International Symposium on Natural Products
Chemistry and Chemical Biology2012
Hangzhou, China
November 23-26, 2012
Organizers
Zhejiang University, China
The Management Commission of Hangzhou Economic and Technological Development Zone, China
Nagoya University, Japan
Sponsors
ZhejiangUniversity of Technology, China
National Natural Science Foundation of China (NSFC)
Asian Chemical Biology Initiative, Japan
Japan Society for the Promotion of Science (JSPS)
Baicao Traditional Chinese Medicine Co., Ltd.
Covered Topics
1. Isolation and Structure Elucidation of Natural Products
2. Chemosynthesis and Biosynthesis of Natural Products
3. Chemical Biology and Related Areas
4. Drug Discovery and Development
Organization
Honorary Chairmen
Prof. Yinchu Shen (Member of the Chinese Academy of Engineering, ZhejiangUniversity of Technology)
Chairmen
Prof. Jianhua Qi (ZhejiangUniversity)
Prof. Daisuke Uemura (NagoyaUniversity)
Academic Committee
Chairmen of the Academic Committee
Prof. Makoto Ojika (NagoyaUniversity)
Prof. Yongzhou Hu (ZhejiangUniversity)
Members of the Academic Committee
Prof. Su Zeng Prof. Yongping Yu Prof. Zhujun Yao
Prof. Zhengwei Fu Prof. Jianhua Qi
Organizing Committee
Chairmen of Organizing Committee
Prof. Jianhua Qi (ZhejiangUniversity)
Prof.Motonari Uesugi (KyotoUniversity)
Prof. Yongping Yu (ZhejiangUniversity)
Members of Organizing Committee
Jianhua Bi Liming Wang Junmin Li Weiguang Shan Jianzhong Chen
Liurong Chen Chen Zhang Ping Wang Rong Sheng Hongbin Zou
Secretariat
Secretary-general
Prof. Ping Wang (ZhejiangUniversity of Technology)
Members of Secretariat
Zhijun Zhu Wei Liu Lan Xiang Tao Liu Wendai Jing Xingyi Zhu Jie Xie Qinying Yan
Schedule
November 23th
Registration
12:00- Yuanzheng Qizhen Hotel
November 24th
Meeting Hall 349, College of Pharmaceutical Sciences, ZhejiangUniversity
Morning Session
8:45-9:05 Opening Remarks
9:05-9:25 Group Photo
9:25-9:30 Memorial Speech for Professor Youji Sakagami
1. 9:30-10:05
Topic: Intriguing natural products from marine sources
Speaker: Prof. Daisuke Uemura (Faculty of Science, KanagawaUniversity, Japan)
Moderator: Prof. Zhujun Yao
2. 10:05-10:40
Topic:The achievements of professor Youji Sakagami, a pioneer of plant and microbial peptide hormone researches
Speaker:Prof. Makoto Ojika (GraduateSchool of Bioagricultural Sciences, Nagoya University, Japan)
Moderator: Prof. Zhujun Yao
3. 10:40-11:15
Topic: SexualreproductioninducersofPhytophthora (Dedicatedtothelate
professorYoujiSakagami)
Speaker: Prof. Jianhua Qi (College of Pharmaceutical Sciences,Zhejiang University, China)
Moderator:Prof. Toshio Nishikawa
4. 11:15-11:50
Topic:Mining functional organic compounds from nature
Speaker:Prof. Renxiang Tan (Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China)
Moderator: Prof. Toshio Nishikawa
12:00-13:30 Lunch
Afternoon Session
5. 13:30-14:05
Topic:Peptide isoprenylation
Speaker: Dr. Masahiro Okada (College of Bioscience and Biotechnology, Chubu University, Japan)
Moderator: Prof. Hirokazu Kawagishi
6. 14:05-14:40
Topic:Integrative approach for target identification of bioactive compounds
Speaker:Prof. Hiroyuki Osada (Chemical Biology Core Facility, RIKEN ASI, Japan)
Moderator:Prof. Hirokazu Kawagishi
7. 14:40-15:15
Topic: Biosynthesis-based natural product discovery
Speaker:Prof. Wen Liu (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, China)
Moderator: Dr. Masahiro Okada
15:15-15:35 Tea Break
8. 15:35-16:10
Topic: Biology-oriented study of natural products: unnatural dual-functional abeo-taxanoids
Speaker: Prof. Zhujun Yao (School of Chemistry and Chemical Engineering,Nanjing University, China)
Moderator: Dr. Masahiro Okada
9. 16:10-16:45
Topic: Synthetic studies on natural products by means of RCM
Speaker: Prof. Tohru Fukuyama (GraduateSchool of Pharmaceutical Sciences, NagoyaUniversity) (GraduateSchool of Pharmaceutical Sciences, University of Tokyo, Japan)
Moderator: Prof. Daisuke Uemura
18:00- Banquet
November 25th
Meeting Hall 349, College of Pharmaceutical Sciences, ZhejiangUniversity
Morning Session
- 8:45-9:20
Topic:Total synthesis of 13-oxyingenol and its natural derivative
Speaker:Prof. Hideo Kigoshi (Department of Chemistry, GraduateSchool of Pure and Applied Sciences, University of Tsukuba, Japan)
Moderator: Prof. Makoto Ojika
- 9:20-9:55
Topic: Synthesis of guanidine-containing natural products
Speaker: Prof. Toshio Nishikawa (GraduateSchool of Bioagricultural Sciences, Nagoya University, Japan)
Moderator: Prof. Makoto Ojika
- 9:55-10:30
Topic:Chemical diversity and the bioactive compounds from marine invertebrates inhabited in South China Sea
Speaker:Prof. Wenhan Lin (State Key Laboratory of Natural and Biomimetic Drugs, Peking University, China)
Moderator: Prof.Motonari Uesugi
4. 10:30-11:05
Topic: Anti-parasitic agents from marine organisms
Speaker: Prof. Yoichi Nakao (School of Advanced Science and Engineering, Waseda University, Japan)
Moderator: Prof.Motonari Uesugi
5. 11:05-11:40
Topic:The angel’s wing mystery-attempt to disclose the molecular mechanism of acute encephalopathy caused by eating angel’s wing oyster mushroom (Sugihiratake)
Speaker:Prof. Hirokazu Kawagishi (GraduateSchool of Science and Technology, Shizuoka University, Japan)
Moderator: Prof. Wenhan Lin
12:00-13:30 Lunch
Afternoon Session
6. 13:30-14:05
Topic: Ajmaline biosynthesis: from alkaloid structure to enzyme structure
Speaker: Prof. Joachim Stöckigt (College of Pharmaceutical Sciences,Zhejiang
University, China)
Moderator: Prof. Wen Liu
7. 14:05-14:40
Topic:Small molecules that block fat synthesis
Speaker: Prof. Motonari Uesugi (Institutes for Integrated Cell-Material Sciences (WPI-iCeMS) and for Chemical Research (ICR), Kyoto University, Japan)
Moderator: Prof. Wen Liu
8. 14:40-15:15
Topic:Analogues of cyclic ADP-ribose and their functions to regulate calcium signal pathway
Speaker:Prof. Liangren Zhang (School of Pharmaceutical Sciences, Peking University, China)
Moderator: Prof. Joachim Stöckigt
15:15-15:35 Tea Break
9. 15:35-16:10
Topic: Food signals and circadian rhythm
Speaker:Prof. Zhengwei Fu (College of Biological and Environmental Engineering, ZhejiangUniversity of Technology, China)
Moderator: Prof. Joachim Stöckigt
10. 16:10-16:45
Topic: Small molecules targeting mitochondrial UQCRB
Speaker:Prof. Ho Jeong Kwon (Chemical genomics NRL, Department of Biotechnology, Yonsei University, Korea)
Moderator: Prof. Hideo Kigoshi
11. 16:45-17:20
Topic: Introduction of Hangzhou Economic and Technological Development Zone
Speaker:Mr. Ronggang Zhang (The Management Commission of Hangzhou Economic and Technological Development Zone)
Moderator: Prof. Hideo Kigoshi
17:20-17:30 Closing Remarks
18:00- Banquet
November 26th
Excursion
1
Intriguing Natural Products from Marine Sources
Daisuke Uemura
Faculty of Science, Kanagawa University, Japan
Many compounds with extraordinary chemical structures and brilliant bioactivities have been identified from marine organisms. In this presentation, I will describe the fascinating natural products I have been investigating to explore novel frontiers in both chemistry and bioscience. My presentation covers three main topics.
- Halichondrin and metagenome-assisted production.
- Luminaolide, a metamorphosis enhancer in coral larvae
- Lyngbyacyclamides A and B, structure and total synthesis
1. Halichondrin and metagenome-assisted production
Halichondrin B was isolated from the black sponge Halichondria okadai, in 1986. Interestingly, this polyether macrolide exhibited antitumor activity both in vitro and in vivo. The mechanism of action of halichondrin B was shown to be a novel one that disrupts the polymerization dynamics of tubulin, which makes this natural product an interesting candidate for the treatment of cancer. However, the difficulty of collecting sufficient material (only 12.5mg from 600kg of sponge) impaired studies for its development. The complete synthesis of halichondrin B in 1992 represented a breakthrough. The total synthesis also revealed that the activity resides in the macrocyclic lactone C1-C38 moiety. Ultimately, the moiety derivative was approved for the treatment of breast cancer in several countries and is now available on the market as the drug Halaven.
Although useful natural products such as halichondrins and okadaic acid have been isolated from extracts of Halichondria okadai, it is not clear whether the black sponge itself synthesizes these compounds. Recent studies have suggested that some as-yet-uncultivable symbiotic microorganisms are true sources of these compounds. Therefore, we isolated the genes of symbiotic bacteria in this black sponge and established a 160,000 fosmid library. I will discuss our marine meta-genome project in detail.
2. Luminaolide, a metamorphosis enhancer in coral larvae
The settlement and metamorphosis of larvae of many marine invertebrates are known to be influenced by crustose coralline algae (CCA). Some of these algae inhibit, while others induce, settlement and/or metamorphosis. In our search for bioactive substances in CCA, we found that fragments of coral rubble with the CCA Hydrolithon reinboldii induced larval metamorphosis in the scleractinian coral Leptastrea purpurea. Based on these observations, we isolated a novel macrodiolide, luminaolide, from H. reinboldii as a natural enhancer of larval metamorphosis by a simple bioassay with larvae of L. purpurea. This is the first example of a macrolide that enhances the metamorphosis of scleractinian coral larvae, and could help to protect coral reefs.
3.Lyngbyacyclamides A and B, structures and total synthesis
Cyanobacteria are photosynthetic prokaryotes and that are widely distributed throughout marine and terrestrial environments. Members of the marine cyanobacteria genus Lyngbya are known to produce structurally interesting and biologically active secondary metabolites. We have purified new compounds lyngbyacyclamides A and B. The biological activities of these compounds are quite unique, since they show toxicity against B16 melanoma cells, but not brine shrimp. Efforts to synthesize these molecules are currently underway so that we can elucidate the mechanism of action of Lyngbyacyclamides.
References
- Exploratory research on bioactive natural products with a focus on biological phenomena., D. Uemura, Proc. Jpn. Acad., Ser. B, 86, 190-201 (2010)
- Construction of a metagenomic library for the marine sponge, Halichondria okadai., T. Abe, F.P. Sahin, K. Akiyama, T. Naito, M. Kisigami, K. Miyamoto, Y. Sakakibara, and D. Uemura, Biosci. Biotechnol. Biochem., 76, 1233-1315 (2012)
- Halichondrins-antitumor polyether macrolides from a marine sponge., Y. Hirata and D. Uemura, Pure Appl. Chem., 58, 701, (1986)
- Luminaolide, a novel metamorphosis-enhancing macrodiolide for scleractinian coral larvae from crustose coralline algae., M. Kitamura, P. Schupp, Y. Nakano, and D. Uemura, Tetrahedron Lett., 50, 6606-6609 (2009)
- Lyngbyacyclamides A and B, novel cytotoxic peptides from marine cyanobacteria Lyngbya sp., Tetrahedron Lett., 51, 6384-6387 (2010)
This presentation is dedicated to the memory of the late Professor Youji Sakagami
1
The Achievements of Professor Youji Sakagami, a Pioneer of Plant and Microbial Peptide Hormone Researches
Makoto Ojika
GraduateSchool of Bioagricultural Sciences, Nagoya University, Japan
Dr. Youji Sakagami,professor of NagoyaUniversity and Yongqian chair professor of ZhejiangUniversity, passed away on April 9, 2012. This deeply disappointed me, as I had been a member of his laboratory for 6 and a half year.Here, I wish to introduce his extraordinary achievements with my deepest condolences.
He had tried to solve many issues on endogenous bioactive substances such as hormones and pheromones. When he started his academic research, he was surprised at the fact that little endogenous peptides had been discovered from plants and microorganisms and made this puzzle his life work. He finally clarified that such endogenous peptides actually existed as uniquely modified forms, contributing to the recent development in the field of the natural peptide research. One of his biggest achievements is the discovery of the plant peptide hormone phytosulfokine (PSK),1 the first example of sulfated peptides, laying the foundations for the general idea of "plant peptide hormones". Furthermore, the biosynthesis and mode of action of PSK have been revealed (Fig. 1).2He then identified a morphogenesis inducer of shoot apices3 and a stomatal differentiation enhancer.4 He also discovered microorganism peptides, e.g., a basidiomycete sex pheromone, tremelogen A-10, as a peptide with a terminal S-farnesylcysteine,5 and one of the Bacillus subtilis quorum sensing pheromones ComX as the first peptide with a unusually modified tryptophan.6Though non-peptides, he identified sexual hormones of the crop pathogen Phytophthora in collaborations with professor Jianhua Qi and me.7,8 These achievements were published in a number of excellent journals such as Science (6 papers) and Nature Chemical Biology (3 papers), and appears to be created from his outstanding research stance: to focus on the issues that had not been reported in reviews and books yet and to purify genuine functional molecules by using originally developed bioassays (but not to predict from genomic data bases).
References
1. Matsubayashi, Y. et al. PNAS, 93, 7623 (1996).
2. Matsubayashi, Y. et al. Science,296, 1470(2002).
3. Kondo, T. et al. Science, 313, 845 (2006).
4. Kondo, T. et al. Plant Cell Physiol.51, 1(2010).
5. Sakagami, Y. et al. Science, 212, 1525 (1981).
6. Okada, M. et al. Nat. Chem. Biol.1, 23 (2005).
7. Qi, J. et al.Science, 309, 1828(2005).
8. Ojika, M. et al. Nat. Chem. Biol. 7, 591 (2011).
Ojika’s representative publications
1. Ojika, M.; Molli, S. D.; Kanazawa, H.; Yajima, A.; Toda, K.; Nukada, T.; Mao, H.; Murata, R.; Asano, T.; Qi,J.; Sakagami, Y. The second Phytophthora mating hormone defines interspecies biosynthetic crosstalk, Nat. Chem. Biol. 7, 591-593 (2011).
2. Ojika, M.; Inukai, Y.; Kito, Y.; Hirata, M.; Iizuka, T.; Fudou, R. Miuraenamides: antimicrobial cyclic depsipeptides isolated from a rare and slightly halophilic myxobacterium,Chem. Asian J.3, 126-133(2008).
3. Ojika, M.; Kigoshi, H.; Yoshida, Y.; Ishigaki, T.; Nisiwaki, M.; Tsukada, I.; Arakawa, M.; Ekimoto, H.; Yamada, K. Aplyronine A, a potent antitumor macrolide of marine origin, and the congeners aplyronines B and C: isolation, structures, and bioactivities,Tetrahedron63, 3138-3167(2007).
4. Qi, J.; Asano, T.; Jinno, M.; Matsui, K.; Atsumi, K.; Sakagami, Y.; Ojika, M. Characterization of a phytophthoramating hormone,Science, 309, 1828(2005).
5.Onodera, K.; Nakamura, H.; Oba, Y.; Ohizumi, Y.; Ojika, M., Zooxanthellamide Cs: vasoconstrictive polyhydroxylated macrolides with the largest lactone ring size from a marine dinoflagellate of Symbiodinium sp. J. Am. Chem. Soc.127, 10406-10411(2005).
1
Sexual Reproduction Inducers of Phytophthora
Jianhua Qi
Institute of Materia Medica, College of Pharmaceutical Sciences,
Zhejiang University, China
(Dedicated to the late professor Youji Sakagami.)
Members of the genus Phytophthoracause devastating plant diseases that threaten crops worldwide.Theability of these species to reproduce sexually might account for their genetic diversity and aggressive pathogenicity.Therefore, characterization of the endogenous factors (-hormones) that stimulate sexual reproduction of the Phytophthora should beessential to control the pathogen.
Since their existence was first proposed by Ashby in 1929, the mating hormones that induced sexual reproduction in Phytophthora have received great attention.1)Howeverseveral decades past, numerous attempts have been made to isolate and determine the structure of these hormones, their details are still unknown.2-4) We spent 11 years on this project. In 2005, 1.2 mg of pure hormone 1was obtained from supernatantof culture broths (approximately 1,830 L)of the A1 mating type. 5)The full planar structure of hormone 1 was determined by the combination analysis of MS, one- and two-dimensional NMR spectra.5) The structure was then confirmed by chemical derivation methods.
To support future synthesis of1, we determined the absolute configuration of the two terminal stereogenic centers, C-3 and C-15, by NMR analysis of the Mosher’s esters of1 and the synthetic model compound.6) We then synthesized four optically pure diastereomers with the fixed 3R and 15R configurations.7) Very small differences among synthesized samples were observed by 13C NMR. Thus, it was difficult to distinguish the natural hormone 1 from the synthetic samples. Consequently, determination of the absolute configurations of the natural hormone 1 by NMR analyses alone could be impossible for this linear diterpene. Therefore, the oospore-inducing activities of the synthesizedisomers were testedin comparison with thatofthe natural hormoneα1.The isomer3R,7R,11R,15Rinduced significant oospore formation on the A2 mating type of P. nicotianae at a dose of 30 ng, which was similar to that of natural hormone 1.7) On the other hand, no remarkable oospore formation was induced by other three isomers at the tested doses. These results indicated that the natural hormone 1 possesses the 3R,7R,11R,15Rabsolute configurations.7)Recently, the absolute stereostructure of the second mating hormone 2 was defined by spectroscopic analysis and total synthesis.8) We have uncovered not only the interspecies universality of hormones but also the pathway by which 2 is biosynthesized from phytol by A2strains and metabolized to 1 by A1 strains as shown in the figure below.
References
1. Ashby, S.F.:Trans. Br. Mycol. Soc.,14, 18-38 (1929).
2. Ko, W.H.:J. Gen. Microbiol.,107, 15-18 (1978).
3. Chern, L.L., Tang, C.S., Ko, W.H.:Bot. Bull. Acad. Sin., 40, 79-85 (1999).
4. Jee, H.J., Tang, C.S., Ko, W.H.:Bot. Bull. Acad. Sin.,43, 203-210 (2002).
5. Qi, J., Asano, T., Jinno, M., Matsui, K., Atsumi, K.,Sakagami,Y., Ojika, M.:Science, 309, 1828-1828 (2005).
6. Ojika, M., Qi, J., Kito, Y., Sakagami, Y.:Tetrahedron Asymmetry, 18, 1763-1765 (2007).
7. Yajima, A., et al.: Nature Chem. Biol., 4, 235-237 (2008).
8. M. Ojika, et al.:Nature Chem. Biol., 7, 591-593 (2011).
Representative Publications
1)Cerebroside-A provides potent neuroprotection after cerebral ischemia through reducing glutamate release and Ca2+ influx of NMDA receptors. L. Li, Y. Bai, R. Yang, Z. Zhang, B. Xu, Z. Qi, J. Qi*, and L. Chen*, The International Journal of Neuropsychopharmacology, 15, 497-507 (2012).
2)Structure-activity relationships of neuritogenic gentiside derivatives. Y. Luo, K. Sun, L. Li, L. Gao, G. Wang, Y. Qu, L. Xiang, L. Chen, Y. Hu, and J. Qi,* ChemMedChem, 6, 1986-1989 (2011).
3)The second Phytophthora mating hormone defines interspecies biosynthetic crosstalk. M. Ojika, S. Molli, H. Kanazawa, A. Yajima, K.Toda T. Nukada, H. Mao, R. Murata, T. Asano, J. Qi, and Y. Sakagami, Nature Chemical Biology, 7, 591-593 (2011).
4) Synthesis and absolute configuration of hormone 1. A. Yajima,* Y. Qin,* X. Zhou, N. Kawanishi, X. Xiao, J. Wang, D. Zhang, Y. Wu, T. Nukada, G. Yabuta, J. Qi,* T. Asano, and Y. Sakagami, Nature Chemical Biology, 4, 235-237 (2008).
5)Granulatoside A, a starfish steroid glycoside, enhances PC12 Cell neuritogenesis induced by nerve growth factor through an activation of MAP Kinase. J. Qi, C. Han, Y. Sasayama, H. Nakahara, T. Shibata, K. Uchida, and M. Ojika, ChemMedChem, 1, 1351-1354 (2006).
6) Characterization of a Phytophthora mating hormone. J. Qi, T. Asano, M. Jinno, K. Matsui, K. Atsumi, Y. Sakagami, and M. Ojika, Science, 309, 1828 (2005).
1
Peptide Isoprenylation
Masahiro Okada
College of Bioscience and Biotechnology, Chubu University, Japan
Bacillus subtilis and related bacilli produce a posttranslationally modified oligopeptide, ComX pheromone,that stimulates natural genetic competence controlled by quorum sensing. Our studies revealed that the ComXRO-E-2 pheromone from B. subtilis strain RO-E-2 had a unique modified tryptophan residue with a geranyl group, forming a tricyclic structure (Figure 1).1) Also, the ComXRO-C-2 pheromone from B. mojavensis strain RO-C-2 was confirmed to have a farnesyl-modified tryptophan residue similar to that of the ComXRO-E-2 pheromone.2) Together with its phylogenetic resemblance to ComX, these findings suggested that posttranslational isoprenoidal modifications of ComX pheromones were classified into two types: geranylation and farnesylation, the ComX pheromones are formed by geranylation or farnesylation on a tryptophan residue at the 3 position of its indole ring. This results in the formation of a tricyclic structure including, a newly formed five-membered ring, similar to proline.
Figure 1. Chemical structure of ComXRO-E-2 pheromone.
Sakagami et al. first reported that the peptide pheromones, tremerogen a-13 and tremerogen A-10, of basidiomycetous yeasts were modified with a farnesyl group on cysteine (Figure 2).3)Posttranslational farnesylation or geranylgeranylation at C-terminal cysteine residue via a thioether linkage is widely observed in eukaryotes and plays a critical role in protein function.