Natural Products Research in China From 2015 to 2016

This review covers the literature published by chemists from China during the 2015–2016 on natural products (NPs), with 1,985 citations referring to 6,944 new compounds isolated from marine or terrestrial microorganisms, plants, and animals. The emphasis is on 730 new compounds with a novel skeleton or/and significant bioactivity, together with their source organism and country of origin.


INTRODUCTION
Natural products (NPs) play an indispensable role in the drug development process and have provided various molecules for research over the years. Among the 1,211 small-molecule drugs approved from 1981 to 2014, 33% were based on NPs or their derivatives (Newman and Cragg, 2016).
Using natural resources to treat disease was the wisdom of the ancient Chinese and there is a long history of Chinese people using traditional Chinese medicines (TCMs) to treat a variety of diseases. NPs research in China originated in the 1920s and began with separation and identification of the main components of TCMs, such as Panax notoginsen (Zhao, 1937), Brucea javanica (Xu and Pan, 1955) as well as Aconitum carmichaeli (Zhao, 1936). The improvement of science and technology after the founding of the People's Republic of China in 1949, along with the establishment of new methods (Colegate and Molyneux, 2007) involved in detection and analysis of compounds led to the rapid development and great achievements of China's NPs research. In particular, huperzine A (Wang et al., 2006), a novel acetylcholinesterase (AChE) inhibitor derived from the Chinese medicinal herb Huperzia serrata, has been used to treat Alzheimer's disease and Youyou Tu was awarded the Nobel Prize in Physiology or Medicine in 2015 for her major contribution to the discovery of artemisinin (Tu, 2011).
By the 1980s, chemists from China not only focused on NPs isolated from TCMs or other terrestrial sources, but also expanded the research to marine natural products (MNPs). The number of new MNPs discovered in China increased exponentially since the 1990s, making China the second most country involved in MNPs discovery behind Japan (Blunt et al., 2016). Taken together, these breakthroughs led to the renewal of NPs research in China.
Reviews of NPs are generally based on their producers [mangrove (Wu et al., 2008), Paeonia , fungi (Wang et al., 2011), etc.], chemical structures [sesquiterpenoids , triterpenoids , lignans (Zhang et al., 2014), alkaloids (Ma et al., 2016e), etc.] and bioactivities [analgesic activity , antiviral activity (Jiang et al., 2010), cytotoxicity (Wang et al., 2014), etc.] while few reviews are based on the country where the authors come from. According to our current research, more than 6,500 papers have been published by chemists from China in the past 2 years covering all aspects related to NPs, and of these, 1,985 were related to new NPs, a total of about 30%. This review covers the literature published from 2015 to 2016 with 1,985 citations (1,103 for 2015 and 882 for 2016) referring to new NPs isolated from terrestrial-or marine-sourced animals, plants, and microorganisms. In total, 6,944 new small-molecule compounds are summarized (3,891 for 2015 and 3,053 for 2016). The emphasis is on new compounds with a novel skeleton or/and significant biological activity. Pharmaceutical data are directly cited from the original paper, and only comparable or more potent activity relative to the positive control is defined as significant activity. For the cytotoxicity values, significant activity means a half maximal inhibitory concentration (IC 50 ) value below 1 µM or 0.5 µg/mL. Chemical structures, together with classifications, taxonomic origins, locations of collections, and biological activities are described in detail. The numbers for all structures in this review are shown in non-italicized bold font.

MARINE MICROORGANISMS
A total of 612 novel NPs was isolated from marine microorganisms in the last 2 years. The percentage of compounds with new skeletons from marine bacteria (19.5%) in this review is much higher than average (5.1%), the percentage of bioactive compounds from marine fungi (36.3%) is also higher than the average (28.4%). A total of 46 references related to 101 NPs with a novel skeleton or/and significant bioactivity are listed below.

MARINE ANIMALS
A total of 189 new NPs was identified from marine animals in 2015-2016 including eight (4.2%) with novel skeletons and 55 (29.1%) with various bioactivities. Herein, we list six references that report 11 NPs with a novel skeleton or/and significant bioactivity.

TERRESTRIAL MICROORGANISMS
A total of 1,081 new NPs was produced by terrestrial microorganisms, of which 970 were produced by fungi. Among the new compounds isolated from fungi, more than 7.9% possessed an unprecedented skeleton. All 158 NPs with novel skeletons or/and significant bioactivities are listed.

TERRESTRIAL ANIMALS
A total of 90 new NPs was isolated from terrestrial insects and other animals. Of these, 37.8% compounds exhibited various bioactivities, much higher than the average of 28.4%. Nine NPs reported in two references with significant bioactivities are listed in this section.

CONCLUSION
This review covers the NPs literatures from 2015 to 2016 by chemists from China and describes 6,944 new NPs reported from 1,985 papers. The average number of new compounds per paper is 3.5. Compared with 2015, the number of new NPs decreased by 22% in 2016 from 3,891 to 3,053. Elucidation of new compounds and assessment of their bioactivities along with methods for their syntheses, corrections of stereochemistry, and mechanistic as well as biosynthetic studies were two major areas of NPs research. However, the discovery of new compounds was undoubtedly the basis of all studies. In recent years, based on the large numbers of identified compounds, chemists increasingly began to focus on the other aspects described above, resulting in the decline of the identification of new compounds in 2016.
According to the survey of the literature from 2015 to 2016 (Supplementary Table 1), 730 new NPs out of 6,944 identified compounds possessed significant bioactivity and/or a novel skeleton. Their detailed information is compiled in this review.
A total of 1,765 papers were published in over 110 international journals in the past two years. Figure 13 shows the total number of NP articles from China sorted by journal. Natural Product Research (publications/percentage in total publications of China, 221/12%) was the first choice for chemists from China to publish their newly discovered NPs followed by Journal of Natural Products (164/9%), Journal of Asian Natural Products Research (122/7%), and Fitoterapia (109/6%). Notably, more than a quarter of articles (457 articles) were published in 38 journals with impact factors ≥3.0. The Journal of Natural Products, as a recognized journal in the field of NPs, undoubtedly attracted the most contributions (164 articles) and was followed by RSC Advances (66 articles), Organic Letters (62 articles), and Marine Drugs (22 articles); among all articles related to new NPs published in these journals, 34, 47, 50, and 35% were contributed by Chinese NPs chemists, respectively (Figure 14).     These results indicate that chemists from China play an irreplaceable role in NPs research and have made great contributions to the discovery of new compounds. It is also worth noting that there were only a few articles relevant to new NPs published in top chemistry journals with significant worldwide influence, such as Angewandte Chemie International Edition (China/total, 2/27), Chemical Science (3/4), and Journal of the American Chemical Society (2/5) (Figure 13). This review of the current progress of NPs chemistry shows that a multidisciplinary approach is henceforth an inevitable trend. Strengthening interdisciplinary cooperation is essential and biosynthesis, bioinformatics, and pharmacology as well as computer-aided technologies should be integrated to advance the discovery of more lead compounds with the potential to be developed into drugs. Currently, chemists from China face the challenging task of value mining of identified NPs rather than simply elucidating the structures of novel compounds. Molecules with unprecedented skeletons always attract attention and interest in the NPs research field. In 2015-2016, 134 papers (7% in total) were published and reported 352 NPs (5% in total) with novel skeletons. The dominant biological sources of new skeletal NPs were terrestrial plants (papers/percentage in 134 papers, 79/58%), terrestrial fungi (26/19%), and marine fungi (13/10%) (Figure 15A), from which 213 (percentage in all novel skeletons, 61%), 75 (21%), and 34 (10%) new skeletal NPs were isolated, respectively ( Figure 15C). However, the percent occurrence of novel skeletons out of each biological source was slightly different. Marine actinomyctes possessed the highest occurrence of novel skeletons in 21% of papers ( Figure 15B) and 19% of NPs ( Figure 15D) followed by terrestrial fungi (10%, 8%), terrestrial bacteria (8%, 3%), and marine fungi (8%, 6%). This indicated that the microorganism, especially marine actinomyctes, was the major biological source of new skeletal compounds in China with great potential for research, and deserved to be extensively studied.
The results showed that 28% of new NPs displayed a variety of bioactivities. The dominant bioactivities were cytotoxicity, anti-inflammatory activity, and antiviral activity with 7%, 5%, and 3% ratios in all NPs ( Figure 16A) and 25%, 18%, and 11% ratios in all bioactive NPs (Figure 16B), respectively. Biological sources were also taken into consideration when compiling the data. A total of 68% of the bioactive compounds were isolated from terrestrial plants followed by terrestrial and marine fungi with 12% and 9% ratios, respectively ( Figure 16C). The distribution between biological sources and bioactivities was also analyzed (Figure 16D). Cytotoxicity and anti-inflammatory activity were the major bioactivities of NPs isolated from marine animals and terrestrial plants, whereas cytotoxic and antibacterial activities were dominant for those from marine fungi. This analysis may serve as a guideline for purposeful investigation of bioactive NPs.
As reviewed in this article, China had made enormous strides in NPs chemistry development and contributed substantial numbers of promising bioactive molecules to drug research in the past two years. We believe that there will continue to be a steady development of NPs research in China, and large numbers of more extensive studies as well as innovative approaches will be available in the near future.

AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.