Design and Synthesis of New CDK2 Inhibitors Containing Thiazolone and Thiazolthione Scafold with Apoptotic Activity

El‐Sattar, Nour E. A. Abd; Badawy, Eman H. K.; AbdEl-Hady, Wafaa H.; Abo-Alkasem, Mohamed I.; Mandour, Asmaa A.; Ismail, Nasser S. M.

doi:10.1248/cpb.c20-00714

Cited by 28 publications

(19 citation statements)

References 29 publications

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“…p -value (the p -value for significance of regression). The external validation was carried out utilizing compound 8 and two reported compounds V , VI with similar scaffold ( Figure 15 ) [ 6 , 48 ]. The estimated activity for the external test set was very close to its observed activity ( Table 5 ), that is, support the established QSAR model in the present work.…”

Section: Resultsmentioning

confidence: 99%

“…CDK2 has an important catalytic role in the complex of cyclin-dependent protein kinase; its activity is essential for cell cycle progress [ 5 ]. The cyclin protein family modulates CDK activities throughout the cell cycle where specific activating phosphorylation for CDK apoenzymes is required through CDK-activating kinase, which is a CDK complex, and also, complex formation with cyclins is needed for optimum kinase activity [ 5 , 6 ]. CDK2 is associated mainly with the regulatory subunits including either cyclin A or E with overexpression in human cancer as in ovarian, breast, endometrial, lung and thyroid carcinomas, osteosarcoma, and melanoma [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…CDK2 is associated mainly with the regulatory subunits including either cyclin A or E with overexpression in human cancer as in ovarian, breast, endometrial, lung and thyroid carcinomas, osteosarcoma, and melanoma [ 7 ]. The activation of the CDK2 through cyclin A is claimed to be an essential step through the progression from the S phase, and this makes CDK2 the principal target for most inhibitory drugs [ 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

et al. 2021

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New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-−C2 functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C2-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC50 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC50 ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC50 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

et al. 2021

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“…The in vitro cytotoxic activities of the synthesized compounds were estimated using MTT method. 29–32 The test used human cancer cell lines including colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7). Anti-proliferative activity was represented in IC 50 values ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, docking study and anticancer evaluation of new trimethoxyphenyl pyridine derivatives as tubulin inhibitors and apoptosis inducers

et al. 2021

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“…Cell-dependent kinase (CDK) is involved in many tumors related biological processes, such as cell cycle, immune checkpoint ( Hume et al, 2020 ), RNA transcription ( Al-Sanea et al, 2021 ), cell proliferation ( Liu J. et al, 2021 ). Recently, there have been studies on CDK4 ( Pandey et al, 2021 ) and CDK6 ( Pandey et al, 2021 ), but the mechanism of CDK2 ( El-Sattar et al, 2021 ) in cancer is relatively lacking. In our study, we deeply studied CDK2 and constructed the related immune prediction model.…”

Section: Discussionmentioning

confidence: 99%

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

Liu

Chen

et al. 2021

Front. Cell Dev. Biol.

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BackgroundTumor microenvironment (TME) plays important roles in different cancers. Our study aimed to identify molecules with significant prognostic values and construct a relevant Nomogram, immune model, competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD).Methods“GEO2R,” “limma” R packages were used to identify all differentially expressed mRNAs from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Genes with P-value <0.01, LogFC>2 or <-2 were included for further analyses. The function analysis of 250 overlapping mRNAs was shown by DAVID and Metascape software. By UALCAN, Oncomine and R packages, we explored the expression levels, survival analyses of CDK2 in 33 cancers. “Survival,” “survminer,” “rms” R packages were used to construct a Nomogram model of age, gender, stage, T, M, N. Univariate and multivariate Cox regression were used to establish prognosis-related immune forecast model in LUAD. CeRNA network was constructed by various online databases. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to explore correlations between CDK2 expression and IC50 of anti-tumor drugs.ResultsA total of 250 differentially expressed genes (DEGs) were identified to participate in many cancer-related pathways, such as activation of immune response, cell adhesion, migration, P13K-AKT signaling pathway. The target molecule CDK2 had prognostic value for the survival of patients in LUAD (P = 5.8e-15). Through Oncomine, TIMER, UALCAN, PrognoScan databases, the expression level of CDK2 in LUAD was higher than normal tissues. Pan-cancer analysis revealed that the expression, stage and survival of CDK2 in 33 cancers, which were statistically significant. Through TISIDB database, we selected 13 immunodepressants, 21 immunostimulants associated with CDK2 and explored 48 genes related to these 34 immunomodulators in cBioProtal database (P < 0.05). Gene Set Enrichment Analysis (GSEA) and Metascape indicated that 49 mRNAs were involved in PUJANA ATM PCC NETWORK (ES = 0.557, P = 0, FDR = 0), SIGNAL TRANSDUCTION (ES = –0.459, P = 0, FDR = 0), immune system process, cell proliferation. Forest map and Nomogram model showed the prognosis of patients with LUAD (Log-Rank = 1.399e-08, Concordance Index = 0.7). Cox regression showed that four mRNAs (SIT1, SNAI3, ASB2, and CDK2) were used to construct the forecast model to predict the prognosis of patients (P < 0.05). LUAD patients were divided into two different risk groups (low and high) had a statistical significance (P = 6.223e-04). By “survival ROC” R package, the total risk score of this prognostic model was AUC = 0.729 (SIT1 = 0.484, SNAI3 = 0.485, ASB2 = 0.267, CDK2 = 0.579). CytoHubba selected ceRNA mechanism medicated by potential biomarkers, 6 lncRNAs-7miRNAs-CDK2. The expression of CDK2 was associated with IC50 of 89 antitumor drugs, and we showed the top 20 drugs with P < 0.05.ConclusionIn conclusion, our study identified CDK2 related immune forecast model, Nomogram model, forest map, ceRNA network, IC50 of anti-tumor drugs, to predict the prognosis and guide targeted therapy for LUAD patients.

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Design and Synthesis of New CDK2 Inhibitors Containing Thiazolone and Thiazolthione Scafold with Apoptotic Activity

Cited by 28 publications

References 29 publications

Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

Design, synthesis, docking study and anticancer evaluation of new trimethoxyphenyl pyridine derivatives as tubulin inhibitors and apoptosis inducers

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

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