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Landon Diaz
Landon Diaz

Bioactive Natural Products: Chemistry And Biology

The Laboratory of Bioorganic Chemistry (LBC) explores biomedical problems at the interface of chemistry and biology. Founded by the late John Daly in 1978, LBC has a rich history of chemical research that includes organic synthesis, medicinal chemistry, natural products chemistry, structural biology and pharmacology.

Bioactive Natural Products: Chemistry and Biology

The Kellogg Lab promotes a transdisciplinary approach to research, integrating analytical metabolomics, chemical biology, natural products chemistry, molecular biology, and ethnobotany to characterize bioactive natural products (metabolites) that interface with therapeutic targets to modulate human, plant, and animal health. We pursue ethnobotanical collaborations to discover new plant chemistry, and study botanical and environmental microbiomes and fungi for antimicrobial metabolites. Our lab uses a concerted approach, combining field screening, analytical metabolomics and bioinformatics with advanced analytical techniques, multi-platform chromatographic separations, isolation of lead compounds, and detailed structural and biological analysis to characterize active constituents as well as elucidate the mechanistic pathways of action. We also work to develop new bioanalytical and computational tools to expand the analytical capabilities of metabolomic analyses in chemistry, infectious disease biology, and ecology. Lead projects currently underway include examination of the phyllosphere for antimicrobial compounds; volatile metabolomics to elucidate bacterial-fungal interactions in the soil environment; and gut homeostasis and microbiome metabolism of dietary plants.

At the heart of our research interests are the chemistry and biology of natural products, enduring leads for basic cell biology studies and drug development. These are unique and often structurally complex molecules that are designed to interact in highly specific ways with various cellular receptors and by homology those found in humans. Our interest in a particular natural product target typically stems from a combination of biological activity and sometimes complex structure. Overall our group is engaged in developing novel synthetic strategies and methods towards the total synthesis of natural products and more recently, isotopically-labelled biosynthetic precursors, to enable further inquiries into their biological mechanism of action at the molecular level, opening possibilities for drug development, and fundamental questions regarding the biosynthesis of these genetically encoded small molecules.

At the heart of our research interests is the chemistry and biology of natural products, which is an exciting and enduring interdisciplinary area for discoveries in basic cell biology impacting human health. Natural products are unique and often structurally complex molecules that are designed to interact in highly specific ways with various cellular receptors and, due to protein homology, those found in humans. Our particular synthetic targets are chosen based on an interest of structural novelty and complexity in addition to provocative biological activity and importantly, unknown molecular mechanism of action. Some targets are chosen based on the presence of β-lactones or functionality derivable from β-lactones, a privileged class of heterocycles useful for activity based-protein profiling given their ability to covalently modify their protein targets. Thus, our group is engaged in developing novel synthetic strategies towards these naturally occurring compounds or derivatives that in turn serve are useful drug leads and invaluable probes for inquiries into cell biology via a forward chemical genetics approach. Our highly collaborative research is bolstered by We recently developed a toolbox of a reagents/methods that will more rapidly couple a natural product to its putative cellular receptor and these methods are being used in the soon to be established collaboration center, the CPRIT Natural Product Synthesis and Biological Chemistry Laboratory at Baylor enabling synthesis and synthesis optimization of drug leads. In a recent venture, advanced biosynthetic intermediates are being synthesized and utilized to establish biosynthetic pathways in marine sponges.

Natural product research has expanded tremendously since the discovery of morphine in the late 1800s. The identification of bioactive compounds for potential new drug discovery from natural products begins from the chemical aspects of separating and isolating the compounds by chromatographic methods followed by characterization and structural elucidation using modern spectroscopic techniques. These fractions and compounds are then subjected to various biological screening in vitro and in vivo before proceeding to clinical trials. Natural product research is now a combination of many fields including chemistry, biology, pharmacology, medicine, and so forth.

Within the field of organic chemistry, the definition of natural products is usually restricted to organic compounds isolated from natural sources that are produced by the pathways of primary or secondary metabolism.[7] Within the field of medicinal chemistry, the definition is often further restricted to secondary metabolites.[8][9] Secondary metabolites (or specialized metabolites) are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage.[10] Many secondary metabolites are cytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against prey, predators, and competing organisms.[11] Secondary or specialized metabolites are often unique to species, which is contrasted to primary metabolites which have broad use across kingdoms. Secondary metabolites are marked by chemical complexity which is why they are of such interest to chemists.

Natural sources may lead to basic research on potential bioactive components for commercial development as lead compounds in drug discovery.[12] Although natural products have inspired numerous drugs, drug development from natural sources has received declining attention in the 21st century by pharmaceutical companies, partly due to unreliable access and supply, intellectual property, cost, and profit concerns, seasonal or environmental variability of composition, and loss of sources due to rising extinction rates.[12]

Natural products especially within the field of organic chemistry are often defined as primary and secondary metabolites. A more restrictive definition limiting natural products to secondary metabolites is commonly used within the fields of medicinal chemistry and pharmacognosy.[13]

Pharmacognosy provides the tools to detect, isolate and identify bioactive natural products that could be developed for medicinal use. When an "active principle" is isolated from a traditional medicine or other biological material, this is known as a "hit". Subsequent scientific and legal work is then performed to validate the hit (eg. elucidation of mechanism of action, confirmation that there is no intellectual property conflict). This is followed by the hit to lead stage of drug discovery, where derivatives of the active compound are produced in an attempt to improve its potency and safety.[32][33] In this and related ways, modern medicines can be developed directly from natural sources.[citation needed]

Animals also represent a source of bioactive natural products. In particular, venomous animals such as snakes, spiders, scorpions, caterpillars, bees, wasps, centipedes, ants, toads, and frogs have attracted much attention. This is because venom constituents (peptides, enzymes, nucleotides, lipids, biogenic amines etc.) often have very specific interactions with a macromolecular target in the body (e.g. α-bungarotoxin from cobras).[58][59] As with plant feeding deterrents, this biological activity is attributed to natural selection, organisms capable of killing or paralyzing their prey and/or defending themselves against predators being more likely to survive and reproduce.[59]

Many natural products have very complex structures. The perceived complexity of a natural product is a qualitative matter, consisting of consideration of its molecular mass, the particular arrangements of substructures (functional groups, rings etc.) with respect to one another, the number and density of those functional groups, the stability of those groups and of the molecule as a whole, the number and type of stereochemical elements, the physical properties of the molecule and its intermediates (which bear on the ease of its handling and purification), all of these viewed in the context of the novelty of the structure and whether preceding related synthetic efforts have been successful (see below for details).[citation needed] Some natural products, especially those less complex, are easily and cost-effectively prepared via complete chemical synthesis from readily available, simpler chemical ingredients, a process referred to as total synthesis (especially when the process involves no steps mediated by biological agents). Not all natural products are amenable to total synthesis, cost-effective or otherwise. In particular, those most complex often are not. Many are accessible, but the required routes are simply too expensive to allow synthesis on any practical or industrial scale. However, to be available for further study, all natural products must yield to isolation and purification. This may suffice if isolation provides appropriate quantities of the natural product for the intended purpose (e.g. as a drug to alleviate disease). Drugs such as penicillin, morphine, and paclitaxel proved to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant synthetic chemistry contributing).[citation needed] However, in other cases, needed agents are not available without synthetic chemistry manipulations.[citation needed]

In general, the total synthesis of natural products is a non-commercial research activity, aimed at deeper understanding of the synthesis of particular natural product frameworks, and the development of fundamental new synthetic methods. Even so, it is of tremendous commercial and societal importance. By providing challenging synthetic targets, for example, it has played a central role in the development of the field of organic chemistry.[92][93] Prior to the development of analytical chemistry methods in the twentieth century, the structures of natural products were affirmed by total synthesis (so-called "structure proof by synthesis").[94] Early efforts in natural products synthesis targeted complex substances such as cobalamin (vitamin B12), an essential cofactor in cellular metabolism.[90][91] 041b061a72


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