the synthetic utility. The chemical structure of the product was determined by X-ray single-crystal structure analysis. A possible mechanism for this transformation is proposed to explain the reaction process.

| S-EPMC9145198 | biostudies-literature

Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors

Project description:Drug resistance presents a major obstacle to the successful treatment of glioblastoma. Autophagy plays a key role in drug resistance, particularly in relation to targeted therapy, which has prompted the use of autophagy inhibitors to increase the effectiveness of targeted therapeutics. The ability of two Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306, to induce autophagy was evaluated in the human glioblastoma cell line U87 and its multidrug-resistant counterpart U87-TxR. Autophagy markers were assessed by flow cytometry, microscopy, and Western blot, and induction of autophagy by these compounds was demonstrated after 3 h as well as 48 h. The effects of Si306 and pro-Si306 on cell proliferation and cell death were examined in the presence or absence of autophagy inhibition by bafilomycin A1. Combined treatments of Si306 and pro-Si306 with bafilomycin A1 were synergistic in nature, and the inhibition of autophagy sensitized glioblastoma cells to Src tyrosine kinase inhibitors. Si306 and pro-Si306 more strongly inhibited cell proliferation and triggered necrosis in combination with bafilomycin A1. Our findings suggest that modulation of Si306- and pro-Si306-induced autophagy can be used to enhance the anticancer effects of these Src tyrosine kinase inhibitors and overcome the drug-resistant phenotype in glioblastoma cells.

| S-EPMC9605466 | biostudies-literature

One-Flask Synthesis of Pyrazolo[3,4-d]pyrimidines from 5-Aminopyrazoles and Mechanistic Study.

Project description:A novel one-flask synthetic method was developed in which 5-aminopyrazoles were reacted with N,N-substituted amides in the presence of PBr₃. Hexamethyldisilazane was then added to perform heterocyclization to produce the corresponding pyrazolo[3,4-d]pyrimidines in suitable yields. These one-flask reactions thus involved Vilsmeier amidination, imination reactions, and the sequential intermolecular heterocyclization. To study the reaction mechanism, a series of 4-formyl-1,3-diphenyl-1H-pyrazol-5-yl-N,N-disubstituted formamidines, which were conceived as the chemical equivalent of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl-formamidine, were prepared and successfully converted into pyrazolo[3,4-d]pyrimidines. The experiments demonstrated that the reaction intermediates were the chemical equivalents of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl)formamidines. The rate of the reaction could be described as being proportional to the reactivity of amine reactants during intermolecular heterocyclization, especially when hexamethyldisilazane was used.

| S-EPMC6154590 | biostudies-literature

3-Iodo-1H-pyrazolo-[3,4-b]pyridine.

Project description:The title compound, C6H4IN3, is essentially planar, with a dihedral angle of 0.82 (3)° between the planes of the pyridine and pyrazole rings. In the crystal, pairs of mol-ecules are connected into inversion dimers through N-H⋯N hydrogen bonds. C-I⋯N halogen bonds link the dimers into zigzag chains parallel to the b-axis direction. The packing also features π-π stacking inter-actions along (110) with inter-planar distances of 3.292 (1) and 3.343 (1) Å, and centroid-centroid distances of 3.308 (1) and 3.430 (1) Å.

| S-EPMC4051060 | biostudies-literature

Catalytic synthesis of new pyrazolo [3,4-b] pyridine via a cooperative vinylogous anomeric-based oxidation.

Project description:In this study, a novel nano-magnetic metal-organic frameworks based on Fe3O4 namely Fe3O4@MIL-101(Cr)-N(CH2PO3)2 was synthesized and fully characterized. The prepared sample was used as catalyst in the synthesis of pyrazolo [3,4-b] pyridines as convenient medicine by condensation reaction of aldehydes, 5-(1H-Indol-3-yl)- 2H-pyrazol-3-ylamine and 3-(cyanoacetyl)indole via a CVABO. The products were obtained with high yields at 100 °C and under solvent-free conditions.

| S-EPMC9391453 | biostudies-literature

A convenient four-component one-pot strategy toward the synthesis of pyrazolo[3,4-d]pyrimidines.

Project description:An efficient one-pot synthesis of pyrazolo[3,4-d]pyrimidine derivatives by the four-component condensation of hydrazines, methylenemalononitriles, aldehydes and alcohols has been developed via two different reaction pathways. The structures of target products were characterized by IR spectroscopy, NMR ((1)H and (13)C) spectroscopy and HRMS (ESI) spectrometry. The crystal structure of 4-ethoxy-6-(2-nitrophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine was determined by single crystal X-ray diffraction.

| S-EPMC4660965 | biostudies-literature

Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors.

Project description:Fibroblast growth factor receptors (FGFRs) are important targets for cancer therapy. Herein, we describe the design, synthesis, and biological evaluation of a novel series of 1H-pyrazolo[3,4-b]pyridine derivatives as potent and selective FGFR kinase inhibitors. On the basis of its excellent in vitro potency and favorable pharmacokinetic properties, compound 7n was selected for in vivo evaluation and showed significant antitumor activity in a FGFR1-driven H1581 xenograft model. These results indicated that 7n would be a promising candidate for further drug development.

| S-EPMC4904267 | biostudies-literature