RESUMEN
In all probability, natural selection began as ancient marine microorganisms were required to compete for limited resources. These pressures resulted in the evolution of diverse genetically encoded small molecules with a variety of ecological and metabolic roles. Remarkably, many of these same biologically active molecules have potential utility in modern medicine and biomedical research. The most promising of these natural products often derive from organisms richly populated by associated microorganisms (e.g., marine sponges and ascidians), and often there is great uncertainty about which organism in these assemblages is making these intriguing metabolites. To use the molecular machinery responsible for the biosynthesis of potential drug-lead natural products, new tools must be applied to delineate their genetic and enzymatic origins. The aim of this perspective is to highlight both traditional and emerging techniques for the localization of metabolic pathways within complex marine environments. Examples are given from the literature as well as recent proof-of-concept experiments from the authors' laboratories.
Asunto(s)
Fenómenos Fisiológicos Bacterianos , Productos Biológicos/biosíntesis , Productos Biológicos/aislamiento & purificación , Invertebrados/microbiología , Biología Marina , Simbiosis , Microbiología del Agua , Animales , Productos Biológicos/química , Briozoos/citología , Briozoos/microbiología , Cianobacterias/citología , Cianobacterias/aislamiento & purificación , Cianobacterias/fisiología , Ciclotrones , Análisis de Fourier , Hibridación Fluorescente in Situ , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Cytotoxicity-guided fractionation of the organic extract from a Fijian Lyngbya majuscula led to the discovery of desmethoxymajusculamide C (DMMC) as the active metabolite. Spectroscopic analysis including 1D and 2D NMR, MS/MS, and chemical degradation and derivatization protocols were used to assign the planar structure and stereoconfiguration of this new cyclic depsipeptide. DMMC demonstrated potent and selective anti-solid tumor activity with an IC(50) = 20 nM against the HCT-116 human colon carcinoma cell line via disruption of cellular microfilament networks. A linear form of DMMC was generated by base hydrolysis, and the amino acid sequence was confirmed by mass spectrometry. Linearized DMMC was also evaluated in the biological assays and found to maintain potent actin depolymerization characteristics while displaying solid tumor selectivity equivalent to DMMC in the disk diffusion assay. A clonogenic assay assessing cytotoxicity to HCT-116 cells as a function of exposure duration showed that greater than 24 h of constant drug treatment was required to yield significant cell killing. Therapeutic studies with HCT-116 bearing SCID mice demonstrated efficacy at the highest dose used (%T/C = 60% at 0.62 mg/kg daily for 5 days).
Asunto(s)
Antineoplásicos , Cianobacterias/química , Depsipéptidos , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Depsipéptidos/química , Depsipéptidos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Fiji , Células HCT116 , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
Parallel chemical and phylogenetic investigation of a marine cyanobacterium from Panama led to the isolation of two new PKS-NRPS-derived compounds, viridamides A and B. Their structures were determined by NMR and mass spectroscopic methods, and the absolute configurations assigned by Marfey's method and chiral HPLC analysis. In addition to six standard, N-methylated amino and hydroxy acids, these metabolites contained the structurally novel 5-methoxydec-9-ynoic acid moiety and an unusual proline methyl ester terminus. Morphologically, this cyanobacterium was identified as Oscillatoria nigro-viridis, and its 16S rDNA sequence is reported here for the first time. Phylogenetic analysis of these sequence data has identified O. nigro-viridis strain OSC3L to be closely related to two other marine cyanobacterial genera, Trichodesmium and Blennothrix. Viridamide A showed antitrypanosomal activity with an IC50 of 1.1 microM and antileishmanial activity with an IC50 of 1.5 microM.
Asunto(s)
Antiprotozoarios/aislamiento & purificación , Antiprotozoarios/farmacología , Cianobacterias/química , Depsipéptidos/aislamiento & purificación , Depsipéptidos/farmacología , Animales , Antiprotozoarios/química , Depsipéptidos/química , Leishmania mexicana/efectos de los fármacos , Biología Marina , Estructura Molecular , Panamá , Plasmodium falciparum/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacosRESUMEN
The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.