RESUMO
A novel coumarin-based highly water-soluble photocleavable protective group was designed and synthesized, and then this photosensitive protecting group was used to design paclitaxel prodrugs. These novel paclitaxel conjugates demonstrated excellent water solubility, over 100mgmL(-1). Thus, the use of a detergent in the formulation can be omitted completely, even at high doses. Phototaxel 11 released the parent drug, paclitaxel, quickly and efficiently by minimal tissue-damaging 365nm UV light irradiation at low power, while laser activation at 355nm led to extensive decomposition of the prodrug. The carbamate-type prodrug, phototaxel 11, was stable in the dark prior to activation, whereas carbonate-type phototaxel 9 demonstrated poor stability under aqueous conditions. For such prodrugs, tumor-tissue targeting after administration could be achieved by selective light delivery, similar to that used in photodynamic therapy. In addition, newly designed coumarin derivative 8 can be applied in organic chemistry as a photosensitive protective group and for the design of caged compounds.
Assuntos
Cumarínicos/síntese química , Desenho de Fármacos , Paclitaxel/síntese química , Fármacos Fotossensibilizantes/síntese química , Pró-Fármacos/síntese química , Cromatografia Líquida de Alta Pressão , Cumarínicos/química , Cumarínicos/efeitos da radiação , Lasers , Conformação Molecular , Paclitaxel/química , Paclitaxel/efeitos da radiação , Fotoquímica , Fotólise , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Pró-Fármacos/química , Pró-Fármacos/efeitos da radiação , Solubilidade , Estereoisomerismo , Raios Ultravioleta , Água/químicaRESUMO
Since numerous new taxoids active against multidrug resistant (MDR) tumors have been developed and their poor water-solubility is a very real problem in intravenous administration, we have designed and synthesized a series of novel water-soluble taxoid prodrugs (isotaxoids). These prodrugs, a 2'-O-isoform of taxoids, showed promising results with higher water solubility (0.8-1.1 mg/mL) and proper kinetics for parent drug release by a simple pH-dependent chemical mechanism via O-N intramolecular acyl migration. No additional functional auxiliaries are released during the conversion to parent drugs, which would be an advantage in toxicology and general pharmacology, and the cost for the evaluations of auxiliary units in these fields could be saved in prodrug development. In addition, we demonstrate for the first time the successful application of the O-N intramolecular acyloxy migration reaction in the prodrug design, with the exception of the tert-butyloxycarbonyl group, and that this reaction can be provided with no organic solvent and no side products.
Assuntos
Antineoplásicos/síntese química , Pró-Fármacos/síntese química , Taxoides/química , Antineoplásicos/química , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Pró-Fármacos/química , Solubilidade , Relação Estrutura-Atividade , ÁguaRESUMO
A prodrug of paclitaxel which has a coumarin derivative conjugated to the amino acid moiety of isotaxel (O-acyl isoform of paclitaxel) has been synthesized. The prodrug was selectively converted to isotaxel by visible light irradiation (430 nm) with the cleavage of coumarin. Finally, paclitaxel was released by subsequent spontaneous O-N intramolecular acyl migration.
Assuntos
Paclitaxel/química , Fármacos Fotossensibilizantes/síntese química , Pró-Fármacos/síntese química , Estrutura Molecular , Paclitaxel/síntese química , Fármacos Fotossensibilizantes/química , Pró-Fármacos/químicaRESUMO
O-N Intramolecular alkoxycarbonyl (carbonate-carbamate) migration was found to occur as a common reaction of hydroxyamino acids under mild basic aqueous conditions with no formation of side products. Carbonate protective groups migrate to produce amino-protected carbamate derivatives of hydroxyamino acids with high efficiency and purity.