5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases

Vymětalová, Ladislava; Havlı́cěk, Libor; Šturc, Antonín; Skrášková, Zuzana; Jorda, Radek; Pospíšil, Tomáš; Strnad, Miroslav; Kryštof, Vladimı́r

doi:10.1016/j.ejmech.2016.01.011

Cited by 33 publications

(45 citation statements)

References 34 publications

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“…Finally, the best RF model and its applicability domain were validated with a final prediction set consisting of 151 molecules not used for any task before, which were recently reported in the literature [ 50 , 51 , 52 ]. Only 50 molecules of this data set were in the applicability domain of the HCT116 model and were predicted with acceptable accuracy of R 2 = 0.544, RMSE = 1.024 and MAE = 0.879.…”

Section: Resultsmentioning

confidence: 99%

In Silico HCT116 Human Colon Cancer Cell-Based Models En Route to the Discovery of Lead-Like Anticancer Drugs

et al. 2018

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To discover new inhibitors against the human colon carcinoma HCT116 cell line, two quantitative structure–activity relationship (QSAR) studies using molecular and nuclear magnetic resonance (NMR) descriptors were developed through exploration of machine learning techniques and using the value of half maximal inhibitory concentration (IC50). In the first approach, A, regression models were developed using a total of 7339 molecules that were extracted from the ChEMBL and ZINC databases and recent literature. The performance of the regression models was successfully evaluated by internal and external validations, the best model achieved R2 of 0.75 and 0.73 and root mean square error (RMSE) of 0.66 and 0.69 for the training and test sets, respectively. With the inherent time-consuming efforts of working with natural products (NPs), we conceived a new NP drug hit discovery strategy that consists in frontloading samples with 1D NMR descriptors to predict compounds with anticancer activity prior to bioactivity screening for NPs discovery, approach B. The NMR QSAR classification models were built using 1D NMR data (1H and 13C) as descriptors, from 50 crude extracts, 55 fractions and five pure compounds obtained from actinobacteria isolated from marine sediments collected off the Madeira Archipelago. The overall predictability accuracies of the best model exceeded 63% for both training and test sets.

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Section: Resultsmentioning

confidence: 99%

In Silico HCT116 Human Colon Cancer Cell-Based Models En Route to the Discovery of Lead-Like Anticancer Drugs

et al. 2018

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“…Because we have identified CDK5 as an important regulator of both lymphangiogenesis and angiogenesis (Liebl et al , ; Liebl et al , ; Merk et al , ), we utilized a combination of in vitro parameters for phenotypic screening, which indicate the anti‐angiogenic potential of a CDK inhibitor: a reduction in endothelial cell proliferation and migration, and a prevalence for inhibiting CDK5 and CDK2 over other CDKs (Liebl et al , ; Weitensteiner et al , ). Following this workflow, we have screened a series of 16 recently prepared 5‐substituted 3‐isopropyl‐7‐[4‐(2‐pyridyl)benzyl]amino‐1(2)H‐pyrazolo[4,3‐ d ]pyrimidines (Vymetalova et al , ) and were able to select four promising candidates, with about a 1000‐fold increased potency in cellular assays, as compared with the standard compound roscovitine. Three of these compounds were relatively selective for CDK5 (Vymetalova et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…5‐Substituted 3‐isopropyl‐7‐[4‐(2‐pyridyl)benzyl]amino‐1(2)H‐pyrazolo[4,3‐ d ]pyrimidines (Figure ) were synthesized as described previously (Vymetalova et al , ). For better cross reference, the same numbering of compounds has been displayed in Figure as in the original article, in addition to an internal code (Laboratory of Growth Regulators (LGR) numbers).…”

Section: Methodsmentioning

confidence: 99%

“…In the present work, we have investigated the in vitro effects (on functional aspects of endothelial cells) and in vivo applicability of novel inhibitors, 5‐substituted 3‐isopropyl‐7‐[4‐(2‐pyridyl)benzyl]amino‐1(2)H‐pyrazolo[4,3‐ d ]pyrimidines) that have recently been shown to have an inhibitory preference for CDK5 (Vymetalova et al , ), in a murine model of HCC.…”

Section: Introductionmentioning

confidence: 99%

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Anti‐angiogenic effects of novel cyclin‐dependent kinase inhibitors with a pyrazolo[4,3‐d]pyrimidine scaffold

Ulrich

Gromnicka

et al. 2016

British J Pharmacology

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“…New kinase inhibitors are often developed by a multifaceted approach, including high‐throughput screening of compound libraries using biochemical/cellular assays or analogue synthesis. During our decade‐long research on kinase inhibitors, we have ascertained the importance of the heterocyclic core One less explored scaffold, imidazo[1,2‐ c ]pyrimidine, was previously investigated randomly for biological activities, such as antimicrobial, antimycobacterial, antitubercular, inotropic, antiinflammatory, analgesic, antipyretic, and ulcerogenic . Importantly, certain 5,7,8‐ and 2,5,8‐trisubstituted imidazo[1,2‐ c ]pyrimidine derivatives were described as potent Syk and Chk1 protein kinase inhibitors, respectively .…”

Section: Introductionmentioning

confidence: 99%

Imidazo[1,2‐c]pyrimidin‐5(6H)‐one as a novel core of cyclin‐dependent kinase 2 inhibitors: Synthesis, activity measurement, docking, and quantum mechanical scoring

Ajani

Jansa

Köprülüoğlu

et al. 2018

J of Molecular Recognition

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We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2-c]pyrimidin-5(6H)-one scaffold for cyclin-dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure-activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single-digit micromolar IC values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities. The binding modes of the compounds obtained using Glide docking have exhibited up to 2 hinge-region hydrogen bonds to CDK2 and differed in the orientation of the inhibitor core and the placement of the 8-substituents. Semiempirical quantum mechanics-based scoring identified probable favourable binding modes, which will serve for future structure-based design and synthetic optimization of substituents of the heterocyclic core. In summary, we have identified a novel core for CDK2 inhibition and will explore it further to increase the potencies of the compounds and also monitor selectivities against other protein kinases.

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5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases

Cited by 33 publications

References 34 publications

In Silico HCT116 Human Colon Cancer Cell-Based Models En Route to the Discovery of Lead-Like Anticancer Drugs

In Silico HCT116 Human Colon Cancer Cell-Based Models En Route to the Discovery of Lead-Like Anticancer Drugs

Anti‐angiogenic effects of novel cyclin‐dependent kinase inhibitors with a pyrazolo[4,3‐d]pyrimidine scaffold

Imidazo[1,2‐c]pyrimidin‐5(6H)‐one as a novel core of cyclin‐dependent kinase 2 inhibitors: Synthesis, activity measurement, docking, and quantum mechanical scoring

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