RESUMEN
Some hybrids of vinca alkaloids and phomopsin A, linked by a glycine pattern, have been synthesized in one or two steps, by an insertion reaction and shown to inhibit microtubule assembly. These compounds have been elaborated in order to interact with both the "vinca site" and the "peptide site" of the vinca domain in tubulin. Two out of three hybrids are potent inhibitors of microtubules assembly and they present good cytotoxicity against different cell lines. Molecular modelling studies show that they could bind, within the vinca domain, in similar spatial regions as those of vinca and phomopsin thanks to the flexibility provided by the glycine linker used to elaborate these hybrids.
Asunto(s)
Glicina/química , Micotoxinas/síntesis química , Tubulina (Proteína)/química , Alcaloides de la Vinca/síntesis química , Alcaloides/química , Apoptosis , Sitios de Unión , Línea Celular , Guanosina Trifosfato/química , Humanos , Células K562 , Microtúbulos/metabolismo , Modelos Moleculares , Micotoxinas/química , Péptidos/química , Estructura Terciaria de Proteína , Transducción de Señal , Vinblastina/análogos & derivados , Vinblastina/química , Alcaloides de la Vinca/química , VinorelbinaRESUMEN
The synthesis of one of the most potent dual inhibitors of the anti-apoptotic proteins Bcl-xL and Mcl-1 is reported. This analogue of a natural sesquiterpenoid dimer meiogynin A was elaborated by a convergent asymmetric synthesis with 36% yield in ten steps.