RESUMEN
Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (-) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.
Asunto(s)
Antineoplásicos/farmacología , Depsipéptidos/farmacología , Compuestos Epoxi/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Péptidos Cíclicos/farmacología , Animales , Antineoplásicos/química , Depsipéptidos/química , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Epoxi/química , Ésteres , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones SCID , Trasplante de Neoplasias , Péptidos Cíclicos/química , Relación Estructura-ActividadRESUMEN
The synthesis of a novel series of 1,7-annulated indolocarbazoles 2 and 16 is described. These compounds were found to be potent cyclin dependent kinase inhibitors with good antiproliferative activity against two human carcinoma cell lines. These inhibitors also arrested tumor cells at the G1 phase and inhibited pRb phosphorylation.
Asunto(s)
Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Indoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Inhibidores de Crecimiento/síntesis química , Inhibidores de Crecimiento/farmacología , Humanos , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
The synthesis and CDK inhibitory properties of a series of indolo[6,7-a]pyrrolo[3,4-c]carbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.