Combretastatins: from natural products to drug discovery

The combretastatins are a group of anti-mitotic agents isolated from the bark of the South African tree Combretum caffrum. The most potent member is combretastatin A-4, and this compound together with a phosphate pro-drug form have already progressed through into clinical trails for the treatment of solid tumours. What makes this class of compounds rather more interesting than other anti-mitotic agents is that they are also angiogenesis inhibitors, and are being evaluated for their efficacy in the treatment of diabetic retinopathy which is the biggest single cause of blindness They are thus of considerable contemporary interest.     

Lessons from the past and charting the future of marine natural products drug discovery and chemical biology

Marine life forms are an important source of structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. These success stories have had to overcome difficulties inherent to natural products-derived drugs, such as adequate sourcing of the agent and issues related to structural complexity. Nevertheless, several marine-derived agents are now approved, most as "first-in-class" drugs, with five of seven appearing in the past few years. Additionally, there is a rich pipeline of clinical and preclinical marine compounds to suggest their continued application in human medicine. Understanding of how these agents are biosynthetically assembled has accelerated in recent years, especially through interdisciplinary approaches, and innovative manipulations and re-engineering of some of these gene clusters are yielding novel agents of enhanced pharmaceutical properties compared with the natural product.     

Chasing molecules that were never there: misassigned natural products and the role of chemical synthesis in modern structure elucidation

Over the course of the past half century, the structural elucidation of unknown natural products has undergone a tremendous revolution. Before World War II, a chemist would have relied almost exclusively on the art of chemical synthesis, primarily in the form of degradation and derivatization reactions, to develop and test structural hypotheses in a process that often took years to complete when grams of material were available. Today, a battery of advanced spectroscopic methods, such as multidimensional NMR spectroscopy and high-resolution mass spectrometry, not to mention X-ray crystallography, exist for the expeditious assignment of structures to highly complex molecules isolated from nature in milligram or sub-milligram quantities. In fact, it could be argued that the characterization of natural products has become a routine task, one which no longer even requires a reaction flask! This Review makes the case that imaginative detective work and chemical synthesis still have important roles to play in the process of solving nature's most intriguing molecular puzzles.     

Optical barcoding of colloidal suspensions: applications in genomics,proteomics and drug discovery

The enormous amount of information generated through sequencing of the human genome has increased demands for more economical and flexible alternatives in genomics, proteomics and drug discovery. Many companies and institutions have recognised the potential of increasing the size and complexity of chemical libraries by producing large chemical libraries on colloidal support beads. Since colloid-based compounds in a suspension are randomly located, an encoding system such as optical barcoding is required to permit rapid elucidation of the compound structures. We describe in this article innovative methods for optical barcoding of colloids for use as support beads in both combinatorial and non-combinatorial libraries. We focus in particular on the difficult problem of barcoding extremely large libraries, which if solved, will transform the manner in which genomics, proteomics and drug discovery research is currently performed.     

Multi-channel counter-current chromatography for high-throughput fractionation of natural products for drug discovery

A multi-channel counter-current chromatography (CCC) method has been designed and fabricated for the high-throughput fractionation of natural products without complications sometimes encountered with other conventional chromatographic systems, such as irreversible adsorptive constituent losses and deactivation, tailing of solute peaks and contamination. It has multiple independent CCC channels and each channel connects independent separation column(s) by parallel flow tubes, and thus the multi-channel CCC apparatus can achieve simultaneously two or more independent chromatographic processes. Furthermore, a high-throughput CCC fractionation method for natural products has been developed by a combination of a new three-channel CCC apparatus and conventional parallel chromatographic devices including pumps, sample injectors, effluent detectors and collectors, and its performance has been displayed on the fractionation of ethyl acetate extracts of three natural materials Solidago canadensis, Suillus placidus, and Trichosanthes kirilowii, which are found to be potent cytotoxic to tumor cell lines in the course of screening the antitumor candidates. By combination of biological screening programs and preparative high-performance liquid chromatography (HPLC) purification, 22.8 mg 6 beta-angeloyloxykolavenic acid and 29.4 mg 6 beta-tigloyloxykolavenic acid for S. canadensis, 25.3mg suillin for S. placidus, and 6.8 mg 23,24-dihydrocucurbitacin B for T. Kirilowii as their major cytotoxic principles were isolated from each 1000 mg crude ethyl acetate extract. Their chemical structures were characterized by electrospray ionization mass spectrometry, one- and two-dimensional nuclear magnetic resonance. The overall results indicate the multi-channel CCC is very useful for high-throughput fractionation of natural products for drug discovery in spite of the solvent balancing requirement and the lower resolution of the shorter CCC columns.     

Importance of Baylis-Hillman adducts in modern drug discovery

The Baylis-Hillman (BH) reaction plays a fascinating role in the field of synthetic and medicinal chemistry. BH adducts and their derivatives have been used as crucial synthons for the synthesis of various pharmaceutically useful natural products and compounds with carbocyclic or heterocyclic frameworks. This digest letter aims to discuss some key ideas for the synthesis of biologically active scaffolds using BH reaction and raise the awareness of this emerging research domain in modern drug discovery. In this review, we will present and discuss recent reports of various biologically active scaffolds derived from BH reaction, and their reported biological activities.     

Biomarker discovery by proteomics: challenges not only for the analytical chemist

This forum article outlines some of the major challenges in present day biomarker discovery research. Notably the dilemma of reaching sufficient concentration sensitivity versus the required analysis time per sample is highlighted using a model calculation. A number of possible developments and recent research findings are considered to show possible ways out of this dilemma. Finally, the challenge of processing large, megavariate datasets prior to statistical analysis is presented.     

Small molecule natural products in the discovery of therapeutic agents: the synthesis connection

Natural products have been a rich source of agents of value in medicine. They have also inspired, at various levels, the fashioning of nonnatural agents of pharmaceutical import. Hitherto, these nonnatural derivatives have been primarily synthesized by manipulating the natural product. As a consequence of major innovations in the subscience of synthetic methodology, the capacity of synthesis to deal with molecules of considerable complexity has increased dramatically. In this paper, we show by example some total syntheses which draw from strategy-enabling advances in methodology. Moreover, we show how these capabilities can be used to discover and develop new agents of potential pharmaceutical value without recourse to the natural product itself.     

Merging the potential of microbial genetics with biological and chemical diversity: an even brighter future for marine natural product drug discovery

Marine invertebrates and a growing number of marine bacteria are the sources of novel, bioactive secondary metabolites. Structurally, many of these compounds appear to be biosynthesized by polyketide synthases (PKS) and/or nonribosomal peptide synthetases (NRPS) that have also been found in terrestrial microbes. This review highlights scientific advances from 1999-2003 in the emerging field of molecular genetics of polyketide and nonribosomal peptide natural products isolated from marine organisms. The implications of this research towards the development of marine secondary metabolites as a sustainable source of new drugs are discussed.     

A novel approach in drug discovery: synthesis of estrone--talaromycin natural product hybrids

Hetero-Diels-Alder reaction of the steroidal exocyclic enol ethers 14 and 15, obtained from the secoestrones 8 and 9 by reduction, iodoetherification, and elimination, with ethyl O-benzoyldiformylacetate (16) leads to the spiroacetals 17 and 18 as a mixture of four diastereomers. Reduction of the major diastereomers 17a and 18a with DIBAH and subsequent hydrogenation yields the novel natural product hybrids 21, 23, 24, and 25, which possess the structural features of the steroid estrone (7) and the mycotoxin talaromycin 6.     

Natural products for human health: an historical overview of the drug discovery approaches

Natural products (NPs) are secondary metabolites produced and used by organisms for defending or adapting purposes. These molecules were naturally selected during thousands of years to improve the specificity and cover a very wide range of functions, depending on the origin, the habitat and the specific activity carried out in the organism of origin. Due to these intrinsic features, NPs have been used as healing agents since thousands of years and still today continue to be the most important source of new potential therapeutic preparations.The purpose of this review is to provide information about the historical evolution of the NPs investigation methods, focusing attention on the relative benefit/problems emerged after the improvement of the scientific investigations about them, especially over the last two centuries. Taken together, the reported information lead to the central role of NPs in the future of drug development for human needs.     

Molecular scaffolds using multiple orthogonal conjugations: applications in chemical biology and drug discovery

Heteromultifunctional scaffolds that harness sequential "click" reactions will find significant utility in the areas of chemical biology and chemically enabled/enhanced biotherapeutics ("chemologics"). Here we review the existing synthetic technologies that illustrate the considerable potential of the field.