RESUMEN
EC131, a new folate receptor (FR)-targeted drug conjugate, was prepared by covalently attaching the vitamin folic acid (FA) to a potent microtubule-inhibiting agent, maytansinoid DM1, via an intramolecular disulfide bond. When tested on cells in culture, EC131 was found to retain high affinity for FR-positive cells and to provide FR-specific cytotoxicity with an IC(50) in the low nanomolar range. The activity of EC131 was completely blocked in the presence of an excess of free FA, and no activity was detected against FR-negative cells. When evaluated against s.c. FR-positive M109 tumors in BALB/c mice, EC131 showed marked antitumor efficacy. Furthermore, this therapeutic effect occurred in the apparent absence of weight loss or noticeable organ tissue degeneration. In contrast, no significant antitumor activity was observed in EC131-treated animals that were codosed with an excess of FA, thus demonstrating the targeted specificity of the in vivo activity. EC131 also showed marked antitumor activity against FR-positive human KB tumors, but not against FR-negative A549 tumors, in nude mice with no evidence of systemic toxicity during or after the therapy. In contrast, therapy with the free maytansinoid drug (in the form of DM1-S-Me) proved not to be effective against the KB model when administered at its maximum tolerated dose (MTD). Taken together, these results indicate that EC131 is a highly potent agent capable of producing therapeutic benefit in murine tumor models at sub-MTD levels.
Asunto(s)
Antineoplásicos/farmacología , Proteínas Portadoras/metabolismo , Ácido Fólico/farmacología , Maitansina/farmacología , Extractos Vegetales/farmacología , Receptores de Superficie Celular/metabolismo , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Receptores de Folato Anclados a GPI , Ácido Fólico/química , Ácido Fólico/metabolismo , Humanos , Células KB , Dosis Máxima Tolerada , Maitansina/química , Maytenus/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de NeoplasiasRESUMEN
A method has been developed for the methylation of the C3' amide of taxol C and paclitaxel. Taxol C and paclitaxel were sequentially silylated at the 2', 7, and 1-hydroxyl groups with tert-butyldimethylsilyl chloride, triethylsilyl chloride, and dimethylsilyl chloride, respectively. Subsequent reaction with potassium tert-butoxide and methyl iodide provided the corresponding N-methylated taxane derivatives. Removal of the silyl protecting groups furnished N-methyltaxol C and N-methylpaclitaxel.
Asunto(s)
Amidas/química , Taxoides/química , Espectroscopía de Resonancia Magnética , Metilación , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectrofotometría Infrarroja , Taxoides/síntesis químicaRESUMEN
The design and synthesis of a small library of 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7-hydroxyflavone, and heterocyclic analogues of flavopiridol is reported. The potential activity of these compounds as kinase inhibitors was evaluated by cytotoxicity studies in MCF-7 and ID-8 cancer cell lines and inhibition of CDK2-Cyclin A enzyme activity in vitro. The antiproliferative and CDK2-Cyclin A inhibitory activity of these analogues was significantly lower than the activity of flavopiridol. Molecular docking simulations were carried out and these studies suggested a different binding orientation inside the CDK2 binding pocket for these analogues compared to flavopiridol.