RESUMO
Since the discovery of Warfarin in the 1940s, the design of new warfarin-derived anticoagulants for rodent management has been challenging, with mainly structural modifications performed on the C3 position of the coumarin skeleton. In order to better understand the pharmacomodulation of such derivatives, we have synthesized a family of C3 (linear and branched) alkyl-4-hydroxycoumarins, which led to the identification of compounds 5e and 5f as potential short-term active anticoagulants.
Assuntos
4-Hidroxicumarinas/farmacologia , Anticoagulantes/farmacologia , Vitamina K Epóxido Redutases/antagonistas & inibidores , Vitamina K/antagonistas & inibidores , 4-Hidroxicumarinas/administração & dosagem , 4-Hidroxicumarinas/síntese química , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/síntese química , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Fitol/administração & dosagem , Fitol/análogos & derivados , Fitol/síntese química , Fitol/farmacologia , Tempo de Protrombina , Ratos Sprague-DawleyRESUMO
Phytol, a diterpene alcohol was modified to several semisynthetic analogues. Some of the modifications were done logically to enhance lipophilicity of the molecule. Analogues 14, 16 and 18 exhibited antitubercular activity (MIC 15.6-50microg/mL) better than phytol (100microg/mL). The most potent analogue 18 was evaluated for in vivo toxicity in Swiss albino mice and was well tolerated by the experimental animals up to 300mg/kg body weight as a single oral acute dose.
Assuntos
Antituberculosos/síntese química , Oximas/síntese química , Fitol/análogos & derivados , Animais , Antituberculosos/química , Antituberculosos/toxicidade , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/química , Oximas/toxicidade , Fitol/síntese química , Fitol/química , Fitol/toxicidadeRESUMO
[reaction: see text]. A convenient and asymmetric protocol for the synthesis of chiral oligoisoprenoids is described. Typically, a C14 vitamin E side chain 5 was synthesized in 47% yield over four steps. Isomeric purity of 5 was upgraded to >99% R at C-2 and 97% R at C-6 by the statistical formation of stereoisomeric p-phenylenebisurethanes and their diastereomeric separation. In addition, phytol and vitamin K were synthesized in 21% and 28% overall yields, respectively, over five steps from 1.
Assuntos
Fitol/síntese química , Vitamina E/síntese química , Vitamina K/síntese química , Alcenos/química , Alquilação , Alumínio/química , Produtos Biológicos/síntese química , Catálise , Compostos Organometálicos/química , Estereoisomerismo , Zircônio/químicaRESUMO
The exposure of human lymphoid leukemia Molt 4B cells to diol- and triol-types of phytol which were synthesized and identified by Mass, and 1H- and 13C-NMR, led to both growth inhibition and induction of programmed cell death (apoptosis). Morphological changes showing apoptotic bodies were observed in the Molt 4B cells treated with diol- and triol-types of phytol. The fragmentations of DNA by the diol- and triol-types of phytol to oligonucleosomal-sized fragments, that is a characteristic of apoptosis, were observed to be both concentration- and time-dependent. These findings suggest that growth inhibition of Molt 4B cells by the diol- and triol-types of phytol results from the induction of apoptosis in the leukemic cells.