Natural products: a continuing source of novel drug leads.

To create a drug, nature's blueprints often have to be improved through semisynthesis or total synthesis (chemical postevolution). Selected contributions from industrial and academic groups highlight the arduous but rewarding path from natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, substitution, and degradation. The biological, chemical, and socioeconomic environments of antibacterial research are dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for marketed anti-infectives. Surprisingly, numerous "old" classes of antibacterial natural products have never been intensively explored by medicinal chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the "old fashioned" natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival.

Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival?

Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. We determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane pocket of β-tubulin and used their respective side chains to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. Further, our results offer fundamental structural insights into the control mechanisms of microtubule dynamics.

https://science.sciencemag.org/content/sci/339/6119/587.full.pdf

Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents.

Organocatalytic asymmetric epoxidation and aziridination of olefins and their synthetic applications.

This review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly of tubulin to microtubules The emphasis is on providing recent information on those compounds in clinical use or in advanced clinical trials The vinca alkaloids, the combretastatins, NPI-2358, the halichondrin B analogue eribulin, dolastatin 10, noscapine, hemiasterlin, and rhizoxin are discussed as tubulin polymerization inhibitors, while the taxanes and the epothilones are the major classes of tubulin polymerization promoters presented, with brief treatments of discodermolide, eleutherobin, and laulimalide The challenges and future directions of tubulin-interactive natural products-based drug discovery programs are also discussed briefly

Tubulin-interactive natural products as anticancer agents.

The chemistry and biology of epothilones--the wheel keeps turning.

Ever since the initial discovery of the epothilones in 1996 (for example, EpoA (1) and EpoB (2), Figure 1), synthetic chemists have been enamored with their structures from the perspectives of both synthesis and modification. This rather intense and persistent interest is neither surprising nor without merit, for these naturally occurring substances have proven themselves challenging targets for synthesis, powerful tools in biology, and worthy drug candidates currently in clinical trials as anticancer agents. Our structure–activity relationship (SAR) studies within the epothilone class 4] have defined a narrow range of structural motifs that, when present, endow the epothilone molecule with biological activity and have resulted in the development of several potent epothilones such as the methylthio-EpoB analogues 3 and 4. This model was more or less confirmed by a recent electron crystallographic and NMR-based conformational analysis of a tubulin–EpoA complex that appears to accommodate most of the published SAR data. Herein, we report a new study based on this model that has led to the identification of the most potent epothilone reported to date, natural or designed. From the several regions of the epothilone structure where modifications could be made with the potential to improve the activity of the molecule, we chose the heterocyclic ringcontaining side-chain domain. Having previously established the importance of the basic nitrogen atom in its specific location, we set that condition as a structural requirement for any new designs and kept the rest of the structure of EpoB intact. These limits had the advantage that any potential drug candidate I that could emerge from the investigation could, in principle, be produced either by total synthesis or through semisynthesis from a degradation-derived advanced intermediate II and a heterocyclic stannane III by a palladium-catalyzed cross-coupling reaction such as the Stille reaction, for example, as indicated retrosynthetically in Figure 2. Epothilones 5–21 (Figure 3) were designed within the structural constraints mentioned above and with certain further rationales. The beneficial effect of certain lipophilic substituents such as methyl and methylthio groups on tubulin binding and cytotoxicity did not escape our attention, and thus we introduced such moieties on several of these designs (compounds 5–20). We also wanted to probe the effect of additional rings on the heterocyclic side chain (compounds 7, 17–19, and 20) as well as the absence of a ring on the same side chain (compound 21). Finally, we wished to challenge the ability of the tubulin receptor pocket to accommodate bulky halogen substituents such as those in compounds 10 and 12.

http://www.cornellpharmacology.org/faculty/labs/giannakakou/documents/NicolaouKCetal.ChemMedChem2006.pdf

Molecular Design and Chemical Synthesis of a Highly Potent Epothilone

The Chemistry and Biology of Epothilones — The Wheel Keeps Turning

A highly active synthetic epothilone compound whose activity exceeds that of either epothilone EpoA or EpoB when assayed as a cytotoxic agent against a cancer cell line is disclosed as is a pharmaceutical composition containing the synthetic epothilone.

Benjamin A. Pratt

Papers

The chemistry and biology of epothilones--the wheel keeps turning.

Molecular Design and Chemical Synthesis of a Highly Potent Epothilone

The Chemistry and Biology of Epothilones — The Wheel Keeps Turning

Chemical synthesis of a highly potent epothilone

Molecular Design and Chemical Synthesis of a Highly Potent Epothilone.