RESUMO
The asymmetric synthesis and biological activity of (2S,1'S,2'R,3'R)-2-(2'-carboxy-3'-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3' substituted carboxy cyclopropyl glycine is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.
Assuntos
Glicina/síntese química , Receptores de Glutamato Metabotrópico/agonistas , Administração Oral , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , AMP Cíclico/biossíntese , Medo , Glicina/análogos & derivados , Glicina/química , Glicina/farmacologia , Técnicas In Vitro , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
[reaction: see text] A synthesis of cryptophycin 52 is reported using a Shi epoxidation strategy to install the epoxide moiety in a diastereoselective fashion. Several epoxidation results for cryptophycin substrates are disclosed followed by a discussion of the details relating to the preparation of cryptophycin 52 in two synthetic steps from one of the intermediate epoxides.
Assuntos
Antibióticos Antineoplásicos/síntese química , Cianobactérias/química , Depsipeptídeos , Lactamas/síntese química , Lactonas/síntese química , Antineoplásicos Fitogênicos/farmacologia , Cromatografia Líquida de Alta Pressão , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi/síntese química , Paclitaxel/farmacologiaRESUMO
The synthesis of unit A of the cryptophycins from (S)-trans-3-penten-2-ol and from (S)-trans-4-hexen-3-ol has been completed. The key stereodetermining step is a [2,3]-Wittig rearrangement of a propargyl ether. Elaboration of the rearrangement product was accomplished by means of a selective hydroboration-oxidation of a terminal alkyne, Horner-Emmons homologation of the derived aldehyde, followed by selective ozonolytic cleavage and Wittig olefination. This synthesis provides easy access to the series of cryptophycin analogues that incorporate a modified aromatic ring in unit A.