Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis

Michailidou, Maria; Giannouli, Vassiliki; Kotsikoris, Vasilios; Papadodima, Olga; Kontogianni, Georgia; Kostakis, Ioannis K.; Lougiakis, Nikolaos; Chatziioannou, Aristotelis; Kolisis, Fragiskos N.; Marakos, Panagiotis; Pouli, Nicole; Loutrari, Heleni

doi:10.1016/j.ejmech.2016.05.035

Cited by 30 publications

(23 citation statements)

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“…Indeed, in 1 the p K a values of the two 4-piperazinyl nitrogens are 7.44 (R1 substituent) and 8.12 (R2 substituent), whereas in 2 the corresponding numbers are 8.84 (R1 substituent, now a secondary amine) and 7.91 (R2 substituent, a tertiary amine). It is also worth noting that the previously described biological activity of a series of pyrazolo[3,4-c]pyridines including 1 and 2 as promising angiogenesis inhibitors was not correlated in terms of structure-activity relationships (SAR) with the CBS-inhibitory potential presented herein [ 52 ]. Indeed, the most potent CBS inhibitor 1 was shown to inhibit angiogenesis weakly, whereas 2 characterized by the presence of a 3-phenyl group was a very potent inhibitor of angiogenesis but a marginal inhibitor of CBS.…”

Section: Resultsmentioning

confidence: 90%

“…However, among the assayed molecules, the pyrazolopyridine derivative 1 was shown to be the most efficacious inhibitor. This specific molecule was previously synthesized in our lab as a potential inhibitor of angiogenesis [ 52 ]. In this molecule, the central pyrazolo[3,4-c]pyridine core is substituted by three functional groups which are present in many bioactive analogues, namely a n 1 -4-methoxybenzyl group attached to the pyrazole ring together with a 4-methylpiperazin-1-yl group and a 4-(4-methyl-piperazin-1-yl)phenylamino group connected to the nucleus ( Figure 2 B).…”

Section: Resultsmentioning

confidence: 99%

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Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

et al. 2020

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Cystathionine β-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CBS a promising drug target. An in-house focused library of heteroaromatic compounds was screened for CBS modulators by the methylene blue assay and a pyrazolopyridine derivative with a promising CBS inhibitory potential was discovered. The compound activity was readily comparable to the most potent CBS inhibitor currently known, aminoacetic acid, while a promising specificity over the related cystathionine γ-lyase was identified. To rule out any possibility that the inhibitor may bind the enzyme regulatory domain due to its high structural similarity with cofactor s-adenosylmethionine, differential scanning fluorimetry was employed. A sub-scaffold search guided follow-up screening of related compounds, providing preliminary structure-activity relationships with respect to requisites for efficient CBS inhibition by this group of heterocycles. Subsequently, a hypothesis regarding the exact binding mode of the inhibitor was devised on the basis of the available structure-activity relationships (SAR) and a deep neural networks analysis and further supported by induced-fit docking calculations.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

et al. 2020

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“…17,19) The heterocyclic compound 6 was then nitrated and the resulting 3-nitroderivative 7 was treated with methyl iodide, or 4-methoxybenzyl chloride in the presence of potassium carbonate, to provide both regio-isomers 8a, b and 9a, b, respectively, which were chromatographically separated and identified by means of two-dimensional (2D)-NMR experiments. More specifically, in the corresponding nuclear Overhauser effect (NOE) spectra we observed clear cross-peak correlation between the N1 methyl group of 8a, or the N1 methylene group of 8b with H-7, verifying unambiguously the N1 substitution.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Docking Study and Kinase Inhibitory Activity of a Number of New Substituted Pyrazolo[3,4-<i>c</i>]pyridines

et al. 2017

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A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against glycogen synthase kinase 3 (GSK3)α/β as well as against cdc2-like kinases 1 (CLK1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), with good selectivity and remarkable structure-activity relationships (SARs), without being cytotoxic. Molecular simulations in correlation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent.Key words pyrazolopyridine; kinase inhibition; glycogen synthase kinase 3 (GSK3)α/β; purine analogue; molecular simulation Neurodegenerative diseases are among the most challenging diseases with poorly known mechanism and lack of complete cure. Alzheimer's disease (AD) in particular, is the most prevalent cause of dementia, very devastating for the patients and their families, provided that current treatments offer only modest symptomatic relief. This severe mental disorder is mostly aging-associated and represents a global health problem, since it currently affects more than 30 million people worldwide, and its incidence is predicted to rise significantly, due to the increasing average life span. 1) In an effort to explain the pathogenesis of AD, many hypotheses have been explored, among them neurotransmitter modulation, chronic inflammation, metal-induced oxidative stress, elevated cholesterol, and glycogen synthase kinase 3 (GSK-3) implication are of major importance.2) GSK-3 is a ubiquitous serine/threonine kinase, which was first described as the major regulator of glycogen metabolism. It was revealed that GSK-3 plays central roles in important cell signaling pathways, and its malfunction is associated with neurodegeneration and the pathogenesis of several diseases, including diabetes type II, immune and bipolar disorders, chronic inflammation, heart failure and cancer.3) In AD, GSK-3 promotes neuronal death and is a linker between the two histopathological hallmarks: the deposition of extracellular senile plaques composed of amyloid-beta (Aβ) peptide, and the accumulation of hyperphosphorylated microtubule-binding tau protein, leading to tau aggregation and the formation of intracellular neurofibrillary tangles. 4)On the other hand, substantial evidence exists to support the involvement of additional phylogenetically and physiologically relevant protein kinases in neurodegenerative disorders, and, most notably, cyclin dependent kinase 5 (CDK5), 5) dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK 1A), 6) casein kinase 1 (CK1) 7) and cdc2-like kinases CLK1 and CLK2 8) are also investigated as potential targets for the development of novel AD therapeutics. Consequently, the exploitation of small molecule inhibitors for potential inhibitory activity against a set of the above mentioned protein kinases could offer interesting information and assist in the understanding of AD and related tau...

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“…As a continuation of our ongoing program toward the development of multicomponent synthetic methods, 7–10 herein, we introduce an efficient route to the synthesis of several novel spiro[chromeno[4,3- b ]pyrazolo[4,3- e ]pyridine-7,3ʹ-indoline]s. The products consist of an oxindole moiety spiro-fused to a 1,4-dihydropyridine core, which itself is fused on two sides with 1 H -pyrazole and coumarin ring systems. Pyrazolopyridine is a privileged heterocyclic core existing in many synthetic compounds exhibiting inhibition of enterovirus replication 11 and angiogenesis, 12 and shows potential for the treatment of autoimmune diseases and leukocyte malignancies via PI3K inhibition. 13 Pyrazolopyridine-based compounds have also shown antileishmanial, 14 antimicrobial, antiquorum-sensing, and antitumor activities.…”

Section: Introductionmentioning

confidence: 99%

A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

Najafizadeh

Rad‐Moghadam

Kalurazi

2020

Journal of Chemical Research

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The synthesis of spiro[chromeno[4,3- b]pyrazolo[4,3- e]pyridine-7,3ʹ-indoline]s is achieved via three-component reactions of 5-amino-3-methylpyrazole, 4-aminocoumarin, and isatin derivatives. This protocol provides expedient synthesis of 10-unsubstituted derivatives of the parent heterocyclic spiro framework and does not lead to coumarin ring opening. The synthesis is highly convergent as no by-products are present in the reaction mixtures. The spiro products show violet fluorescence emissions depending on the nature of their substituents.

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Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis

Cited by 30 publications

References 51 publications

Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

Synthesis, Docking Study and Kinase Inhibitory Activity of a Number of New Substituted Pyrazolo[3,4-<i>c</i>]pyridines

A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

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