RESUMEN
While 3-O-acetylated betulin derivatives carrying a carbamate moiety at position C-28 are of rather low cytotoxicity for human tumor cell lines, the corresponding C-3 amino(oxo) acetates show good cytotoxicity. For example, an EC50 as low as 2.0µM was found for (3ß) 28-{[(hexylamino)carbonyl]oxy}lup-20(29)-en-3-yl amino(oxo)acetate (16) employing the ovarian cancer cell line A2780.
Asunto(s)
Acetatos/farmacología , Carbamatos/farmacología , Triterpenos/farmacología , Acetatos/química , Carbamatos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Triterpenos/síntesis química , Triterpenos/químicaRESUMEN
The betulinic acid-derived hydroxamates 5-18, the amides 19-24, and betulin-derived bis-carbamates 25-28 as well as the carbamates 31-40 and 44-48 were prepared and evaluated for their antiproliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 µM were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16-20 µM). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 µM for A2780 human ovarian carcinoma cells and EC50 > 30 µM for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19-24 and of betulin derived bis-carbamates 25-28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 µM (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined.
Asunto(s)
Carbamatos/química , Carbamatos/farmacología , Citotoxinas/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Triterpenos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Carbamatos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citotoxinas/síntesis química , Citotoxinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/síntesis química , Ratones , Estructura Molecular , Células 3T3 NIH , Triterpenos Pentacíclicos , Relación Estructura-Actividad , Triterpenos/síntesis química , Triterpenos/farmacología , Ácido BetulínicoRESUMEN
Finding and developing drugs for the treatment of cancer has been challenging scientists for many decades, and using compounds of natural origin represents one of several strategies. Triterpenoic acids are a very promising class of secondary metabolites being able to induce apoptosis while their cytotoxicity is low. Therefore, derivatizations have to be conducted to improve cytotoxicity while retaining their ability to induce programmed cell death. The incorporation of a Michael acceptor into molecules resulted very often in drugs of improved cytotoxicity. Thus, in this study we synthesized and evaluated several Michael acceptor substituted compounds derived from glycyrrhetinic, ursolic, oleanolic and platanic acid. The influence of the presence of such a functional group onto the cytotoxicity was investigated in colorimetric sulforhodamine B assays employing several human cancer cell lines. EC50 values in the single-digit micromolar range were measured. Thus, the incorporation of a Michael acceptor unit into triterpenoic acids enhances the cytotoxicity of these compounds significantly.