RESUMO
A series of N'(1),N'(3)-dialkyl-N'(1),N'(3)-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure-activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas , Hidrazinas/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Camundongos , Camundongos Nus , Modelos Moleculares , Conformação Molecular , Neoplasias Experimentais/patologia , Paclitaxel/química , Paclitaxel/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Seven naturally derived components from hop plant (Humulus lupulus L.) extracts were tested for evaluation of biological activities affecting acne vulgaris. Five strains, Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, Kocuria rhizophila and, Staphylococcus pyogenes, were selected as the main acne-causing bacteria. Hop extracts xanthohumol and the lupulones showed strong inhibitory activities against all of the strains. Although hydrogenated derivatives did not show the same level of activity, naturally occurring xanthohumol, humulones, and lupulones all showed moderate to strong anticollagenase inhibitory activities. Antioxidant capacity was also evaluated with seven different methods based on different reactive oxygen species. Xanthohumol showed the highest activity in total oxygen radical absorbance capacity as well as singlet oxygen absorbance capacity.
Assuntos
Acne Vulgar , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Humulus , Inibidores de Metaloproteinases de Matriz , Extratos Vegetais/farmacologia , Acne Vulgar/tratamento farmacológico , Actinobacteria/efeitos dos fármacos , Compostos de Bifenilo/efeitos adversos , Cicloexenos/farmacologia , Flavonoides , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Testes de Sensibilidade Microbiana , Fitoterapia , Picratos/efeitos adversos , Propionibacterium acnes/efeitos dos fármacos , Propiofenonas/farmacologia , Staphylococcus/efeitos dos fármacos , Terpenos/farmacologiaRESUMO
The interleukin-12 (IL-12) cytokine induces the differentiation of naive T cells to the T helper cell type 1 (Th1) phenotype and is integral to the pathogenesis of Th1-mediated immunologic disorders. A more recently discovered IL-12 family member, IL-23, shares the p40 protein subunit with IL-12 and plays a critical role in the generation of effector memory T cells and IL-17-producing T cells. We introduce a novel compound, STA-5326, that down-regulates both IL-12 p35 and IL-12/IL-23 p40 at the transcriptional level, and inhibits the production of both IL-12 and IL-23 cytokines. Oral administration of STA-5326 led to a suppression of the Th1 but not Th2 immune response in mice. In vivo studies using a CD4+CD45Rbhigh T-cell transfer severe combined immunodeficiency (SCID) mouse inflammatory bowel disease model demonstrated that oral administration of STA-5326 markedly reduced inflammatory histopathologic changes in the colon. A striking decrease in interferon-gamma (IFN-gamma) production was observed in ex vivo culture of lamina propria cells harvested from animals treated with STA-5326, indicating a down-regulation of the Th1 response by STA-5326. These results suggest that STA-5326 has potential for use in the treatment of Th1-related autoimmune or immunologic disorders. STA-5326 currently is being evaluated in phase 2 clinical trials in patients with Crohn disease and rheumatoid arthritis.