RESUMEN
Structure modification of the beta-alanine region (fragment C) of the potent antimitotic agent cryptophycin was investigated. This includes: (1) introduction of substituents at the previously unsubstituted C7 position of the macrolide ring and (2) replacement of the (2R)-3-amino-2-methyl-propanoic acid (beta-alanine) with various (1)-amino acids to give the corresponding 15-membered unnatural cryptophycin analogs.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , beta-Alanina/química , Sustitución de Aminoácidos , Animales , Antineoplásicos/síntesis química , Carcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Depsipéptidos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Neoplasias Pancreáticas/tratamiento farmacológico , Conformación Proteica , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of over 70 difluoropurine analogs was synthesized by varying the C-2, 6 and 8 substituents about the purine ring system. After initial in vitro and in vivo screening, testing concentrated on the 2,6-diaminopurine analog (dFdAP) and the guanosine analog (dFdG). dFDAP appears to be a prodrug for dFdG. Both compounds significantly inhibited mammary tumor growth in mice, caused a moderate inhibition in ovarian and lymphosarcoma models, and demonstrated no activity in lung and melanoma models. This is a narrower spectrum of activity than that of gemcitabine (dFdC). The antitumor activity of dFdAP in human xenografts that are refractory to standard clinical agents was comparable or superior to that of gemcitabine. However, during the preliminary toxicology testing, dFdG was associated with several deaths caused by cardiac toxicity. Therefore, although dFdG is a potentially useful oncolytic, further investigation is required.
Asunto(s)
2-Aminopurina/análogos & derivados , Antineoplásicos/farmacología , Desoxiadenosinas/química , Desoxiadenosinas/farmacología , Desoxiguanosina/análogos & derivados , Guanosina/análogos & derivados , Neoplasias Experimentales/tratamiento farmacológico , 2-Aminopurina/química , 2-Aminopurina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Recuento de Células Sanguíneas/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Desoxiadenosinas/síntesis química , Desoxiguanosina/síntesis química , Desoxiguanosina/química , Desoxiguanosina/farmacología , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Corazón/efectos de los fármacos , Humanos , Técnicas In Vitro , Infusiones Intravenosas , Inyecciones Intraperitoneales , Hígado/efectos de los fármacos , Tejido Linfoide/efectos de los fármacos , Masculino , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Relación Estructura-Actividad , Testículo/efectos de los fármacosRESUMEN
A series of diarylsulfonylureas with exceptionally broad-spectrum activity against syngeneic rodent solid tumors in vivo is described. Their discovery resulted from a program dedicated to in vivo screening for novel oncolytics in solid tumor models, rather than traditional ascites leukemia models. The structures, oral efficacy, side-effect profile, and mechanism of action of these sulfonylureas appear to be distinct from previously known classes of oncolytics. An extensive series of analogues was prepared to probe structure-activity relationships (SAR), with particular focus on the substituent patterns of each aryl domain. Quantitative analysis of these substituent SARs, using the method of cluster significance analysis, showed the lipophilicity of the substituents to be the dominant determinant of activity. One compound from the series, LY186641 (104, sulofenur), has progressed to Phase I clinical trials as an antitumor drug.
