A brief overview of classical natural product drug synthesis and bioactivity

Gen Li† ^a, Mingliang Lou† ^a and Xiangbing Qi *^ab
aNational Institute of Biological Sciences (NIBS), 7 Science Park Road ZGC Life Science Park, Beijing 102206, China. E-mail: qixiangbing@nibs.ac.cn
^bTsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China

First published on 20th November 2021

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Gen Li

Gen Li was born in Xinjiang, China. He received his B.Sc. (2004) in Chemistry from Xinjiang University and his Ph.D. (2011) degree in Chemical Biology from Peking University under the supervision of Professor Xin-Shan Ye. After a seven year research stage at Xinjiang Technical Institute of Physics and Chemistry, CAS, as an assistant professor and associate professor, he joined Qi's group at the National Institute of Biological Science (NIBS) at the beginning of 2019. His research interests focus on the total synthesis of natural products, and medicinal chemistry.

Mingliang Lou

Mingliang Lou was born in Anhui Province, China. He received his BS degree in Biology from Nankai University in 2014. In 2020, he received his Ph.D. degree in Medicinal Chemistry from Peking Union Medical College under the direction of Professor Xiangbing Qi. Currently, he works in the National Institute of Biological Sciences (NIBS) and focuses on natural product synthesis and drug development.

Xiangbing Qi

Xiangbing Qi was born in Shandong, China, and received his Ph.D. in chemistry and biochemistry from UT Southwestern Medical Center, Dallas, in 2005. After postdoctoral training at the University of Illinois Urbana-Champaign and medicinal chemistry research at UT Southwestern Medical Center, Dr Qi joined the faculty at the National Institute of Biological Sciences, Beijing, in 2013 and he is currently the Director of the Chemistry Center. The central theme of the research program is focused on the interface of synthetic chemistry, chemical biology, natural product total synthesis, and medicinal chemistry.

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1. Introduction

For millennia, nature has provided an invaluable source of traditional medicines from a variety of plants, animals, microorganisms, and minerals for humans to treat a wide spectrum of diseases. Since around 2600 BCE the successful use of natural medicines and remedies, particularly plant-originated substances, has been well documented in a large number of countries.¹ The World Health Organization (WHO) estimated in 1985 that more than 4000 million people in the world relied mainly on traditional medicines for their primary health care.² Since the 19^th century, developments in the fields of phytochemistry and analytical chemistry have enhanced humans’ ability to examine natural materials more deeply and to identify pure bioactive constitutes to further leverage the application potential of natural products.

Beginning with the isolation of morphine, the first active principle from the opium poppy, by German pharmacist Friedrich Sertürner in 1806, and followed by its commercialization as an analgesic and sedative by Merck in 1827,³ several active natural products were subsequently purified, such as cocaine and quinine from plant coca and cinchona, respectively (Fig. 1).⁴ However, not until the last century did drug discovery-based natural products come of age due to the scientific breakthroughs in modern chemistry and medicine. The natural products pool was enriched with broader chemical structures and diverse spectrum bioactivities. Compared with conventional synthetic molecules, naturally generated products are characterized by more complex skeletons with a higher molecular mass and a larger number of sp³-hybridized atoms, which can be advantageous for the exploration of small molecule and biomolecule interactions.

Despite the successful discovery of multiple drugs based on original natural products, such as morphine and artemisinin (Fig. 1), they still suffer from source and availability challenges. More importantly, the low success rate of the natural entity in approved drugs emphasizes the importance of structural optimization to improve natural products’ drug-like characteristics during drug development. With the development of new synthetic strategies and methodologies, more complex natural products have been assembled by efficient total synthesis or semisynthesis. The complementation of total synthesis strategies with semisynthetic transformations has been applied widely in the diversity- and bioactivity-oriented synthesis of drug-like entities.

Natural products and their synthetically modified analogs have historically made a remarkable contribution to the development of new drugs. A number of reports and books have reviewed the development of natural product-based drugs,^1,5–13 including antibiotic drugs,^14–16 antitumor agents,^17–20 analgesics,^21,22 and antiparasitic drugs.^23–25 All the reviews mentioned above emphasize that original natural products play significant roles in the drug discovery and development process. This is also confirmed further in the recent survey provided in serial reviews from Newman and Cragg,^5,26–29 which reported that only 463 purely synthetic drugs accounted for 24.6% of 1881 approved new chemical entities between 1981 and 2019. The rest of the new drugs on the market were either derived from the original natural structure or inspired by the rigidly complex skeletons of natural entities; 427 naturally occurring products (N, Newman and Cragg's category) and their structural derivatives (ND) were approved over almost 39 years.

Even though these reviews summarized nicely the natural product-based new drug development, druggability-related synthesis was not intensively tackled. We proposed to provide a brief overview of a miscellaneous collection of complex natural products synthesis and the endeavors of structure–activity relationships (SAR) studies to highlight the impact of chemical synthesis in natural product medicinal chemistry. Given the large number of approved natural product drugs in history, only the representative complex natural products whose chemical synthesis played an important role during the related drugs development are selected here. We admit that some natural products drugs, such as penicillin, vancomycin, ciclosporin, and rapamycin, are also classical and complex, but these are not covered due to limited space. Herein, the total synthesis of eight natural entities that were approved as drugs is presented according to the structural features, and the roles that total synthesis played in drug discovery and development are overviewed. The SAR studies are also discussed extensively.

2. Morphine and morphine derivatives

Morphine (1), isolated in 1806 by a German pharmacist, Friedrich Sertürner, is used primarily to treat both acute and chronic moderate-to-severe pain.^30–34 It functions through selective binding to the μ-type opioid receptor in the brain and spinal cord.^35,36 Many natural analogs and semisynthetic derivatives of morphine have been isolated or synthesized until now, some of which are presented in Fig. 2. The primary source of morphine and its congeners is isolation from the opium poppy, which is greatly affected by climate and political instability.^32,37 Although the morphine biosynthesis pathway has been elucidated and the laboratory scale production of morphine in yeast has been realized, major challenges remain to be addressed before the realization of practical strategies for industrial-scale production.^38,39 Therefore, total synthesis may be a plausible surrogate for extraction in the production of morphine and its derivatives.

The structure of morphine was first proposed by Robinson in 1925, and this structure was supported by Gates’ first total synthesis of morphine in 1952 and later by X-ray analysis in 1954.^40–43 As shown in Fig. 2, there are several intriguing structural features of morphine: a rigid pentacyclic bridged/fused ring structure (designated A, B, C, D, and E), five contiguous stereocenters (C5, C6, C9, C13, and C14) including one quaternary stereocenter (C13), an ether linkage between C4 and C5, two hydroxy groups (C3 and C6), a basic tertiary amine moiety, and a double bond between C7 and C8, which make its total synthesis a challenging task. The numerous studies on the synthesis of morphine alkaloids have led to over 40 synthesis routes, which have been summarized in several recent reviews.^{31,33,34,37,44,45} Selected representative routes for catalytic asymmetric total synthesis of morphine alkaloids will be discussed in the following section.

2.1 Catalytic asymmetric total synthesis of morphine alkaloids

2.2 Structure–activity relationships of morphine derivatives

As the prototypical opioid agonist, morphine (1) has been intensively studied, which led to various types of morphine-related drugs. Representative pentacyclic morphine-based drugs are listed in Fig. 3. There are several structural features that are important for morphine's biological function: the C3 phenolic hydroxy group, C6 allylic hydroxy group and C7–C8 double bond, the B/C cis-fused ring system, the substitution groups at C14, and the amine group. Detailed SAR studies have been summarized previously⁵⁶ and a brief discussion is provided in the following paragraph.

The C3 phenolic hydroxy group is essential for the binding of morphine with the μ receptor. Therefore, codeine (6), the C3 methoxy ether derivative of morphine, shows 10-fold lower potency than morphine.⁵⁷ However, codeine possesses greatly enhanced oral bioavailability. A similar relationship is observed between codeine-derivatized hydrocodone (56) and morphine-derivatized hydromorphone (9), which are the same as oxycodone (11) and oxymorphone (10).⁵⁶ These codeine-derivatives function as prodrugs and must undergo CYP2D6-mediated demethylation of their corresponding phenolic methyl ethers before binding to μ receptors.⁵⁶

The C6 allylic hydroxy group is engaged in a weak hydrogen bond between morphine and its receptor.⁵⁸ However, removal of the hydroxy group increases the molecular lipophilicity and therefore leads to a 10-fold increase in activity.⁵⁹ If the alcohol is oxidized to ketone, a 3-fold decrease in activity is observed; further hydrogenation of the C7–C8 double bond led to hydromorphone (9) with more flexibility in ring C, which shows a 6-fold increase in potency compared with morphine.⁵⁶ Introduction of a β-hydroxy group at C14 transforms hydromorphone (9) into oxymorphone (10), which shows a 2- to 3-fold increase in receptor affinity when compared with hydromorphone (9).

The essential amino nitrogen functions in a protonated form by forming an electrostatic bond with the receptor. Substituents at this nitrogen atom have a great influence on its biological function. A methyl group is commonly observed in morphine-derived agonists; however, naloxone (12) and naltrexone (13), with allyl or cyclopropylmethyl group, respectively, are pure antagonists.

3. Tetracyclines

Following the discovery of chlortetracycline (57) by Duggar in 1945,⁶⁰ several other natural tetracyclines—oxytetracycline (58),⁶¹ tetracycline (59),⁶² and demeclocycline (60),⁶³—were discovered in the following years (Fig. 4). The broad-spectrum activity and low side effects of tetracyclines make them one of the most important classes of antibiotics.⁶⁴ It is well established that tetracyclines function by binding to the 30S ribosomal subunit, which prevents the association of aminoacyl-tRNA with the bacterial ribosome and therefore inhibits bacterial protein synthesis.⁶⁵ Over 70 years of widespread use has resulted in the emergence of bacterial resistance to tetracyclines. There are three main mechanisms responsible for tetracycline resistance: (1) efflux pumps reduce the intracellular tetracycline concentration by exporting tetracycline from the cell; (2) ribosomal protection proteins protect ribosomes from tetracycline inhibition via various mechanisms; and (3) protection enzymes inactivate tetracycline through modification and degradation.^64,66–68 The growing problem of tetracycline resistance calls for much more investigation on the synthesis of tetracycline derivatives for the development of higher potency antibiotic drugs.

In the early 1950s, the structures of chlortetracycline (57) and oxytetracycline (58) were first determined by scientists from Pfizer with the help of Woodward.^69–71 Subsequent studies showed that the tetracyclines share one common nucleus, sancycline (61), which is composed of four linearly fused 6-membered rings (designated A, B, C, and D) with four stereocenters. A combination of different substitution groups, for example, chloride, hydroxy, and methyl, with the different substitution positions on the nucleus could lead to various tetracyclines with more structural complexity. The tetracyclines are frangible under an array of conditions: (1) the C6 hydroxy group undergoes dehydration in acidic media; (2) the C4 dimethylamino group epimerizes in mildly acidic conditions; and (3) the B and C rings undergo a retro-Dieckmann reaction in basic media.^72,73 The important biological functions and the complicated structural features of tetracyclines have attracted much attention of synthetic chemists.

3.1 Total synthesis of tetracyclines

3.2 Structure–activity relationships of tetracycline derivatives

Since the application of chlortetracycline (1) as the first broad-spectrum antibiotic, extensive efforts have been devoted to the SAR studies of tetracyclines, through natural tetracyclines to semisynthetic derivatives and then to fully total synthetic candidates. The tetracycline drugs can be roughly divided into four generations and representative members are presented in Fig. 6.

Naturally isolated tetracyclines are the main members of the first-generation drugs. These natural drugs share a common pharmacophore and comprise different substitution groups at C5, C6, and C7. Several structural features are important for their bioactivities. Maintenance of the four linearly fused six-membered carbocyclic skeleton and the α stereochemical configurations of C4, C4a, C5a, and C12a are essential for their high antibacterial activity.^64,91,92 Chelation with metal ions has a great influence on tetracyclines’ activity, and the keto–enol systems (C1–C3 and C11–C12) and the carboxamide (C2), which are the sites of interaction with ions, are necessary.^64,91 Alkylation of the carboxamide (C2) generally decreases activity, whereas suitable substituents can increase the water solubility, as in the case of the prodrug lymecycline.^64,92 Removal of the C4 dimethylamino or its replacement with higher alkylamino groups reduces activity.⁹¹ Furthermore, esterification of the C12a hydroxy group diminishes the activity.

However, as mentioned above, the C6 hydroxy group in these natural products is labile and undergoes dehydration in acidic media to produce anhydrotetracycline, which shows nephrotoxicity.⁹³ Therefore, removal of the C6 hydroxy group and further modifications through semisynthesis led to two second-generation drugs, doxycycline (94) and minocycline (98), which are more stable while maintaining similar or even higher antibacterial activity.^94,95

The widespread use of tetracycline antibiotics has brought about serious resistance problems, which has led to the call for more-effective drugs. Investigations on C9-substituted tetracyclines led to the discovery of one glycylcycline named tigecycline (101), which is a derivative of minocycline (98).⁹⁶ Tigecycline (101) shows high potency on tetracycline-resistant strains that utilize the efflux and ribosomal protection mechanisms of resistance.⁹⁷ However, tigecycline (101) is only available in an injectable formulation.⁹¹ Further modifications led to the discovery of omadacycline (99), which is a C9-aminomethylcycline. Compared with tigecycline (101), omadacycline (99) shows improved oral bioavailability while maintaining activity against tetracycline-resistant bacteria.⁹⁸ Another C7-aminomethylcycline, sarecycline (100), was approved as a narrow-spectrum tetracycline for the treatment of acne.

The success of the second- and third-generation tetracycline drugs indicates the potential role of the tetracycline pharmacophore in developing new antibiotics. However, the use of semisynthesis, as opposed to total synthesis, for the modification of tetracyclines has inherent limitations. The power of total synthesis is demonstrated by the approval of eravacycline (97),^89,99 the first fully synthetic tetracycline drug. We believe that total synthesis will play a much more important role in the campaign against growing antibiotic resistance.

4. Macrolides

The macrolides, a series of macrocyclic lactones with 14-, 15- and 16-membered rings and decorated with one or two sugar moieties are primarily isolated from different Streptomyces spp. The first macrolide and wide-spread antimicrobial agent, erythromycin (102), was isolated in 1952 from the culture broth of Saccharopolyspora erythera, and its structure features, a highly substituted 14-membered lactone bearing 10 chiral carbon atoms, and configuration were successively defined by chemical and X-ray diffraction studies.^100–102 Inspired by its excellent and broad-spectrum activity against Gram-positive pathogens, the mechanism by which erythromycin binds to the 23S RNA of the 50S ribosomal subunit to hamper the exit peptide tunnel and inhibit protein synthesis was elucidated and confirmed further by determining the crystal structure of erythromycin bound to the 50S ribosomal subunit.^103,104 Since erythromycin was launched as Ilosone to treat bacterial infections of the respiratory tract, skin, and soft tissues, the problem of varying levels of resistance to macrolides has been uncovered; resistance was characterized as resulting from the expression of efflux proteins in Gram-positive pathogens,^105,106 a change in erythromycin binding site in mutated ribosomal proteins,¹⁰⁷ and bio-modifications of macrolides by methylase^108,109 and esterases.^110,111 In addition, erythromycin is unstable, especially in acidic environments, due to ketal formation between the C6 and C12 hydroxy groups and the C9 ketone; this undesired side reaction alters the structural properties and leads to low safety and bioavailability.¹¹² To effectively address these problems and improve the drug-likeness potential of natural macrolides, total synthesis and semisynthesis strategies for the macrolides and their structural analogs have been explored to develop novel lead structures with new molecular features and mechanisms of actions.

4.1 Total synthesis of macrolides

4.2 Structure–activity relationships of macrolide derivatives

Since the discovery of erythromycin as the first macrolide with broad-spectrum antibacterial activity, the development of more potential novel antibiotic candidates has been spurred, leading to the preparation and testing of hundreds of macrolide derivatives. As mentioned above, spiroketal formation between the ketone at C9 with hydroxy groups at C6 and C11 under acidic conditions contributes to the low stability of erythromycin. To avoid this unpleasant side effect, a more acid-resistant and powerful derivative with a 6-O-methyl group was developed by Ōmura and co-workers in 1984; six years later this derivative, clarithromycin (133), was approved for clinical use (Fig. 7).¹¹⁸ Meanwhile, a 15-membered ring of azamacrolide was furnished through Beckmann rearrangement of erythromycin A oxime at C9. This new strategy from Lazarevski's group led to a novel chemical scaffold with excellent stability and activity; this chemical was approved as a new drug in 1988, named azithromycin (124). In addition, the C3-cladinose moiety was shown to be unnecessary for protein contact.¹¹⁹ The success of the marketed drug telithromycin (134) showed that its ability to bind to the ribosome was improved by the introduction of a C11/C12 carbamate ring with an extended aryl substituted alkyl chain, and binding was also improved by oxidation of the C3 hydroxy group to give C3 ketone without sugar.^120–122 However, a more effective antibiotic is urgently needed because of the serious drug resistance problem induced by the widespread use of the antibiotic. The development of more drug-like candidates for clinical applications, such as cethromycin (135) and solithromycin (136), is currently underway.

5. Vinca alkaloids

Vinblastine (137) and vincristine (138) are characteristic members of the biologically important vinca alkaloids (Fig. 8). Along with these two alkaloids, derivatives of these alkaloids, including vindesine (139), vinorelbine (140), and vinflunine (141), have been widely applied as well-known antitumor drugs. These molecules function through binding to tubulin, which disrupts microtubule function and results in mitotic arrest and apoptosis.^123–127

Vinblastine and vincristine were isolated from the leaves of Catharanthus roseus in 1958 and 1961,^128–130 respectively, and their absolute configuration was determined by X-ray crystallography in 1965.¹³¹ Both vinblastine and vincristine possess an upper velbanamine subunit and a lower vindoline or vindoline-derived subunit. For vinblastine, the lower vindoline subunit contains a pentacyclic skeleton (ABCDE rings), which bears six contiguous stereocenters on ring C with two quaternary chiral centers. The upper velbanamine subunit is composed of four rings, including one 9-membered ring C′. There are three stereocenters in the upper subunit, including the C16′ quaternary chiral center resulted from the linkage between the two subunits. The pharmaceutical importance combined with their intriguing structural features make this kind of alkaloid attractive synthetic targets, and great endeavors from the synthetic community in the past several decades have resulted in several elegant total syntheses of vinblastine and vincristine. These strategies are discussed in the following section.

5.1 Total synthesis of vinca alkaloids

5.2 Structure–activity relationships of vinblastine derivatives

Extensive SAR studies on vinblastine and related natural or synthesized derivatives led to the approval of several important antitumor drugs, some of which are listed in Fig. 8. However, the emergence of drug resistance caused by overexpression of the drug efflux pump phosphoglycoprotein (Pgp) calls for more potent vinblastine derivatives to be synthesized and evaluated in the future. Since several review papers have given a detailed summary of the SAR results,^147–150 we briefly discuss research progress achieved in recent years, especially those in Boger's laboratory (Fig. 9 and Table 1).

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Although substitution at the C12′ position of ring A′ in the upper velbanamine subunit (200 and 201) often led to reduced activity, substitution at the C10′ gave promising candidates. Applying their one-pot Fe(III)-mediated coupling and oxidation reaction, Boger and co-workers synthesized a series of vinblastine derivatives including the C10′-substituted ones.¹⁵¹ These derivatives exhibited activity that correlated with the size and shape of the substituents: 10′-chlorovinblastine 203 matched the potency of vinblastine; 10′-fluorovinblastine 202 exhibited an 8-fold increase in activity against both a sensitive (HCT116) and a vinblastine-resistant tumor cell line (HCT116/VM46); in contrast, derivatives bearing the larger (SMe, 204) or rigidly extended (CN, 205) substituents were 10–100-fold less potent. According to the X-ray structure of vinblastine bound to tubulin¹²⁷ and the results of activity assays, the authors proposed that the 10′-fluorine substituent interacts with the protein at a hydrophobic site uniquely sensitive to steric interactions.¹⁵¹

Initial substitution of the C20′ hydroxy group with a hydrogen atom (206) or free amine (207) gave derivatives with less potency.^152,153 Acetylation of the free amine (208) resulted in activity improvement, and a derivative with the urea group (209) showed comparable potency with vinblastine. However, these derivatives exhibited a further decrease in activity against a resistant HCT116/VM46 cell line compared with vinblastine. Further substitution of the terminal nitrogen led to improved activity against both sensitive and resistant cell lines (210 and 211). Finally, they found that the isoindoline-substituted compound 212 exhibited a 10-fold increase in activity against the sensitive HCT116 cell line and an 80-fold increase in activity against the resistant HCT116/VM46 cell line.

Replacement of the C16′ methyl ester with an ethyl ester (213), a cyano group (214), a primary carboxamide (215), or a hydroxy group (216) dramatically reduced the activity against both sensitive and resistant cell lines.¹⁵⁴ Derivatives (217–220) containing 6,6-, 5,5-, and 5,6-membered DE ring systems, instead of the vindoline 6,5-DE ring, were synthesized.¹⁵⁵ Among these analogs, 220 and 218 matched the potency of vinblastine and C17-deacetoxyvinblastine, respectively. Studies also showed that the N1-methyl group, C20 ethyl group, C14–C15 double bond, and C11 methoxy group were all essential to vinblastine's cytotoxic activity.¹⁵⁰

6. Taxol

One of the most famous natural taxane products, taxol (221, paclitaxel) was first isolated from the stem bark of Pacific yew by Wall and Wani in 1966, and in 1971 its complex structure was elucidated by NMR techniques and X-ray crystal structural analysis as a diterpenoid with a unique 6-8-6 tricyclic carbon skeleton bearing 11 stereocenters, an unusual oxetane ring, and a β-phenylisoserine chain ester at C13 (Fig. 10).¹⁵⁶ Because of its potent anticancer activity, the worldwide academic and industrial research communities have developed different taxane agents for clinical use in the treatment of various cancers, including the marketed Taxol® and Anzatax®, as well as the synthetic structural derivatives under the tradenames Taxotere®, Jevtana®, and Abraxane®. In addition to its unique structure, taxol also demonstrates modes of action different from those of known anticancer agents. Mechanistic studies showed that during cancer cell mitosis, taxol diffuses through nanopores in the microtubule to bind the β-tubulin subunit on the inner surface of the microtubule, thereby inhibiting the microtubule depolymerization process and arresting the cell in the late G₂/M phase, which blocks the cell division and leads to apoptosis. Cancer cells are believed to have a higher cell division rate than “normal” cells; therefore, they are more sensitive to taxol.^157–159 As observed for other target-specific anticancer drugs, the mechanism of action discussed above and the long-term use as a first-line treatment have given rise to resistance against taxane anticancer agents. The actual resistance mechanisms are unclear, even though many of these mechanisms have been uncovered in different cell lines. For example, the over-expression of the mdr1 gene gives rise to the drug efflux of the membrane-bound P-glycoprotein. The abnormal expression of microtubule-associated proteins leads to drug resistance.

Scarcity of the natural resources of taxane entities hampers the development of taxane-derived anticancer agents, and scientists from academia and industry never stop procuring the taxane products on an industrial scale. Research groups around the world have been working on the synthesis of taxanes and testing accessible synthetic strategies for the construction of the 20-carbon skeleton of the taxane family.

6.1 Total synthesis of taxol

6.2 Structure–activity relationships of taxol derivatives

The discovery of taxol as one of the most potent anticancer agents spurred a large number of academic and industrial researchers to investigate the SAR for identifying lead compounds with drug-likeness potential. However, the complex structure of taxol, a heavily oxygenated polycyclic diterpenoid, presents a huge challenge for pharmaceutical studies that call for a substance-rich library. A number of studies have uncovered the still-incomplete SAR information about taxol. This information has been described by several reviews,^179–183 and is summarized here in Fig. 11.

Studies on the modifications at C1, such as removal and esterification, revealed that the C1-OH is not essential for the activity of taxol.¹⁸⁴ In addition, C7-OH, C9-CO, and C10-OAc play insignificant roles in the anticancer activity of taxol.^185–188 SAR studies have shown that the benzoyl group at C2 is necessary for activity; 2-deoxy-taxol displayed decreased antitumor activity,¹⁸⁹ and 2-benzoate analogs did not lead to any remarkable improvement in biological activity in a microtubule assay or cytotoxicity test.¹⁸⁹ The acetoxy group at C4 was also demonstrated to be essential for activity, and the analog 4-deoxytaxol was inactive on several tumor cell lines.^190,191 However, oxetane plays a critical role in the bioactivity of taxol, and analogs in which the oxygen atom was replaced by nitrogen, sulfur, or other heteroatoms did not significantly enhance antitumor activity.^192,193

SAR studies revealed that the N-benzoyl-β-phenylisoserine side chain is essential for the antitumor activity of taxol, and this chain has attracted more extensive investigation than any other functional group of taxol.^194–198 A number of analogs with a modified side chain exhibit stronger activity than taxol, some of which are listed in Fig. 12, including two marketed drugs, docetaxel (Taxotere®, 1995) and cabazitaxel (Jevtana®, 2010).

7. Artemisinin

(+)-Artemisinin (QingHaoSu) (Fig. 13, 5), the most used drug against malaria worldwide, was isolated from the traditional Chinese medicine plant Artemisia annua L. in 1972 by Youyou Tu, who shared the 2015 Noble Prize for this discovery,¹⁹⁹ and (+)-artemisinin-based combination therapy is advocated by WHO. Artemisinin is a sesquiterpene lactone, and its structure is characterized by a unique 1,2,4-trioxane moiety, a pharmacophore that is a necessary endoperoxide bridge for the development of novel antimalaria drugs through semisynthesis of (+)-artemisinin. So far, pharmacological studies have not fully elucidated the exact mechanism of action of (+)-artemisinin, which is believed to be a pro-drug of carbon-centered free radical that plays a substantial role in antimalarial produced by cleavage of its endoperoxide ring inside erythrocytes. Upon bio-activation, the binding of (+)-artemisinin with low valent ions in hemin leads to reduction of the endoperoxide ring to produce an O radical, which subsequently generates a carbon free radical. This free radical is suggested to alkylate heme in the late stage of the parasite life cycle and react with reduced glutathione (GSH) in the early life-ring stage, after which cellular targets are selectively damaged.^200–205 Due to its different mechanism of action, (+)-artemisinin shows higher efficacy against multi-drug-resistant malaria compared with the old antimalarial agent quinine and synthetic drug chloroquine. However, along with the widespread use of (+)-artemisinin-based combination therapy in the world have come reports of resistance from different regions. The mechanism of artemisinin-resistance is unclear enough and mainly attributed to the C580Y mutation in Kelch13 (K13) of parasites, and associated elevation of the lipid product phosphatidylinositol-3-phosphate (PI3P). It may influence host remodeling, functions of the apicoplast and food vacuole, all of which protect the parasites against artemisinin challenge.^206,207 Therefore, there is an urgent need to develop novel drugs with new chemical scaffolds and, of course, different mechanisms of action would be excellent. But (+)-artemisinin is still sourced from plants with low yield, which limits the development of more efficient drugs. Therefore, exploring chemical synthesis methods, especially for the total synthesis of (+)-artemisinin, is important for academia and the pharmacy industry.

7.1 Total synthesis of artemisinin

7.2 Structure–activity relationships of artemisinin derivatives

Since the discovery of artemisinin (5) as an excellent antimalaria agent, the structural analogs such as dihydroartemisinin (294), artemether (296), arteether (342), artesunic acid (295), and sodium artesunate (343) have been investigated (Fig. 14); this is because the poor physicochemical properties of artemisinin (6), including its low solubility in both oil and water, and short half-life (t_1/2), limits its first-line clinical use. A large number of artemisinin derivatives and analogs have been explored in systematic SAR studies as part of an effort to seek more potential drug candidates.^222–229

In 2008, the first resistance to artemisinin was reported in Africa. Because of its worldwide use for a long time, WHO recommends artemisinin-based combination therapy (ACT) with different mechanisms and longer half-life instead of monotherapy using artemisinin to avoid the development and spread of resistance to artemisinin. The first-generation artemisinin-derived analogs dihydroartemisinin (294), artemether (296), arteether (342), artesunic acid (295), and sodium artesunate (343) were prepared by semisynthetic modifications at C10 with an acetal linkage; these analogs have improved physicochemical properties compared with their parent molecule, such as higher water-solubility. They are recommended by WHO to be used in combination with therapies such as ASAQ Winthrop (sodium artesunate-amodiaquine), Eurartesim (dihydroartemisinin-piperaquine), and ASMQ (sodium artesunate-mefloquine) for the treatment of malaria.

However, the drawbacks of analogs with the acid-sensitive acetal linkage include a short half-life and neurotoxicity. To overcome these drawbacks, the second-generation analogs without acetal groups were designed to improve the drug-like properties; in particular compounds 347 and 348 showed better activity (Fig. 15).²³⁰

The essential role of the peroxy bridge of artemisinin, which is the pharmacophore, in the development of antimalarials was established early after its discovery, and it was confirmed by the inactive analog deoxoartemisinin 349.²³¹ The orientation of the peroxide bond in the chemical scaffold of analogs is also important. For example, the tricyclic analog 350, which has a flexible peroxide ring displayed weaker antimalarial activity compared with the parent molecule artemisinin (Fig. 16).²³²

A number of semisynthetic analogs with tricyclic 1,2,4-trixoanes in a rigid scaffold lacking the D ring of artemisinin were developed, and many of them exhibited potential antimalarial activities in lower nanomolar ranges, such as analogs 351, 352, and 353 (Fig. 17).

Most semisynthetic drug-like analogs with complex chemical scaffolds are probably not suitable for pharmaceutical industry-scale production. The natural product yingzhausu A (354) has an accessible endoperoxide ring and displays good antimalarial activity. Spurred by this finding, a large number of simple analogs with endoperoxides have been designed and some of them display good antimalarial activity and offer great potential as drug candidates (Fig. 18).^233,234

8. Ecteinascidins

Ecteinascidins are a family of marine natural products containing two or three tetrahydroisoquinoline subunits (Fig. 19). Many ecteinascidin members show antiproliferative activity against several tumor cell lines.^235,236 Among these bioactive ecteinascidins, ecteinascidin 743 (Et-743, trabectedin, 357) was approved in 2007 for the treatment of advanced soft-tissue sarcoma and ovarian cancer, and lurbinectedin (363), one synthetic ecteinascidin derivative, was approved in 2020 for the treatment of metastatic small cell lung cancer.^237,238 Et-743 was first isolated in 1990 from a Caribbean tunicate Ecteinascidia turbinate and its absolute stereochemistry was determined in 1992 with the help of the X-ray crystal structure of its N12-oxide derivative.^239,240 Extensive studies of Et-743 show that this molecule functions by forming covalent adducts with DNA after binding to the minor groove of DNA and alkylating DNA at the N2 position of guanine.^241–243 The adducts can bend the DNA structure toward the major groove,^244,245 disrupt the interaction between DNA and DNA-binding proteins,²⁴⁶ and induce double-strand breaks (DBSs),²⁴⁷ all of which contribute to Et-743's antiproliferative activity on various cancer cell lines.

However, the natural source of Et-743 is limited: only 1.0 g of Et-743 can be isolated from about 1.0 ton of tunicate, which hampered its preliminary clinical studies.^235,236 In 1996, Corey and co-workers reported the first synthetic route for Et-743, which was initially used for its industrial production.²⁴⁸ A semisynthetic route relying on Corey's synthetic route was developed in 2000 for the commercial manufacture of Et-743.²⁴⁹ Apart from its biological function, Et-743 also has several structural features that make it a quite challenging but attractive synthetic target: (1) three tetrahydroisoquinoline moieties with different substitution patterns; (2) eight rings including one bridged 10-membered lactone ring containing a sulfur atom; (3) seven chiral centers including one spiro center; and (4) a labile carbinolamine functional group. Continuous efforts from the synthetic community have led to outstanding achievements in the total synthesis of Et-743 and we discuss them in the following section.

8.1 Total synthesis of Et-743

8.2 Structure–activity relationships of ecteinascidin derivatives

Although the reported total synthetic routes are not amenable to scaling-up for manufacturing ET-743 on an industrial scale, transformations developed in these studies provide access to diverse ecteinascidin derivatives, some of which are listed in Fig. 20. These synthesized ecteinascidin derivatives make SAR studies of Et-743 possible and have led to the development of more anti-tumor molecules including the approved drug lurbinectedin (363) and PM00104 (468), which is in phase II clinical trials. We give a short discussion about the SAR studies on ecteinascidin derivatives in the following section (Fig. 20 and Tables 2, 3).

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After achieving the first total synthesis of Et-743, Corey and co-workers synthesized a series of Et-743 analogs from a common intermediate, which led to the discovery of one simpler and more stable anti-tumor molecule named Pt 650 (phthalascidin, 462).²⁵⁷ In 2002, Saito and co-workers isolated Et-770 (360), an analog of Et-743, from the pretreated Thai tunicate Ecteinascidia thurstoni with potassium cyanide.²⁵⁸ Both Pt 650 and Et-770 showed antiproliferative activities on various cancer cell lines. Synthesis and evaluation of more synthesized analogs of Pt 650 and Et-770 revealed the structural features for high potent biological activities.^257–263

A cyano or a hydroxy group at the C21 position is essential and is responsible for alkylating DNA. Et-788 (449) with an amide group at C21 and 464 with hydrogen at C21 showed a significant decrease in activity compared with their corresponding parent compounds.^257,261 Oxidation of the sulfur atom in Et-770 led to Et-786, which resulted in dramatically diminished cytotoxicity.²⁵⁹ Protection of the C18 and C6′ phenolic hydroxy groups with allyl (450) or acetate (451) decreased cytotoxicity.^259,260 Protection of the C18 phenolic hydroxy group with MOM (465) also resulted in diminished antitumor activity.²⁵⁷

Modifications at the 2′-N position revealed that the 2′-N-allylated compound 452 showed activity similar to that of Et-770 (360), while several 2′-N amide derivatives including nitrogen-containing heterocycles (453 and 454) and cinnamoyl derivatives (455 and 456) exhibited improved cytotoxicity.^260–262 Notably, 454 and 456, respectively, exhibited approximately 50- and 70-fold higher cytotoxicity to the HCT116 cancer cell line than Et-770 (360).²⁶¹

Evaluation of the cytotoxicity of a series of C6′ aromatic ester derivatives showed that 457 and 458 with a nitro group or a methoxy group on the benzene ring exhibited activities similar to Et-770 (360).²⁶² However, derivatives with a bromo group on the benzene ring (459) or a naphthyl group (460) showed significantly decreased cytotoxicity. The incorporation of a nitrogen-containing heterocyclic ester group (461) resulted in a moderate increase in activity. For Pt 650 analogs, derivatives possessing a propionyl (466) or a methyl (467) protecting group on the C5 phenolic hydroxy group were slightly less effective than the parent compound Pt 650 (462).²⁵⁷ These results indicate the promising role of total synthesis in the future development of ecteinascidin-type and related natural products into drugs.

9. Calicheamicin γ^I₁

Calicheamicin γ^I₁ (474) is a potent antitumor antibiotic that was isolated from Micromonospora echinospora ssp in 1986. One year later, its structure was defined as an enediyne with a bicyclo[7.3.1]tridec-9-ene-2,6-diyne system, a unique N–O glycosidic linkage, and a methyl trisulfide moiety; other members of the calicheamicin family were also discovered (Fig. 21).^264–266 Several natural products containing the enediyne were also found in the 1980s, such as Neocarzinostatin chromophore (476),²⁶⁷ Esperamicin A1 (477),²⁶⁸ and Dynemicin A (478)²⁶⁹ (Fig. 21). Calicheamicin γ^I₁ displays excellent activity against Gram-negative and -positive bacteria at concentrations lower than 1 pg mL⁻¹. It demonstrated extreme toxicity to all cells, indicating that it has extraordinary potency against cancer cells. Investigation of its mechanism showed that calicheamicin γ^I₁ targets and binds to the DNA minor groove, and then undergoes the Bergman cyclization after bioreductive activation to produce a biradical, 1,4-didehydrobenzene, which subsequently abstracts hydrogen atoms from the deoxyribose backbone of DNA to generate sugar radicals. The latter undergo oxygen-dependent reactions and finally induce double-strand DNA breaks.^270–272 Because of its excellent activity and site-specific targeting, gemtuzumab ozogamicin (Mylotag®), a calicheamicin γ^I₁ derivative, was approved by the FDA in 2000 as an antibody–drug conjugate (ADC) to treat CD-33-positive myeloid leukemia. Unfortunately, 10 years later it was withdrawn from the market because of its serious side effects. In 2017, inotuzumab ozogamicin (Besponsa®), also derived from calicheamicin γ^I₁, was approved by the FDA as an ADC medication to treat relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia. All in all, the fascinating structure and highly potent drug-likeness characteristics of calicheamicin γ^I₁ have spurred chemists to meet the huge challenge of developing strategies for the total synthesis of calicheamicin γ^I₁.

9.1 Total synthesis of calicheamicin γ^I₁

9.2 Structure–activity relationships of calicheamicin γ^I₁ derivatives

As mentioned above, since calicheamicin γ^I₁ was discovered as a 10-membered enediyne with highly potent cytotoxicity against tumors, a number of synthetic analogs have been designed and used as ADC payloads in preclinical evaluations and clinical tests against tumors. According to the mechanism of action described, the enediyne subunit of calicheamicin γ^I₁ that plays an irreplaceable role in the generation of DNA lesions through the Bergman rearrangement is unchangeable, and the allylic trisulfide serves as a trigger to induce cycloaromatization. Studies of the semisynthetic aglycon analogs revealed that the role of carbohydrate fragments is to facilitate DNA binding and confer target specificity.^270,288 To date, SAR research has mainly focused on the modification and simplification of oligosaccharide fragments or trisulfide groups.

The four calicheamicin γ^I₁ analogs (Fig. 23), the natural products 471 and 472 and synthetic compounds 528 and 529, were all conjugated to CT-M-01 and the resultant derivatives were tested for therapeutic efficacy against MX-1 xenograft tumors. The results showed that compounds 472 and 528 with the DNA binding unit and the lack or modifications of amino sugar fragments showed stronger therapeutic efficacy than the parent molecule 474 and the derivatives 471 and 529, which missed the rhamnose at the DNA binding region. This result suggested that a rhamnose at the end of the binding region is required for ADC medications.²⁸⁹ CMB-401 (530) was further developed using a more stable amide-disulfide-based linker to conjugate it with hCTMO1 based on the structure of compound 528, and this compound was tested in phase I and phase II studies against epithelial ovarian cancer. However, no patients had objective responses in the phase II investigation. Scientists speculated that the sterically hindered disulfide failed to release the drug from the ADC payload.²⁸⁸

Calicheamicin θ^I₁ (Fig. 24, 531), a novel derivative of calicheamicin γ^I₁, was developed using thioester to replace the methyl trisulfide and prepared through total synthesis by the Nicolaou group. After the test, calicheamicin θ^I₁ was hypothesized to be a powerful biological tool for generating specific DNA lesions because of its highly potent and selective DNA cleaving, apoptosis-inducing, and cytotoxic properties.²⁹⁰ It was also discovered that calicheamicin θ^I₁ (531) effectively suppressed liver metastases in a novel syngeneic model of murine neuroblastoma and CD19-positive malignancies.^291,292 In some analogs, the allylic trisulfide was replaced by isopropyl disulfide or functionalized to improve the stability and solubility (Fig. 24, 532 and 533).^293,294 Gemtuzumab ozogamicin (Mylotag®, 534) and inotuzumab ozogamicin (Besponsa®, 535) are ADC drugs approved to treat myeloid leukemia and B-cell malignancies by the FDA in 2000 and 2017, respectively. Because of the important role that the linker plays in the effective release of the calicheamicin derivative from the conjugation product, allowing it to access the DNA target, a linker, 4-(4-acetylphenoxy)butanoic acid, was added to condensate drug and antibody. This conjugate showed stability in physiological buffer (pH 7.4) and the calicheamicin derivative was efficiently released inside lysosomes (pH 4.0) (Fig. 25).²⁹⁵

10. Conclusions

In this review, we discussed the total synthesis and SAR studies of eight representative families of natural products applied in the treatment of various human diseases. Although just the tip of the iceberg, these examples demonstrate the essential role of total synthesis in natural product drugs’ discovery: development of efficient transformations for natural products synthesis, especially the deep-seated structural modifications that are otherwise tough to achieve; and providing adequate and sustainable supplies of natural products and their analogs for clinical studies and use. From another standpoint, total syntheses of natural products, which often contain complex structural features, also promote the development of synthetic chemistry by inspiring the discovery of new reactions and reagents for rapid molecular assembly and structural diversifications. In combination with the development of other disciplines, such as synthetic biology and chemical biology, chemical synthesis will continue to play a profound role in functional mechanism elucidation, new biological target identification, and natural product medicinal chemistry.

Abbreviations

AcOH	Acetic acid
AIBN	2,2′-Azobisisobutyronitrile
BHT	Butylated hydroxytoluene
Boc2O	Di-tert-butyl dicarbonate
BOPCl	Bis(2-oxo-3-oxazolidinyl)phosphinic chloride
BPO	Benzoyl peroxide
CSA	Camphorsulfonic acid
DABCO	1,4-Diazabicyclo[2.2.2]octane
DBU	1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM	Dichloromethane
DEAD	Diethyl azodicarboxylate
1,2-DFB	1,2-Difluorobenzene
DIPAMP	(Ethane-1,2-diyl)bis[(2-methoxyphenyl)(phenyl)phosphine]
DIPEA	N,N-Diisopropylethylamine
DMAP	4-(N,N-Dimethylamino)pyridine
DMDO	Dimethyldioxirane
DME	1,2-Dimethoxyethane
DMF	N,N-Dimethylformamide
DMSO	Dimethyl sulfoxide
Dppp	1,3-Bis(diphenylphosphino)propane
DTBMP	2,6-Di-tert-butyl-4-methylpyridine
EDCI	N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
HFIP	Hexafluoroisopropanol
HMPA	Hexamethylphosphoramide
IBX	2-Iodoxybenzoic acid
KHMDS	Potassium bis(trimethylsilyl)amide
LDA	Lithium diisopropylamide
LICA	Lithium N-isopropylcyclohexylamide
LiDBB	Lithium di-tert-butylbiphenyl
LiHMDS	Lithium bis(trimethylsilyl)amide
LTMP	Lithium tetramethylpiperidide
m-CPBA	meta-Chloroperoxybenzoic acid
MesLi	Mesityllithium
MS	Molecular sieve
MsCl	Methanesulfonyl chloride
NaHMDS	Sodium bis(trimethylsilyl)amide
NBS	N-Bromosuccinimide
NMO	4-Methylmorpholine N-oxide
NTf2	Bis(trifluoromethylsulfonyl)imide
Pd2(dba)2	Bis(dibenzylideneacetone)palladium
PhNTf2	Bis(trifluoromethanesulfonyl)aniline
PMP	1,2,2,6,6-Pentamethylpiperidine
PPTS	Pyridinium p-toluenesulfonate
Red-Al	Sodium bis(2-methoxyethoxy)aluminiumhydride
[Rh(COD)Cl]2	Chloro(1,5-cyclooctadiene)rhodium(I) dimer
Rt	Room temperature
SARs	Structure–activity relationships
TBAF	tert-Butylammonium fluoride
TBAI	tert-Butylammonium iodide
TBSOTf	tert-Butyldimethylsilyl trifluoromethanesulfonate
TESOH	Triethylsilanol
Tf2O	Trifluoromethanesulfonic anhydride
TFA	Trifluoroacetic acid
TFAA	Trifluoroacetic anhydride
TFE	2,2,2-Trifluoroethanol
TfOH	Trifluoromethanesulfonic acid
THF	Tetrahydrofuran
TMEDA	Tetramethylethylenediamine
TMSCl	Chlorotrimethylsilane
TMSCN	Trimethylsilyl cyanide
TMSH	Trimethylsulfonium hydroxide
TMSimid	1-(Trimethylsilyl)imidazole
TMSOH	Trimethylsilanol
TPAP	Tetrapropylammonium perruthenate
TPP	Triphenylphosphine
TsOH	p-Toluenesulfonic acid

Author contributions

X. Q. conceived the study; G. L., M. L. and X. Q. prepared the manuscript; all authors discussed the contents and commented on the manuscript.

Conflicts of interest

The authors declare no conflict of interests.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No. 21971018). We gratefully acknowledge the Beijing Municipal Government and Tsinghua University for financial support.

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Footnote

† These authors made equal contribution.

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