RESUMO
A new tool, ML-J-DP4, provides an efficient and accurate method for determining the most likely structure of complex molecules within minutes using standard computational resources. The workflow involves combining fast Karplus-type J calculations with NMR chemical shifts predictions at the cheapest HF/STO-3G level enhanced using machine learning (ML), all embedded in the J-DP4 formalism. Our ML provides accurate predictions, which compare favorably alongside with other ML methods.
Assuntos
Imageamento por Ressonância Magnética , Teoria Quântica , Espectroscopia de Ressonância Magnética/métodos , Aprendizado de MáquinaRESUMO
A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.
Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Desenho de Fármacos , Glucose/análogos & derivados , Isoxazóis/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glucose/síntese química , Glucose/química , Glucose/farmacologia , Humanos , Isoxazóis/química , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
The design and synthesis of biomass-derived triazoles and the in vitro evaluation as potential anticancer agents are described. The discovery of base-catalyzed retro-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues.