Text|Ming Yue is deceased
Editor|Bright Moon is deceased
preface
Nature has evolved to produce natural products with high target affinity and specificity, and natural products have been the richest source of functional regulators of novel biomolecules.
Organic chemists have been interested in natural products since Waller's chemical synthesis of urea, which has led to the development of the field of natural product synthesis over the past two centuries, so the synthesis of natural products plays an important role in drug discovery and chemical biology.
With the introduction of novelty, innovative concepts, and strategies for synthetic efficiency, 21st century natural product synthesis is poised to meet the challenges and complexities of natural product chemistry and will continue to be critical to the advancement of biomedical science.
The role of natural products in chemistry
Over the years, nature has evolved to produce small ligands (or natural products) for macromolecular targets in organisms, which contain domains similar to many human proteins.
As a result of the process of natural selection, natural products have a unique and broad chemical diversity with optimal interaction with biological macromolecules, and due to this diversity and specificity, natural products have proven to be the richest source of new drug development to date.
Of the 1355 new chemical entities (NCEs) experimented between 1981 and 2010, 540 (40%) NCEs were natural products or derived from natural products.
In particular, 63 (64%) of the 99 small molecule anticancer drugs developed and 78 (75%) of the 104 antibiotics developed were derived from natural products.
Representative examples are penicillin V (antibiotic), erythromycin (antibiotic), paclitaxel (anticancer), artemether (antimalarial), galantamine (treatment of Alzheimer's disease) (Figure 1).
Figure 1 Examples of natural products or natural product-derived drugs
In addition to their key role in the development of new drugs, natural products have had profound implications for chemical biology as regulators of biomolecular function.
Many natural products, including Brefieldin A (protein transport), forskolin (cAMP signaling), cyclosporine A (NFAT/lymphocyte signaling), rapamycin (mTOR signaling), and trapoxin B (epigenetics) have been used to systematically explore important cellular components, molecular events, and signaling pathways (Figure 2).
Figure 2 Examples of natural products that contribute to chemical biology.
The contribution of product synthesis to chemistry
Since Waller's synthesis of urea, organic chemists have developed a keen interest in natural products and have driven the field of natural product synthesis to take advantage of their unique structural diversity, interesting biological activity, and high target affinity and specificity.
The following examples illustrate the important role of natural product synthesis in drug discovery and chemical biology probe development.
Spongelactone is a natural product of polyketone compounds that was first isolated from Caribbean deep-sea sponge-lytic discemia in 1990.
It has been reported to inhibit the proliferation of cancer cells by stabilizing microtubules and blocking the G2/M phase of the cell cycle.
Therefore, it is considered a promising candidate for clinical development as a chemotherapy drug for a variety of cancers, and because of its significant antitumor activity, spongelactone has attracted great interest from the pharmaceutical industry.
However, there are huge material supply issues that limit the process of round skin spongelactone into clinical development.
Since spongelactone makes up only 0.002wt%D of dry matter, solubility is a rare natural source and does not provide the number of spongelactone required for clinical studies.
So synthetic chemists rose to the challenge of developing a scalable synthetic method to deal with the complex structure of sponge lactones, culminating in the first total synthesis of sponge lactones in 1993.
Since then, several other fully synthesized and reported various fragment constructions of spongelactone, with a 39-step synthesis of 60 g (+)-spongelactone (26 steps in the longest linear sequence) reported in 2004 (Protocol I).
Novartis gram-level synthesis of Scheme 1 (+)-round spongelactone.
The ability to manufacture natural products at this level of complexity suggests that full synthesis of complex, challenging natural product targets can be achieved, providing sufficient material for clinical research with the help of modern synthetic chemistry.
Without assuming its full complexity, some intermediates in natural product synthesis have key structural elements responsible for the biological activity of the parent natural product.
These intermediates can be used to determine the pharmacophores of natural products and are an important starting point for the synthesis of analogues, and the potential of this approach is illustrated by microglobulins, a highly effective analogue of soft spongein B (Protocol 2).
Scheme 2 Eisai synthesis of ezhibulin mesylate
Preliminary biological studies suggest that it interferes with microtubule dynamics by binding the periwinkle domain of tubulin in a noncompetitive manner and inhibits the growth of microtubules, ultimately leading to G2/M cell cycle arrest and apoptosis.
Given its promising anticancer activity in vitro and in vivo, soft spongein B was accepted by the National Cancer Institute for preclinical development in the early 1980s.
However, its future as a possible new chemotherapy drug remains uncertain due to severe material supply constraints that hinder the progress of natural products through the drug discovery pipeline.
Combination of soft sponge with natural products
Although the availability of soft spongein B extracted from sponges is very limited, its unique biological properties make it a highly attractive target.
The establishment of a synthetic route of soft spongein B allows the synthesis and evaluation of structurally simplified analogues that preserve his anticancer activity.
Biologically active natural products can be considered "privileged" scaffolds, which are evolutionarily selected for binding to specific regions of biological macromolecules.
They have the potential to address sparsely populated and underexplored chemical spaces, and as a result, many academic and industrial research programs prepare compounds to mimic the unique structural diversity of natural products.
Often, structural modifications with the potential to enhance biological properties may not be available directly from natural products.
However, when hypothesis-driven natural product analogues can be prepared by natural product synthesis already established synthetic routes.
Vancomycin, discovered by a pharmaceutical company, is a clinically important glycopeptide antibiotic that acts by binding to D-ala-D-Ala in peptidoglycan, an important component of bacterial cell wall biosynthesis (figure 3).
Fig. 3 Structure of vancomycin and amidovancomycin
Following the emergence of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin became the antibiotic of choice for the treatment of resistant bacterial infections; However, resistance to vancomycin has also developed.
The only significant form of resistance stems from the change of terminal D-alanine to D-lactic acid in the peptidoglycan precursor. This modification significantly reduces vancomycin's affinity for peptidoglycans, rendering it ineffective.
Following the total synthesis of vancomycin, they synthesized a series of analogues, including an analogue that modified an amide located deep inside vancomycin to amidine (Figure 3).
This amide-toamidine modification preserves the activity of a large number of antibiotics against vancomycin-sensitive strains, improves the binding affinity of the compound to the modified peptidoglycan in vancomycin-resistant strains, and restores the full antimicrobial activity of vancomycin-resistant bacteria.
This work demonstrates that structurally complex molecules in the field of natural product synthesis can not only be fabricated by total synthesis, but also systematically modified and evaluated.
In addition to its key role in drug discovery, natural product synthesis is being used to address the fascinating challenges posed by biology.
Enabling biologically significant natural products to be obtained in sufficient quantities and modifying the structure of natural products for chemical probe development has become an additional goal for synthetic chemists.
Therefore, the synthesis of natural products has a special role in chemical biology.
Isolated from colonial marine sea squirts, diazoamide A has attracted considerable attention from the organic chemistry community due to its potent cytotoxicity to various types of human cancer cell lines (Figure 4).
Figure 4 Structure of diazoamide A and its biotinylated derivatives
Initial NCI comparative screening showed that diazoamide A's antitumor activity derives from its microtubule-binding activity.
However, detailed mechanistic studies suggest that diazoamide A does not compete with other tubulin binders such as colchicine or vinblastine.
Based on the interesting biological activity and significant molecular structure of diazoamide A, the total synthesis of diazoamide A was completed, paving the way for structural modifications for the study of mode of action.
Notably, these studies also helped to correct the X-ray misallocation structure of diazoamide A and led to the discovery of misassignment, its origins, and the key structural reassignment that he proposed and synthetically confirmed.
Using a biotinylated derivative of diazoamide A (Figure 4), when determining ornithine-aminotransferase ™ (OAT), a mitochondrial matrix enzyme, is a molecular target of natural products.
These mechanistic studies propose a unique mode of action involving OAT and identify the protein as a target for chemotherapy drug development.
Here, the total synthesis of diazoamide A proved to be a key milestone leading to the discovery of the unexpected contradictory function of OAT in mitotic cell division.
Another good example highlighting the contribution of natural product synthesis to revealing mechanistic details is the work of Boger's group on , CC-1065, and (Figure 5).
Figure 5 Structures of duocarmycins, yatakemycin and CC-1065
These abnormal, cytotoxic natural products selectively bind and alkylate small grooves rich in DNA in the AT region.
By utilizing systematic total synthesis and basic chemical principles of natural products, a series of synthetic analogues were then generated and the relationship between the structure, reactivity and biological efficacy of natural products was determined.
Conformational changes caused by DNA binding are then used to disrupt key intercalamide conjugation in natural products, activate cyclopropane for nucleophile attack, and act as a catalyst for DNA alkylation. (Figure 6).
Figure 6 (+)-DNA alkylation model of duocarmycin SA.
In addition to elucidating the catalytic mechanism of CC-1065, they also revealed a parabolic relationship between intrinsic chemical reactivity and biological activity by fabricating analogues with a range of structural modifications.
These findings are only possible with efficient, convergent full synthesis suitable for system simulation synthesis.
epilogue
Due to their wide structural diversity and interesting biological activity, natural products make significant contributions in biomedical sciences.
In particular, natural products have been a major driver of many drug discovery initiatives in the pharmaceutical industry, however, the pharmaceutical industry has gradually become less serious about natural product chemistry over the past decade.
This downturn can be attributed to a variety of factors: First, the development of combinatorial chemistry and the introduction of high-throughput screening (HTS) for specific molecular targets have prompted many companies to abandon natural product extract libraries.
Challenges associated with isolating and purifying active ingredients from complex natural product extracts, lack of new entities in natural products, and finally, challenges in compound supply and lack of adequate structural diversification strategies in preclinical and clinical studies.
However, modest success in combinatorial chemistry and HTS, tremendous advances in automation of chromatography and spectroscopy, and the emergence of genome mining, novel heterologous expression systems, and metabolic engineering have reignited interest in natural products as valuable resources for drug discovery.
At the same time, in order to meet the challenges of material supply and the lack of adequate structural diversification strategies, the organic chemistry community has been introducing new and exciting developments to the synthesis of natural products, and as a result, the synthesis of natural products is becoming more and more complex.