RESUMO
Extensive investigations on the influence of diastereomeric ratios of deoxyribonucleoside phosphoramidites on stereo-reproducibility of solid phase synthesis of phosphorothioate oligodeoxyribonucleotides via the phosphoramidite approach indicate that the process is stereoreproducible and under inherent process control.
Assuntos
Oligonucleotídeos Antissenso/química , Tionucleotídeos/química , Tionucleotídeos/síntese química , Cromatografia Líquida de Alta Pressão , EstereoisomerismoRESUMO
Oligodeoxyribonucleotide phosphorothioates undergo desulfurization in presence of metal in aqueous ammonia at elevated temperatures. The extent of sulfur loss and chain cleavage have been investigated.
Assuntos
Amônia , Oligodesoxirribonucleotídeos/química , Aço Inoxidável , Tionucleotídeos/química , Sequência de Bases , Estabilidade de Medicamentos , Vidro , Ressonância Magnética Nuclear Biomolecular , ÁguaRESUMO
Taxol (1) is a highly potent antitumor agent, exerting its mechanism of action by promoting the assembly of stable microtubules in cells. We are reporting on the first synthesis and biological evaluation of taxol derivatives with substituted phenyl rings at the C-13 N-benzoyl-(2'R,3'S)-3'-phenylisoserine side chain of taxol (1). Two taxol derivatives were synthesized, one possessing a N-(p-chlorobenzoyl)-(2'R,3'S)-3'-phenylisoserine side chain (2) and the other one a N-benzoyl-(2'R,3'S)-3'-(p-chlorophenyl)isoserine side chain (3). The synthesis of the novel phenylisoserine side chains was achieved through the asymmetric synthesis of 3-hydroxy-4-aryl-2-azetidinone derivatives via the ester enolate-imine cyclocondensation reaction. The 2-azetidinones 14 and 15 were acylated with p-chlorobenzoyl chloride and benzoyl chloride, respectively, to form the N-acyl beta-lactams 16 and 17. Subsequent coupling of 16 and 17 to 7-(triethylsilyl)baccatin III (6) in the presence of pyridine and DMAP afforded, after removal of the protecting groups, the desired taxol analogues 2 and 3 in excellent yields. The newly synthesized derivatives 2 and 3 were tested in the tubulin assembly assay and also evaluated for their cytotoxicity against B16 melanoma cells. It was found that the taxol derivatives 2 and 3 had activity comparable to taxol (1).
