RESUMEN
Pathogenic microbes rapidly develop resistance to antibiotics. To keep ahead in the "microbial war", extensive interdisciplinary research is needed. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (ie., beta-lactamase) and even induction of efflux mechanisms. A combination of chemical syntheses, microbiological and biochemical studies demonstrate that the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the biosyntheses and use of microbe-selective iron-chelating compounds called siderophores. Our studies, and those of others, demonstrate that siderophores and analogs can be used for iron transport-mediated drug delivery ("Trojan Horse" antibiotics) and induction of iron limitation/starvation (Development of new agents to block iron assimilation). Recent extensions of the use of siderophores for the development of novel potent and selective anticancer agents are also described.
Asunto(s)
Antibacterianos , Antineoplásicos , Bacterias/metabolismo , Diseño de Fármacos , Hierro/metabolismo , Neoplasias/tratamiento farmacológico , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/uso terapéutico , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antituberculosos/síntesis química , Antituberculosos/química , Antituberculosos/uso terapéutico , Bacterias/genética , Sistemas de Liberación de Medicamentos , Farmacorresistencia Microbiana , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazoles/química , Oxazoles/metabolismo , Sideróforos/química , Sideróforos/metabolismoRESUMEN
[reaction: see text] Amamistatins A and B are natural products found to have anti-proliferative effects against MCF-7, A549, and MKN45 human tumor cell lines (IC50 0.24-0.56 microM). It was proposed that their activity was due to histone deacetylase (HDAC) inhibition mediated by the N-formyl-N-hydroxy lysine moiety. Amamistatin B fragment analogs were synthesized and screened for biological activity. These compounds were modest HDAC inhibitors and showed antitumor activity against MCF-7 and PC-3 human tumor cells.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Oxazoles/síntesis química , Oxazoles/farmacología , Antineoplásicos/química , Productos Biológicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/química , Estructura Molecular , Oligopéptidos/química , Oxazoles/químicaRESUMEN
Amamistatins A and B, natural products isolated from a strain of Nocardia, showed growth inhibition against three human tumor cell lines (IC(50) 0.24-0.56 microM). Structurally related mycobactins affect the growth of both mycobacterial and human cells through interference with iron chelation. To further probe the biological activity of this class of compounds, the total syntheses of amamistatin B and two analogs were completed, and the synthetic samples were screened for tumor cell growth inhibition, HDAC inhibition, and Mycobacterium tuberculosis growth inhibition. Amamistatin B (15) and diastereomer 18 were both active against MCF-7 cells (IC(50) 0.12-0.20 microM), and less so against PC-3 cells (IC(50) 8-13 microM). Amamistatin B only moderately inhibited the growth of M. tuberculosis (MIC 47 microM) but showed growth promotion of Mycobacterium smegmatis and other bacteria.