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Bioorg Chem ; 92: 103239, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513938


Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo[1,5-a][1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC50 of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug.

Future Med Chem ; 10(24): 2815-2833, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30526043


AIM: Colon cancer is the third leading cause of death worldwide; therefore, there is a need for an effective therapy with lower side effects. METHODS: A series of 8-alkyl-2,4-bisbenzylidene-3-nortropinones 3 & 14-39 was prepared via Claisen-Schmidt condensation of 8-alkyl-3-nortropinones 11-13 with different aromatic aldehydes. The target compounds were screened for their antiproliferative activity. RESULTS: Most of the prepared compounds showed promising antiproliferative activity against many of 60 National Cancer Institute cell lines at 10 µM. Furthermore, 8-ethyl-2,4-bis(3,4-dimethoxybenzylidene)-8-nortropin-3-one 29 and its 3,4,5-trimethoxy analog 30 were the most active compounds against HCT116 cell line with IC50 values 0.01 and 0.46 µM, respectively. Using CODESSA-Pro software, a significant 2D-quantitative structure-activity relationship (QSAR) model was obtained. CONCLUSION: The 8-Alkyl-2,4-bisbenzylidene-8-azabicyclo[3.2.1]octan-3-one represents an interesting core for further structural optimization to obtain more promising hits.

Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Proliferação de Células/efeitos dos fármacos , Alquilação , Antineoplásicos/síntese química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Compostos de Benzilideno/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Relação Quantitativa Estrutura-Atividade
Eur J Med Chem ; 134: 304-315, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28427017


Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 µM) than that of the reference drug (doxorubicin, IC50 = 9.8 µM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 µM and 6.7 µM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10-4 folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.

Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Fenotiazinas/química , Fenotiazinas/farmacologia , Apoptose/efeitos dos fármacos , Aromatase/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia