Natural products as leads to antitumor drugs

The discussion in this short review emphasizes that the main and future source of novel natural products as leads to antitumor agents is probably in the areas of biology that cannot be seen, i.e. the microbial world. The review discusses the role of microbes in the production of secondary metabolites that were initially thought to be from marine invertebrates and goes on to discuss the potential for a number of well-known anticancer agents isolated from plant sources to actually be the products of a microbe-plant interaction and finishes with a discussion of the potential of microbial “cryptic clusters” as sources of novel agents/leads to anti-tumor treatments.     

Microbial antagonism: a neglected avenue of natural products research

Competition amongst microbes for space and nutrients in the marine environment is a powerful selective force which has led to the evolution of a variety of effective strategies for colonising and growing on surfaces. We are particularly interested in the chemical ecology of marine epibiotic bacteria which live on the surfaces of marine algae or invertebrates. Over 400 strains of surface-associated bacteria from various species of seaweed and invertebrate from Scottish coastal waters were isolated and 35% of them shown to produce antimicrobial compounds. This is a much higher proportion than free living marine isolates or soil bacteria. In addition, many strains which did not normally produce antibiotics could be induced to do so by exposing them to small amounts of live cells, supernatants from other bacterial cultures or other chemicals. Thus the number of strains able to produce antibiotics appears to be much higher than previously thought. Induction of antibiotic production was elicited by other marine epibionts and also by terrestrial human pathogens such as Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. An understanding of this type of chemical induction and the factors regulating non-constitutive secretion of antimicrobial compounds will allow more effective strategies for searching for new chemotherapeutic antibiotics to be designed.     

Microbial transformations of natural antitumor agents: oxidation of lapachol by Penicillium notatum.

The naphthoquinone lapachol (1) is readily metabolized by several fungi and streptomycetes. Preparative-scale fermentations with Penicillium notatum (UI 1602) provided a major polar metabolite (4), which was isolated and identified as an intermediate of the Hooker oxidation. The metabolite was synthesized by reacting lapachol with hydrogen peroxide under alkaline conditions.     

Microbial transformations of natural antitumor agents: conversion of lapachol to dehydro-alpha-lapachone by Curvularia lunata

Microbial transformation of lapachol, a naturally occurring naphthoquinone, was carried out by Curvularia lunata (NRRL 2178). The fungus brings about oxidative cyclization of the substrate to dehydro-alpha-lapachone, which was isolated and characterized by nuclear magnetic resonance and mass spectral analyses; its structure was verified by chemical synthesis. The metabolite is a naturally occurring chromene possessing antibacterial and antitumor activities.     

天然来源抗肿瘤化合物作用于MAPK通路的机制

天然来源抗肿瘤活性产物是抗肿瘤药物先导化合物的重要资源。促分裂原活化蛋白激酶(MAPK)通路是细胞内重要的信号转导系统,可以调节细胞的生长、凋亡、黏附、迁移等过程,继而影响肿瘤的发生、发展、侵袭、转移,是潜在的抗肿瘤药物作用靶点之一。本文将对天然来源化合物作用于MAPK信号通路的靶点分子及生物效应进行阐述,为肿瘤的化学预防及治疗提供启发。     

Plant natural products: the molecular genetic basis of biosynthetic diversity

Significant advances have been made concerning the biosynthesis, regulation and genetic manipulation of plant natural products. These include insights into the structural biology of isoprenoid cyclization and polyketide condensation reactions, a better understanding of the molecular biology of plant cytochrome P450s and O-methyltransferases, and new information on the effects of natural products on human health.     

Microbial transformations of natural antitumor agents: conversion of lapachol to dehydro-alpha-lapachone by Curvularia lunata.

Microbial transformation of lapachol, a naturally occurring naphthoquinone, was carried out by Curvularia lunata (NRRL 2178). The fungus brings about oxidative cyclization of the substrate to dehydro-alpha-lapachone, which was isolated and characterized by nuclear magnetic resonance and mass spectral analyses; its structure was verified by chemical synthesis. The metabolite is a naturally occurring chromene possessing antibacterial and antitumor activities.     

Structural and functional relationships of natural and artificial dimeric bovine ribonucleases: New scaffolds for potential antitumor drugs

Protein aggregation via 3D domain swapping is a complex mechanism which can lead to the acquisition of new biological, benign or also malignant functions, such as amyloid deposits. In this context, RNase A represents a fascinating model system, since by dislocating different polypeptide chain regions, it forms many diverse oligomers. No other protein displays such a large number of different quaternary structures. Here we report a comparative structural analysis between natural and artificial RNase A dimers and bovine seminal ribonuclease, a natively dimeric RNase with antitumor activity, with the aim to design RNase A derivatives with improved pharmacological potential.     

Plant natural products active against snake bite--the molecular approach

The article surveys the substances identified in plants reputed to neutralize the effects of snake venoms. Protective activity of many of them against the lethal action of the venom of the jararaca (Bothrops jararaca) snake was confirmed by biological assays. It was shown that all belong to chemical classes capable of interacting with macromolecular targets--receptors and enzymes. In a few cases it has been shown that exogenous natural micromolecules can mimic the biological activity of endogenous macromolecules. From the evidence presented, it can be inferred that micromolecules which neutralize the action of snake venoms mechanistically replace endogenous antitoxic serum proteins with venom neutralizing capacity such as produced by some animals.     

Unraveling the molecular components and genetic blueprints of stem cells

Remarkable progress in stem cell biology research over the past few years has provoked a promise for the future of tissue regeneration and gene therapies; so much so, that the use of stem cells in clinical therapy seemed to be just around the corner. However, we now realize there is still a huge task before us to improve our understanding of the nature of stem cells before utilizing them to benefit human health. Stem cell behavior is determined by specific gene products; thus, unraveling the molecular components and genetic blueprints of stem cells will provide important insight into understanding stem cell properties. Here we summarize the research of various groups using microarray technology and other approaches to determine the gene expression profiles in stem cells, particularly in hematopoietic stem cells (HSCs). These works have, to a certain degree, helped to narrow down the candidate genes predominantly expressed in HSCs, revealed a list of stemness genes, and indirectly demonstrated the wide-open chromatin state of stem cells and, with it, the molecular basis of the multipotentiality of stem cells.     

亚肉座菌天然产物的分离鉴定及抗肿瘤活性

亚肉座菌能侵染粉虱和介壳虫,具有悠久的生物防治历史,但关于其天然产物的种类及抗肿瘤活性研究尚不深入。本研究借助硅胶柱、HPLC等色谱技术从亚肉座菌发酵液中分离纯化到6个化合物。基于核磁共振和质谱数据解析,化合物1–6依次鉴定为:5α,8α-表二氧-24(R)-甲基胆甾-6,22-二烯-3β-醇5α,8α-epidioxy-24(R)-methylcholesta-6,22-diene-3β-ol(1),杜斯塔宁dustanin(2),3β-乙酸基-15α,22-二羟基何伯烷3β-acetoxy-15α,22-dihydroxyhopane(3),麦角固醇ergosterol(4),7β,15α,22-三羟基何伯烷7β,15α,22-trihydroxyhopane(5)和5-(羟甲基)呋喃-3-羧酸flufuran(6),化合物1和6为首次从虫生真菌中获得。对化合物进行抗肿瘤活性测试发现,化合物1和5对人肝癌细胞(BEL-7404)展示显著的抗肿瘤活性,IC50值分别为28μmol/L和12.4μmol/L,而它们对人正常肝脏细胞(HL-7702)和肾脏上皮细胞(HEK-293T)均未呈现出明显活性。该研究对阐明亚肉座菌代谢产物及其活性提供了重要数据,为开发抗肿瘤新药提供了理论参考。     

Microbial transformations of natural antitumor agents: use of solubilizing agents to improve yields of hydroxylated ellipticines.

Aromatic hydroxylation of the antitumor alkaloid ellipticine by Aspergillus alliaceus results in the formation of both 8- and 9-hydroxyellipticines. Experiments designed to increase yields of microbial hydroxylation focused on enhancing the water solubility of ellipticine in aqueous fermentation media by use of wetting agents or solubilizing polymers, or both. Yields of hydroxylated metabolites were determined by high-performance liquid chromatography with the use of a mu-Bondapak-phenyl column and a mobile phase of acetonitrile--0.1% (NH4)2CO3 (1:1). Polyvinylpyrrolidone (molecular weight, 40,000) and polyoxyethylated vegetable oil (Emulphor 620) increased the water solubility of ellipticine and the yield of hydroxylated metabolites.     

Inheritance of allelic blueprints for methylation patterns

We have developed a strategy to distinguish between the methylation patterns of homologous chromosomes in tissues, and to follow these patterns in human pedigrees. This genetic approach uncovered evidence of variation in the methylation of allelic sites on homologous chromosomes. This variation was tissue-specific and reproducible after transmission through the germ line, demonstrating that homologous chromosomes have distinct blueprints for the tissue-specific regulation of methylation. Furthermore, this approach can be used to study the relationship between parental imprinting and methylation in native mammalian loci.