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Artemisinin, a miracle of traditional Chinese medicine Ling Yi Konga and Ren Xiang Tan*b The 2015 Nobel Prize in Physiology or Medicine, shared by Professor Youyou Tu, focused worldwide attention on artemisinin, a natural product antimalarial drug inspired by traditional Chinese medicine
Received 29th October 2015
(TCM). This is the first Nobel Prize in natural sciences presented to a Chinese scientist for her impactful research work in China in collaboration with other Chinese scientists. We are delighted to provide the
DOI: 10.1039/c5np00133a
background and implications of the discovery of artemisinin, along with our personal viewpoints toward
www.rsc.org/npr
the affordability of modern medicines from natural products.
Alexander Fleming received the Nobel Prize in Physiology or Medicine in 1945 for his discovery of penicillin, a fungal natural product-based anti-infectious agent symbolizing the antibiotics era. Selman Waksman was awarded the same prize in 1952 for his driving role in unravelling streptomycin as the rst bacterial metabolite-derived antibiotic. Aer 63 years, this prestigious prize was recently announced to be awarded to natural product discoverers again. More eye-catching was that Youyou Tu, a senior Chinese pharmacologist at the China Academy of Traditional Chinese Medicine, was granted half of the prize for her major contribution to the discovery of artemisinin, which led eventually to a family of powerful antimalarial drugs. The artemisinin-related story has received and is attracting global attention from academics, industries, and politicians. More notably, this recognition represents the rst Nobel Prize in a natural science presented to a Chinese scientist, who completed this internationally impactful work in China in collaboration with her Chinese colleagues. Such a prestigious award to a TCM investigator, along with those discoverers of penicillin, streptomycin and avermectin (fellow 2015 Nobel awardees Satoshi Omura and William Campbell), collectively signies the extractability of modern drugs from TCMs and microbial natural products. Artemisinin is an annual wormwood (Artemisia annua L.) derived sesquiterpene lactone endoperoxide, which inhibits malaria parasite replication. Artemether, arteether and sodium artesunate are artemisinin derivatives which have also been licensed as drugs against severe malaria (Fig. 1). Even four decades aer its discovery, the artemisinin-based combination therapies (ACTs) remain the rst prioritized recommendation by the World Health Organization (WHO) for malaria treatment.
a
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
b
Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. E-mail: [email protected]
This journal is © The Royal Society of Chemistry 2015
If reminiscing on the whole process of artemisinin discovery and development, more impressive stories can be narrated because it was found from TCM in a specialized political atmosphere with key inspiration from the traditional medical practice, and eventually developed into a family of single compound-based antimalarials (Fig. 1).
Artemisinin discovery was co-triggered by war and tradition The Viet Nam War (1955–1975) in the tropical forests led to a widespread transmission of malaria, which could not be cured by any drugs available at that time and thus was a serious lifethreatening danger to both armies and local residents. Upon the Vietnamese leader's request in 1964 for help to alleviate the malaria threat, the Chinese government launched a top-priority research project aimed at new antimalarial discoveries. Preliminary efforts were focused on synthetic quinolines and dichroine (an alkaloid from Dichroa febrifuga Lour.). Unfortunately, the two-year endeavor terminated in failure, and the relevant officials had a re-coordination meeting on May 23, 1967 to initiate a new program branded as the “523 Project” (‘523’ representing ‘May 23rd’).1 Before Youyou Tu joined the “523 Project” in 1969, Chinese researchers had screened approximately 10 000 herbal medicines and compounds, yet delivered no appropriate lead candidates. To continue the work, it was suggested to select herbal medicines with malaria-treating records for further assays. Youyou Tu and her colleagues surveyed all consultable traditional antimalarial recipes to realize that the herb under the Artemisia genus was a component of ca. 640 recipes, though short of its exact taxonomical classication at the species level in ancient TCM monographs. Aer their intensive screening efforts, they focused on the annual wormwood whose antimalarial effect was also recorded in the Compendium of Materia Medica written by Shizhen Li (1518–1593). However, they found
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Fig. 1
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A class of anti-antimalarials derived from artemisinin.
that the inhibition rate of the wormwood extract on malaria protozoa in mice was unstable and changed in a range of 12– 68% in repeated assessments. To address this mystery, Youyou Tu and her colleagues scrutinized the classical description of using the Artemisia herb for malaria treatment. She got special inspiration from a ‘manual-like' description: “Extraction of a handful of fresh wormwood with ca. 400 mL water gives the ‘wormwood juice’, which, aer drunk, helps to treat malaria”, as per Principal Prescriptions for Emergency compiled by Ge Hong in 340 AD in China's Eastern Jin Dynasty. Youyou Tu realized that the antimalarial wormwood phytochemical(s) might be labile and decompose upon the evaporation of extraction solvents (water or aqueous alcohol) at higher temperature. Thus, the wormwood was re-extracted with ethyl ether to afford the anticipated extract under no. 191, which exhibited a repeatable inhibition rate of 100% against malaria in mice.1,2 So, one of Youyou Tu’s important contributions toward the nal discovery of artemisinin lies in her rst-time application of ethyl ether to extract the antimalarial wormwood phytochemical. Chemists were then aware of the decomposition of artemisinin over 60 C owing to its endoperoxide moiety.
Ling Yi Kong received his PhD in Medicinal Chemistry in 1992 from Shenyang College of Pharmacy, and continued his twoyear postdoctoral research at China Pharmaceutical University, where he has been working ever since. He was promoted to full professor (1997), dean of the School of Traditional Chinese Pharmacy (1997–2012), and vice-president since 2013. He was a visiting scholar to Meijo University, Japan (1998–1999), and a visiting professor to Kyushu University, Japan (2009). His research interest is the discovery of bioactive products from traditional Chinese medicines and other natural sources with potential application as medicines. He has authored some 300 scientic publications and seven monographs.
1618 | Nat. Prod. Rep., 2015, 32, 1617–1621
Artemisinin structure challenged chemists Shortly aer the above nding, a clinical trial was conducted by Juzhong Liang's team (Yunnan Institute of Materia Medica) to validate the antimalarial effect of the A. annua extract, which in turn expedited the fractionation procedure for the active phytochemical. In 1972, Youyou Tu and her collaborator Zhenxing Wei (Shandong Institute of Traditional Chinese Medicine) obtained a puried compound originally called “qinghaosu” (renamed later as ‘artemisinin') simply according to the Chinese pronunciation of “a sweet wormwood-derived essential chemical”. To researchers' expectations, the antimalarial efficacy of pure artemisinin was assessed in the clinic to be more potent than quinoline drugs by Guoqiao Li and his coworkers at Guangzhou University of Chinese Medicine. However, it was surprisingly difficult to elucidate the structure of artemisinin, thereby severely hampering the further development of artemisinin-based antimalarial(s). Such a challenge interested Weishan Zhou at the Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS). Zhou's group was able to elucidate the structure of artemisinin by
Ren Xiang Tan received his B.S. in 1983 and M.S. in 1986 from China Pharmaceutical University, and his Ph.D in 1990 in Organic Chemistry from Lanzhou University. Aer joining Nanjing University as an associate professor in 1992, he was promoted to Professor (1994) and Chair Professor (1999). He was a visiting scholar to Technical University of Berlin (Germany, Prof. F. Bohlmann), University of Lausanne (Switzerland, Prof. K. Hostettmann), and University of California, San Diego (USA, Prof. W. Fenical). His research interests include the structure, biosynthesis, and bioactivity of symbiont-derived natural products. He has authored 4 monographs (editor-in-chief), 27 patents, and 300+ papers.
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chemical derivation and spectral analysis (though very primitive at that time). In 1975, Xiaotian Liang and Dequan Yu (Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College) reported the endoperoxide-carrying structure of yingzhaosu A, an antimalarial sesquiterpene from Artabotrys hexapetalus (L.f.) Bhandari.3 Inspired by the structure of yingzhaosu A, Weishan Zhou and his colleague Yulin Wu speculated and proved the presence of the endoperoxide motif in the artemisinin molecule, whose ultimate structure was elucidated through X-ray single crystal diffraction in 1977.4 With this progress, the absolute conguration of artemisinin was subsequently determined in conjunction with chemical reactions by Weishan Zhou and his coworkers, such as Xingxiang Xu.4–6 The assignment of the structure of artemisinin led to the characterization of dihydroartemisinin, which is chemically more modiable.6 This enabled many medicinal chemists, such as Dayuan Zhu, Haoming Gu and Ying Li (Shanghai Institute of Materia Medica, CAS),7 and Xu Liu (Guilin Pharmaceutical Factory), to investigate the structure–activity relationship of artemisinin and its analogues to collectively afford a series of dihydroartemisinin derivatives, including artemether, arteether and sodium artesunate, which have been licensed as antimalarial drugs (Fig. 1) prescribed singly or in combination with other antimalarials.
Artemisinin-derived drugs revolutionized malaria treatment Malaria has been a life-threatening disease since ancient times. Quinine used to be the most effective antimalarial agent in the 19th century, and newly synthesized chloroquine and primaquine also rescued many malaria patients aer World War II. However, owing to the rapid development of drug resistance in the 1960s, these alkaloidal antimalarials became insufficiently effective or inactive, and malaria infection went out control again in many parts of the world, particularly in Southeast Asia and Africa. The unprecedented structure and satisfying potency of artemisinin made it distinct from the alkaloidal antimalarials in its mode of action. This is why artemisinin-based combination therapies have been repeatedly recommended by the WHO as the most effective strategy for the treatment of malaria nowadays. Artemisinin-derived drugs are being prescribed in over 30 countries. In the continent of Africa alone, artemisininbased drugs are annually prescribed for approximately 250 million patients. As the Nobel Prize Committee announced (http://www.nobelprize.org/nobel_prizes/medicine/laureates/ 2015/press.html), when used in combination therapy, it is estimated to reduce mortality from malaria by more than 20% overall and by more than 30% in children, highlighting that over 100 000 lives have been saved each year.
Artemisinin supply is guaranteed chemically and biologically Many elegant research achievements have been carried out to provide a stable supply of artemisinin. Although the brilliant
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Natural Product Reports
total synthesis of artemisinin remains uncommercialized, alternative synthetic points of access towards artemisinin have been developed from citronellal,8 limonene,9 piperitone,10 and b-pinene.11 In 2012, Cook and Zhu reported their ve-step synthesis of artemisinin from cyclohexenone with an overall yield of 14%, which seems to be a promising approach of supplying artemisinin.12 In A. annua, artemisinic acid is an abundant biosynthetic precursor of artemisinin, and has been used as a starting material for the semi-synthesis of artemisinin-based drugs.13,14 Utilizing a special catalyst, Wangbin Zhang et al. accomplished the synthesis of artemisinin from artemisinic acid in a yield of approximately 60%, thereby providing a new promising scalable production of artemisinin-derived medicines.15 With such an advancement, it is now feasible to prepare artemisinin from its biosynthetic precursors such as amorpha fruticosa-4,11-diene,16 artemisinic acid,17 and dihydroartemisinic acid,18 all being richly affordable through metabolic engineering technologies as developed by Keasling et al.19,20 Yet, there has been no report describing the production of artemisinin itself by any non-botanical vectors such as yeast, presumably due to the lack of the ‘special cellular environment' required by artemisinin biosynthesis in the glandular trichome cells of A. annua.21 Meanwhile, knowledge about the antimalarial mechanism of action of artemisinin drugs is accumulating quickly.22,23 In 2006, the rst artesunate-resistant case was noticed in Cambodia, and the tolerance of artemisinin-derived drugs has been a renewed global concern. The loss of efficacy of artemisininbased antimalarials may result from the mutation of some malaria protozoan genes.24 For example, the protozoan genes K13 and PfKelch13 were found to be closely related to the tolerance to artemisinin-derived medicines.25,26 Needless to say, the artemisinin discovery-based Nobel Prize doesn’t mean the nal victory in our race with malaria protozoa, which, in the authors' opinion, could be endless.
Concluding remarks Traditional medicines such as TCMs have been optimised from one dynasty to another as a brilliant and versatile arsenal useful to cure various diseases. The records and descriptions in ancient medical monographs were gradually nalized directly according to clinical feedback from patients who repeatedly received particular sorts of traditional medications. The narrated artemisinin story does underscore the possibility that the impact of TCM could be multiplied incalculably by multicultural and multi-disciplinary understandings of these historic treasures. Yet, we should be aware that the development of artemisinin into single compound-based antimalarials relied on later-emerged pharmaceutical technologies. All medicines, either traditional or modern, must be safe and effective to work for the common and sole goal of improving human health, thus in the present investigation aimed at new drugs from TCMs or natural products sourced elsewhere, researchers should follow modern theories, use updated techniques, and develop licensed medicines according to well-rened procedures.
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The artemisinin story has also visualized the governmental role in directing research activities. Probably as in other countries, most scientists in China can choose their own projects and apply for nancial support through various pipelines which reect the necessity of society. More scientic progress in China is being perceived and cited globally. Inspired by the artemisinin story, more Chinese scientists may dedicate themselves to addressing the unsolved key issues that affect human survival on this lovely but challenging planet. However, as implicated by artemisinin-based antimalarials, such a civilization-promoting goal could only be achieved through multi-disciplinary collaboration among thoughtful and persistent scientists across traditions, cultures and nations. Back to nature, all phytochemicals including artemisinin are biosynthesized for the tness of plants to arrays of biotic and abiotic environmental factors.27 Single-celled microbes are also efficient producers of natural products with important biological properties and seem more sensitive to stimuli perceived from their surroundings. In this sense, the long-time and changing natural selection keeps driving both macro- and micro-organisms to evolve continuously, and to reshape their natural product chemical proles. This makes natural products unpredictable, both structurally and biologically. That is why natural products remain a reliable source of lead compounds in drug discovery, because of their unique chemical space and potential interactions with disease-associated proteins.28,29 Biological resources are abundant and renewable on Earth, and the well-investigated species are just a small percentage of the total. Mysterious tropical forests, vast oceans and microorganisms in special environments are particularly rich sources of bioactive natural products. Furthermore, more molecular complexity can be generated via an extending list of approaches such as genome mining30 and chemically induced biosynthesis.31,32 Such facts, along with the 2015 Nobel Prize to artemisinin and avermectin discoverers, collectively promote the renaissance of natural products chemistry, which may attract more industrial enthusiasm to expedite the discovery of new biomolecule-derived drugs necessary nowadays and in the future.
Acknowledgements The authors thank Prof. Guo-Qiang Lin (SIOC, CAS) for generously providing valuable documents, and Drs. Ming Hua Yang (China Pharmacetical Univ.) and Kun Du (Nanjing Univ.) for their help in the literature search and gure preparation.
References 1 R. H. Li, Y. Rao and D. Q. Zhang, J. Dialectics Nat., 2013, 35, 107–121. 2 Y. L. Wu, Progr. Chem., 2009, 21, 2365–2371. 3 X. T. Liang, D. Q. Yu, W. L. Wu and H. C. Deng, Acta Chim. Sin., 1979, 37, 215–230. 4 Qinghaosu Antimalarial Coordinating Research Group, Chin. Sci. Bull., 1977, 22, 142–145.
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5 Qinghaosu Research Group of Institute of Biophysic, Sci. China, 1979, 11, 1114–1128. 6 J. M. Liu, M. Y. Ni, J. F. Fan, Y. Y. Tu, Z. H. Wu, Y. L. Wu and W. S. Zhou, Acta Chim. Sin., 1979, 37, 129–143. 7 Y. Li, P. L. Yu, Y. X. Chen, L. Q. Li, Y. Z. Gai, D. S. Wang and Y. P. Zheng, Chin. Sci. Bull., 1979, 24, 667–669. 8 J. S. Yadav, B. Thirupathaiah and P. Srihari, Tetrahedron, 2010, 66, 2006–2009. 9 J. S. Yadav, R. S. Babu and G. Sabitha, Tetrahedron Lett., 2003, 44, 2387–2389. 10 A. A. Mitchell, K. M. C. Wesley and J. W. Clive, J. Am. Chem. Soc., 1992, 114, 974–979. 11 G. Schmid and W. Hoeinz, J. Am. Chem. Soc., 1983, 105, 624–625. 12 C. Y. Zhu and S. P. Cook, J. Am. Chem. Soc., 2012, 134, 13577– 13579. 13 B. Ye and Y. L. Wu, Tetrahedron, 1989, 45, 7287–7290. 14 T. L. Peter and M. N. Deanne, Tetrahedron Lett., 1992, 33, 1029–1032. 15 W. B. Zhang, D. L. Liu and Q. J. Yuan, China Pat., 201210181561.7, 2012. 16 P. J. Westfall, D. J. Pitera, J. R. Lenihan, D. Eng, F. X. Woolard, R. Regentin, T. Horning, H. Tsuruta, D. J. Melis, A. Owens, S. Fickes, D. Diola, K. R. Benjamin, J. D. Keasling, M. D. Leavell, D. J. McPhee, N. S. Renninger, J. D. Newman and C. J. Paddon, Proc. Natl. Acad. Sci. U. S. A., 2012, 109, E111–E118. 17 F. L´ evesque and P. H. Seeberger, Angew. Chem., Int. Ed. Engl., 2012, 51, 1706–1709. 18 M. Farhi, E. Marhevka, J. Ben-Ari, A. Algamas-Dimantov, Z. Liang, V. Zeevi, O. Edelvaum, B. Spotzer-Rimon, H. Abelinvich, B. Schwartz, T. Tzra and A. Vainstein, Nat. Biotechnol., 2011, 29, 1072–1074. 19 J. D. Keasling, Science, 2010, 330, 1355–1358. 20 C. J. Paddon, P. J. Westfall, D. J. Pitera, K. Benjamin, K. Fisher, D. McPhee, M. D. Leavell, A. Tai, A. Main, D. Eng, D. R. Polichuk, K. H. Teoh, D. W. Reed, T. Treynor, J. Lenihan, M. Fleck, S. Bajad, G. Dang, D. Dengrove, D. Diola, G. Dorin, K. W. Ellens, S. Fickes, J. Galazzo, S. P. Gaucher, T. Geistlinger, R. Henry, M. Hepp, T. Horning, T. Iqbal, H. Jiang, L. Kizer, B. Lieu, D. Melis, N. Moss, R. Regentin, S. Secrest, H. Tsuruta, R. Vazquez, L. F. Westblade, L. Xu, M. Yu, Y. Zhang, L. Zhao, J. Lievense, P. S. Covello, J. D. Keasling, K. K. Reiling, N. S. Renninger and J. D. Newman, Nature, 2013, 496, 528– 532. 21 P. S. Covello, K. H. Teoh, D. R. Polichuk, D. W. Reed and G. Nowak, Phytochemistry, 2007, 68, 1864–1871. 22 N. J. White, Science, 2008, 320, 330–335. 23 J. Wiesner, R. Ortmann, H. Jomaa and M. Schlitzer, Angew. Chem., Int. Ed., 2003, 42, 5274–5293. 24 U. E. Ludwing, R. J. Webb, I. D. A. V. Goethem, J. M. East, A. G. Lee, M. Kimura, P. M. O. Neill, P. G. Bray, S. A. Ward and S. Krishna, Nature, 2003, 424, 957–961. 25 F. Ariey, B. Witkowski, C. Amaratunga, J. Beghain, A. C. Langlois, N. Khim, S. Kim, V. Duru, C. Bouchier, L. Ma, P. Lim, R. Leang, S. Duong, S. Sreng, S. Suon,
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C. M. Chuor, D. M. Bout, S. Menard, W. O. Rogers, B. Genton, T. Fandeur, O. Mitto, P. Ringwald, J. L. Bras, A. Berry, J. C. Barale, R. M. Fairhurst, F. B. Vical, O. M. Puijalon and D. Menard, Nature, 2014, 505, 50–55. 26 A. Mbengue, S. Bhattacharjee, T. Pandharkar, H. Liu, G. Estiu, R. V. Stahelin, S. S. Rizk, D. L. Njimoh, Y. Ryan, K. Chotivanich, C. Nguon, M. Ghorbal, J. J. L. Rubio, M. Pfrender, S. Emrich, N. Mohandas, A. M. Dondorp, O. Wiest and K. Haldar, Nature, 2015, 520, 683–687. 27 J.-K. Weng, New Phytol., 2014, 201, 1141–1149. 28 D. J. Newman and G. M. Cragg, J. Nat. Prod., 2012, 75, 311– 335.
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29 J. L. Medina-Franco, K. Martinez-Mayorga and N. Meurice, Expert Opin. Drug Discovery, 2014, 9, 151–165. 30 K. Yamanaka, K. A. Reynolds, R. D. Kersten, K. S. Ryan, D. J. Gonzalez, V. Nizet, P. C. Dorrestein and B. S. Moore, Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 1957–1962. 31 W. Yan, H. M. Ge, G. Wang, N. Jiang, Y. N. Mei, R. Jiang, S. J. Li, C. J. Chen, R. H. Jiao, Q. Xu, S. W. Ng and R. X. Tan, Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 18138– 18143. 32 L. P. Lin, P. Yuan, N. Jiang, Y. N. Mei, W. J. Zhang, H. M. Wu, A. H. Zhang, J. M. Cao, Z. X. Xiong, Y. Lu and R. X. Tan, Org. Lett., 2015, 17, 2610–2613.
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Cite this: Nat. Prod. Rep., 2015, 32, 1617
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Artemisinin, a miracle of traditional Chinese medicine Ling Yi Konga and Ren Xiang Tan*b The 2015 Nobel Prize in Physiology or Medicine, shared by Professor Youyou Tu, focused worldwide attention on artemisinin, a natural product antimalarial drug inspired by traditional Chinese medicine
Received 29th October 2015
(TCM). This is the first Nobel Prize in natural sciences presented to a Chinese scientist for her impactful research work in China in collaboration with other Chinese scientists. We are delighted to provide the
DOI: 10.1039/c5np00133a
background and implications of the discovery of artemisinin, along with our personal viewpoints toward
www.rsc.org/npr
the affordability of modern medicines from natural products.
Alexander Fleming received the Nobel Prize in Physiology or Medicine in 1945 for his discovery of penicillin, a fungal natural product-based anti-infectious agent symbolizing the antibiotics era. Selman Waksman was awarded the same prize in 1952 for his driving role in unravelling streptomycin as the rst bacterial metabolite-derived antibiotic. Aer 63 years, this prestigious prize was recently announced to be awarded to natural product discoverers again. More eye-catching was that Youyou Tu, a senior Chinese pharmacologist at the China Academy of Traditional Chinese Medicine, was granted half of the prize for her major contribution to the discovery of artemisinin, which led eventually to a family of powerful antimalarial drugs. The artemisinin-related story has received and is attracting global attention from academics, industries, and politicians. More notably, this recognition represents the rst Nobel Prize in a natural science presented to a Chinese scientist, who completed this internationally impactful work in China in collaboration with her Chinese colleagues. Such a prestigious award to a TCM investigator, along with those discoverers of penicillin, streptomycin and avermectin (fellow 2015 Nobel awardees Satoshi Omura and William Campbell), collectively signies the extractability of modern drugs from TCMs and microbial natural products. Artemisinin is an annual wormwood (Artemisia annua L.) derived sesquiterpene lactone endoperoxide, which inhibits malaria parasite replication. Artemether, arteether and sodium artesunate are artemisinin derivatives which have also been licensed as drugs against severe malaria (Fig. 1). Even four decades aer its discovery, the artemisinin-based combination therapies (ACTs) remain the rst prioritized recommendation by the World Health Organization (WHO) for malaria treatment.
a
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
b
Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China. E-mail: [email protected]
This journal is © The Royal Society of Chemistry 2015
If reminiscing on the whole process of artemisinin discovery and development, more impressive stories can be narrated because it was found from TCM in a specialized political atmosphere with key inspiration from the traditional medical practice, and eventually developed into a family of single compound-based antimalarials (Fig. 1).
Artemisinin discovery was co-triggered by war and tradition The Viet Nam War (1955–1975) in the tropical forests led to a widespread transmission of malaria, which could not be cured by any drugs available at that time and thus was a serious lifethreatening danger to both armies and local residents. Upon the Vietnamese leader's request in 1964 for help to alleviate the malaria threat, the Chinese government launched a top-priority research project aimed at new antimalarial discoveries. Preliminary efforts were focused on synthetic quinolines and dichroine (an alkaloid from Dichroa febrifuga Lour.). Unfortunately, the two-year endeavor terminated in failure, and the relevant officials had a re-coordination meeting on May 23, 1967 to initiate a new program branded as the “523 Project” (‘523’ representing ‘May 23rd’).1 Before Youyou Tu joined the “523 Project” in 1969, Chinese researchers had screened approximately 10 000 herbal medicines and compounds, yet delivered no appropriate lead candidates. To continue the work, it was suggested to select herbal medicines with malaria-treating records for further assays. Youyou Tu and her colleagues surveyed all consultable traditional antimalarial recipes to realize that the herb under the Artemisia genus was a component of ca. 640 recipes, though short of its exact taxonomical classication at the species level in ancient TCM monographs. Aer their intensive screening efforts, they focused on the annual wormwood whose antimalarial effect was also recorded in the Compendium of Materia Medica written by Shizhen Li (1518–1593). However, they found
Nat. Prod. Rep., 2015, 32, 1617–1621 | 1617
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Published on 12 November 2015. Downloaded by University of Newcastle on 13/12/2016 07:14:30.
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Fig. 1
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A class of anti-antimalarials derived from artemisinin.
that the inhibition rate of the wormwood extract on malaria protozoa in mice was unstable and changed in a range of 12– 68% in repeated assessments. To address this mystery, Youyou Tu and her colleagues scrutinized the classical description of using the Artemisia herb for malaria treatment. She got special inspiration from a ‘manual-like' description: “Extraction of a handful of fresh wormwood with ca. 400 mL water gives the ‘wormwood juice’, which, aer drunk, helps to treat malaria”, as per Principal Prescriptions for Emergency compiled by Ge Hong in 340 AD in China's Eastern Jin Dynasty. Youyou Tu realized that the antimalarial wormwood phytochemical(s) might be labile and decompose upon the evaporation of extraction solvents (water or aqueous alcohol) at higher temperature. Thus, the wormwood was re-extracted with ethyl ether to afford the anticipated extract under no. 191, which exhibited a repeatable inhibition rate of 100% against malaria in mice.1,2 So, one of Youyou Tu’s important contributions toward the nal discovery of artemisinin lies in her rst-time application of ethyl ether to extract the antimalarial wormwood phytochemical. Chemists were then aware of the decomposition of artemisinin over 60 C owing to its endoperoxide moiety.
Ling Yi Kong received his PhD in Medicinal Chemistry in 1992 from Shenyang College of Pharmacy, and continued his twoyear postdoctoral research at China Pharmaceutical University, where he has been working ever since. He was promoted to full professor (1997), dean of the School of Traditional Chinese Pharmacy (1997–2012), and vice-president since 2013. He was a visiting scholar to Meijo University, Japan (1998–1999), and a visiting professor to Kyushu University, Japan (2009). His research interest is the discovery of bioactive products from traditional Chinese medicines and other natural sources with potential application as medicines. He has authored some 300 scientic publications and seven monographs.
1618 | Nat. Prod. Rep., 2015, 32, 1617–1621
Artemisinin structure challenged chemists Shortly aer the above nding, a clinical trial was conducted by Juzhong Liang's team (Yunnan Institute of Materia Medica) to validate the antimalarial effect of the A. annua extract, which in turn expedited the fractionation procedure for the active phytochemical. In 1972, Youyou Tu and her collaborator Zhenxing Wei (Shandong Institute of Traditional Chinese Medicine) obtained a puried compound originally called “qinghaosu” (renamed later as ‘artemisinin') simply according to the Chinese pronunciation of “a sweet wormwood-derived essential chemical”. To researchers' expectations, the antimalarial efficacy of pure artemisinin was assessed in the clinic to be more potent than quinoline drugs by Guoqiao Li and his coworkers at Guangzhou University of Chinese Medicine. However, it was surprisingly difficult to elucidate the structure of artemisinin, thereby severely hampering the further development of artemisinin-based antimalarial(s). Such a challenge interested Weishan Zhou at the Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS). Zhou's group was able to elucidate the structure of artemisinin by
Ren Xiang Tan received his B.S. in 1983 and M.S. in 1986 from China Pharmaceutical University, and his Ph.D in 1990 in Organic Chemistry from Lanzhou University. Aer joining Nanjing University as an associate professor in 1992, he was promoted to Professor (1994) and Chair Professor (1999). He was a visiting scholar to Technical University of Berlin (Germany, Prof. F. Bohlmann), University of Lausanne (Switzerland, Prof. K. Hostettmann), and University of California, San Diego (USA, Prof. W. Fenical). His research interests include the structure, biosynthesis, and bioactivity of symbiont-derived natural products. He has authored 4 monographs (editor-in-chief), 27 patents, and 300+ papers.
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chemical derivation and spectral analysis (though very primitive at that time). In 1975, Xiaotian Liang and Dequan Yu (Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College) reported the endoperoxide-carrying structure of yingzhaosu A, an antimalarial sesquiterpene from Artabotrys hexapetalus (L.f.) Bhandari.3 Inspired by the structure of yingzhaosu A, Weishan Zhou and his colleague Yulin Wu speculated and proved the presence of the endoperoxide motif in the artemisinin molecule, whose ultimate structure was elucidated through X-ray single crystal diffraction in 1977.4 With this progress, the absolute conguration of artemisinin was subsequently determined in conjunction with chemical reactions by Weishan Zhou and his coworkers, such as Xingxiang Xu.4–6 The assignment of the structure of artemisinin led to the characterization of dihydroartemisinin, which is chemically more modiable.6 This enabled many medicinal chemists, such as Dayuan Zhu, Haoming Gu and Ying Li (Shanghai Institute of Materia Medica, CAS),7 and Xu Liu (Guilin Pharmaceutical Factory), to investigate the structure–activity relationship of artemisinin and its analogues to collectively afford a series of dihydroartemisinin derivatives, including artemether, arteether and sodium artesunate, which have been licensed as antimalarial drugs (Fig. 1) prescribed singly or in combination with other antimalarials.
Artemisinin-derived drugs revolutionized malaria treatment Malaria has been a life-threatening disease since ancient times. Quinine used to be the most effective antimalarial agent in the 19th century, and newly synthesized chloroquine and primaquine also rescued many malaria patients aer World War II. However, owing to the rapid development of drug resistance in the 1960s, these alkaloidal antimalarials became insufficiently effective or inactive, and malaria infection went out control again in many parts of the world, particularly in Southeast Asia and Africa. The unprecedented structure and satisfying potency of artemisinin made it distinct from the alkaloidal antimalarials in its mode of action. This is why artemisinin-based combination therapies have been repeatedly recommended by the WHO as the most effective strategy for the treatment of malaria nowadays. Artemisinin-derived drugs are being prescribed in over 30 countries. In the continent of Africa alone, artemisininbased drugs are annually prescribed for approximately 250 million patients. As the Nobel Prize Committee announced (http://www.nobelprize.org/nobel_prizes/medicine/laureates/ 2015/press.html), when used in combination therapy, it is estimated to reduce mortality from malaria by more than 20% overall and by more than 30% in children, highlighting that over 100 000 lives have been saved each year.
Artemisinin supply is guaranteed chemically and biologically Many elegant research achievements have been carried out to provide a stable supply of artemisinin. Although the brilliant
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total synthesis of artemisinin remains uncommercialized, alternative synthetic points of access towards artemisinin have been developed from citronellal,8 limonene,9 piperitone,10 and b-pinene.11 In 2012, Cook and Zhu reported their ve-step synthesis of artemisinin from cyclohexenone with an overall yield of 14%, which seems to be a promising approach of supplying artemisinin.12 In A. annua, artemisinic acid is an abundant biosynthetic precursor of artemisinin, and has been used as a starting material for the semi-synthesis of artemisinin-based drugs.13,14 Utilizing a special catalyst, Wangbin Zhang et al. accomplished the synthesis of artemisinin from artemisinic acid in a yield of approximately 60%, thereby providing a new promising scalable production of artemisinin-derived medicines.15 With such an advancement, it is now feasible to prepare artemisinin from its biosynthetic precursors such as amorpha fruticosa-4,11-diene,16 artemisinic acid,17 and dihydroartemisinic acid,18 all being richly affordable through metabolic engineering technologies as developed by Keasling et al.19,20 Yet, there has been no report describing the production of artemisinin itself by any non-botanical vectors such as yeast, presumably due to the lack of the ‘special cellular environment' required by artemisinin biosynthesis in the glandular trichome cells of A. annua.21 Meanwhile, knowledge about the antimalarial mechanism of action of artemisinin drugs is accumulating quickly.22,23 In 2006, the rst artesunate-resistant case was noticed in Cambodia, and the tolerance of artemisinin-derived drugs has been a renewed global concern. The loss of efficacy of artemisininbased antimalarials may result from the mutation of some malaria protozoan genes.24 For example, the protozoan genes K13 and PfKelch13 were found to be closely related to the tolerance to artemisinin-derived medicines.25,26 Needless to say, the artemisinin discovery-based Nobel Prize doesn’t mean the nal victory in our race with malaria protozoa, which, in the authors' opinion, could be endless.
Concluding remarks Traditional medicines such as TCMs have been optimised from one dynasty to another as a brilliant and versatile arsenal useful to cure various diseases. The records and descriptions in ancient medical monographs were gradually nalized directly according to clinical feedback from patients who repeatedly received particular sorts of traditional medications. The narrated artemisinin story does underscore the possibility that the impact of TCM could be multiplied incalculably by multicultural and multi-disciplinary understandings of these historic treasures. Yet, we should be aware that the development of artemisinin into single compound-based antimalarials relied on later-emerged pharmaceutical technologies. All medicines, either traditional or modern, must be safe and effective to work for the common and sole goal of improving human health, thus in the present investigation aimed at new drugs from TCMs or natural products sourced elsewhere, researchers should follow modern theories, use updated techniques, and develop licensed medicines according to well-rened procedures.
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The artemisinin story has also visualized the governmental role in directing research activities. Probably as in other countries, most scientists in China can choose their own projects and apply for nancial support through various pipelines which reect the necessity of society. More scientic progress in China is being perceived and cited globally. Inspired by the artemisinin story, more Chinese scientists may dedicate themselves to addressing the unsolved key issues that affect human survival on this lovely but challenging planet. However, as implicated by artemisinin-based antimalarials, such a civilization-promoting goal could only be achieved through multi-disciplinary collaboration among thoughtful and persistent scientists across traditions, cultures and nations. Back to nature, all phytochemicals including artemisinin are biosynthesized for the tness of plants to arrays of biotic and abiotic environmental factors.27 Single-celled microbes are also efficient producers of natural products with important biological properties and seem more sensitive to stimuli perceived from their surroundings. In this sense, the long-time and changing natural selection keeps driving both macro- and micro-organisms to evolve continuously, and to reshape their natural product chemical proles. This makes natural products unpredictable, both structurally and biologically. That is why natural products remain a reliable source of lead compounds in drug discovery, because of their unique chemical space and potential interactions with disease-associated proteins.28,29 Biological resources are abundant and renewable on Earth, and the well-investigated species are just a small percentage of the total. Mysterious tropical forests, vast oceans and microorganisms in special environments are particularly rich sources of bioactive natural products. Furthermore, more molecular complexity can be generated via an extending list of approaches such as genome mining30 and chemically induced biosynthesis.31,32 Such facts, along with the 2015 Nobel Prize to artemisinin and avermectin discoverers, collectively promote the renaissance of natural products chemistry, which may attract more industrial enthusiasm to expedite the discovery of new biomolecule-derived drugs necessary nowadays and in the future.
Acknowledgements The authors thank Prof. Guo-Qiang Lin (SIOC, CAS) for generously providing valuable documents, and Drs. Ming Hua Yang (China Pharmacetical Univ.) and Kun Du (Nanjing Univ.) for their help in the literature search and gure preparation.
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