RESUMEN
The synthesis of a small series of 2-nitroimidazoles in which the ß-amino alcohol side chain was amidated with a range of alkylating/acylating functionality is described. Synthetic methodologies were developed that generally provided for selective N-acyl versus N,O-bisacyl products. In vitro, target analogs showed minimal radiosensitization activity, with only a few exhibiting a sensitizer enhancement ratio (SER) >2.0 and C(1.6) values comparable to reference agents RB-6145 and RSU-1069. In an assay to determine potential to alkylate biomolecules, representative analogs showed <1% of the alkylating activity of RSU-1069. In vivo, one analog showed an enhancement ratio of 1.6 relative to vehicle control when tested in B6C3F1 mice with an implanted KHT sarcoma. The data reinforce prior findings that there is a correlation between alkylation potential and in vivo activity.
Asunto(s)
Acilación/efectos de los fármacos , Alquilantes/síntesis química , Alquilantes/farmacología , Diseño de Fármacos , Nitroimidazoles/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Ensayos de Selección de Medicamentos Antitumorales , Ratones , Misonidazol/análogos & derivados , Misonidazol/farmacología , Nitroimidazoles/síntesis química , Nitroimidazoles/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Relación Estructura-ActividadRESUMEN
[structure: see text] Nucleoside phosphoramidites bearing a fluorous dimethoxytrityl (FDMT) group were used to synthesize fluorous-tagged oligonucleotides, which were subjected to solid-phase extraction using a pH-stable fluorinated adsorbent. On-column detritylation afforded the purified oligonucleotides. The fluorous affinity purification method offers one-pass loading without ammonia removal, high selectivity for the removal of failure sequences, high recoveries (typically 70-100%), and the ability to purify long oligonucleotides (e.g., 50-100-mers).