Chemical and biological diversity of new natural products from marine sponges: a review (2009–2018)

Marine sponges are productive sources of bioactive secondary metabolites with over 200 new compounds isolated each year, contributing 23% of approved marine drugs so far. This review describes statistical research, structural diversity, and pharmacological activity of sponge derived new natural products from 2009 to 2018. Approximately 2762 new metabolites have been reported from 180 genera of sponges this decade, of which the main structural types are alkaloids and terpenoids, accounting for 50% of the total. More than half of new molecules showed biological activities including cytotoxic, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, enzyme inhibition, and antimalarial activities. As summarized in this review, macrolides and peptides had higher proportions of new bioactive compounds in new compounds than other chemical classes. Every chemical class displayed cytotoxicity as the dominant activity. Alkaloids were the major contributors to antibacterial, antifungal, and antioxidant activities while steroids were primarily responsible for pest resistance activity. Alkaloids, terpenoids, and steroids displayed the most diverse biological activities. The statistic research of new compounds by published year, chemical class, sponge taxonomy, and biological activity are presented. Structural novelty and significant bioactivities of some representative compounds are highlighted. Marine sponges are rich sources of novel bioactive compounds and serve as animal hosts for microorganisms, highlighting the undisputed potential of sponges in the marine drugs research and development. Supplementary Information The online version contains supplementary material available at 10.1007/s42995-022-00132-3.


Introduction
Marine sponges are the oldest metazoan group with approximately 15,000 species having been described, of which 8553 species were accepted (Thomas et al. 2010;Van Soest et al. 2012). Under extreme marine environments, sponges continue to produce novel bioactive metabolites to protect them from threats of predators, competitors, and pathogens (Paul et al. 2006;Wu et al. 2021a). Their chemical arsenal encompasses terpenoids, alkaloids, polyketides, peptides, steroids, and so on. Starting with the isolation of nucleoside derivatives from sponge Tectitethya crypta, the discovery of sponge-derived natural products experienced a rapid growth period, followed by a stable period. Up to now, more than 18,149 new compounds have been isolated from sponges with an increasing number of over 200 new compounds isolated yearly (Carroll et al. 2021;Hu et al. 2015). Many of these molecules demonstrated diverse biological activities, such as anticancer, antibacterial, antifungal, anti-inflammatory, antiviral, antioxidant, antimalarial, and pest resistance properties (Abraham et al. 2021;Carroll et al. 2020;. For this reason, sponges continue to be an attractive subject for natural product chemists based on the large number of compounds produced, the diversity of structures encountered, and the therapeutic potential of molecules. This review summarizes sponge-derived 2762 new compounds with 1419 bioactive from 878 original research papers during 2009-2018. These new compounds in terms of published year, chemical class, sponge taxonomy, and biological activity are classified, analyzed, and evaluated. Structural novelty and excellent pharmacological activities of some representative compounds are highlighted.

Statistical research of new compounds
The data are based on the literature search in the SciFinder database with marine sponge as the key word, English as the language, and the time limit of 2009-2018. Approximately 2762 new metabolites have been reported from sponges between 2009 and 2018, more than half of which showed pharmacological activity. As shown in Fig. 1A, the number of new compounds gradually decreased in a three or 4-year cycle, probably because research on MNPs from sponges gradually shifted to sponge-derived microorganisms due to increasing evidence that symbiotic microorganisms rather than sponges were likely to be the real producers of bioactive compounds (Liu et al. 2019;Zhang et al. 2017). In addition, microorganisms have the ability to reproduce indefinitely and to easily be mined genomically to obtain target metabolites (Cao and Wang 2020; Meng et al. 2021;Peng et al. 2021;Zhang et al. 2021). The proportion curve of new bioactive compounds compared to total new compounds showed that the proportion fluctuated in a small range each year. This may indicate that the rate of bioactivity screening research and discovery of new natural products was relatively stable. In addition, sampling methods, extraction and separation techniques, structure identification technology, and biological screening methods have reached a relatively mature level.
Notably, the compounds are counted only once when they are analyzed by bioactivity or inactivity. However, multi-active compounds are counted multiple times when they are classified according to the following ten bioactivity groups. Figure 2 shows percentage distribution of new compounds with different bioactivities for 2009-2018. Obviously, nearly half of the new bioactive compounds showed anticancer/cytotoxic activity with the number of 808 (49.1% of the total new bioactive compounds). The main reasons of this result are likely the long term and large amount of scientific research funds supporting cancer drug discovery, big programs with the aim to discover anticancer drugs, and rapid development of effective detection technology for cytotoxicity such as MTT, XTT, and SRB assays (Hu et al. 2015). This was followed by antibacterial activity at 215 (13.1%), enzyme inhibition activity at 135 (8.2%), antifungal activity at 103 (6.3%), and antimalarial activity at 67 (4.1%). These results were consistent with the previous reviews where the two major bioactivities reported by compounds from sponges were cytotoxicity followed by antimicrobial (antifungal and antibacterial) activity (Abdelaleem et al. 2020). It is worth noting that this does not mean major bioactivities of sponge-derived compounds are cytotoxicity and antimicrobial activities. The difficulty of the biological screening model may affect this result to a certain extent. For instance, viruses are underrepresented as targets in  pharmacological screening efforts due to the requirement of biochemical assay counter screens and inherent complexity of cell-based assays of viruses, making them expensive and time consuming (O'rourke et al. 2018).
The new compounds are divided into nine chemical classes including alkaloids, terpenoids, hydroxybenzene/quinones, lipids, macrolides, polyketides, peptides, steroids, and others. However, it is noteworthy that macrolides and steroids are often classified as polyketides and lipids, respectively. Here we list macrolides and steroids separately because of their significant pharmacological activity and large quantities, respectively. Figure 1B shows the number and proportion of new bioactive compounds in each chemical class. 823 and 693 new compounds belonged to alkaloids and terpenoids, respectively, adding up to more than half of the total. Similarly, these two classes contributed 50% of all new bioactive compounds. Although the number of bioactive alkaloids and terpenoids was the largest, the highest proportion of bioactives belonged to macrolides with 84.0% followed by peptides with 64.3%. Two recent reviews summarized marine-derived macrolides with therapeutic potential, which displayed a wide range of bioactivities including cytotoxic, antifungal, antiviral, antibacterial, antimitotic, and other activities (Wu et al. 2021b;Zhang et al. 2021). Peptides were promising drug candidates due to their reduced size, stability, low immunogenicity, and diversity of bioactivities including anti-proliferative, antiviral, anti-coagulant, antioxidant, antiobesity, antidiabetic, antihypertensive, and calcium-binding activities (Gogineni and Hamann 2018;Hu et al. 2015). This was then followed by steroids with 62.6%, hydroxybenzene/quinones with 49.0%, alkaloids with 48.1%, and terpenoids with 47.5%. Figure 3A shows the proportion of different activities in each category of chemical compounds for 2009-2018. The analyzed data shows that bioactivity distribution is slightly affected by chemical structures. All chemical groups displayed cytotoxicity as the dominant activity with the proportion ranging from 37.0% to 97.5%. Especially for macrolides, cytotoxic compounds accounted for 97.5% of the total active compounds, highlighting that they encompass many potential antitumor drug leads. Regardless of cytotoxic property, alkaloids, terpenoids, and lipids mainly showed antibacterial activity, while hydroxybenzene/quinones, polyketides, and steroids displayed enzyme inhibition, antimalarial, and pest resistance property as major activities, respectively. In addition, the distribution of all types of activities but cytotoxicity displayed by peptides was relatively average.
As shown in Fig. 3B, the analyzed data shows that alkaloids, terpenoids, lipids, and peptides were responsible for cytotoxic activity. The major contributors to antibacterial activity were alkaloids, terpenoids, and lipids. The most promising antifungal agents from sponges appear to be alkaloids and polyketides. A certain number of alkaloids, terpenoids, and peptides exhibited antimalarial activity. Only alkaloids and peptides were reported from sponges this decade to possess antiviral activity. The main anti-inflammatory metabolites were terpenoids, hydroxybenzenes/quinones, and peptides. Alkaloids and hydroxybenzenes/quinones were the primary antioxidant constituents of the sponges. Alkaloids and terpenoids were responsible for enzyme inhibition activity while steroids, polyketides, alkaloids, and terpenoids contributed to pest resistance activity. Alkaloids, terpenoids, and steroids displayed the most diverse biological activities.
The World Porifera Database is utilized by the taxonomic classification of the sponges mentioned in the original research papers. According to the world porifera database, sponges are composed of 5 classes and 39 orders. As shown in Fig. 4, during 2009-2018, about 4 classes and 21 orders were studied for discovery of new metabolites, with the class Demospongiae being the most prolific producer with 2447 new compounds reported. Orders Dictyoceratida, Haplosclerida, Poecilosclerida, and Tetractinellida from the class Demospongiae were the most productive orders, giving 595, 455, 406, and 327 new compounds, respectively.

Conclusions and outlooks
Marine sponges continue to be prolific producers of structurally diverse compounds with valuable therapeutic potential. In this review, we summarize sponge-derived new compounds over the years 2009-2018 in terms of published year, chemical class, sponge taxonomy, and biological activity. The number of new compounds gradually decreased probably because natural product chemists turned their research focus to sponge symbiotic microorganisms which may be the real producers of bioactive compounds. More than half of new metabolites reported during this period showed biological activity. The major reported bioactivities were anticancer/cytotoxic activity (49.1%), antibacterial activity (13.1%), enzyme inhibition activity (8.2%), antifungal activity (6.3%), and antimalarial activity (4.1%). All chemical groups displayed cytotoxicity as a dominant activity. Alkaloids (823) and terpenoids (693) represented two main structural types of new compounds, adding up to more than half of the total. Within the most prolific class Demospongiae, Orders Dictyoceratida, Haplosclerida, Poecilosclerida, and Tetractinellida contributed the largest quantities, producing 595, 455, 406, and 327 new compounds, respectively. Structural novelty and excellent pharmacological activities of some representative compounds are highlighted.
It should be noted that the statistical results of new bioactive compounds are not comprehensive and influenced by many factors. First, not all new metabolites isolated from sponges were tested for biological activity because of scarcity of quantity. Second, many bioactive compounds were only studied for one or two types of bioassays due to lack of effective biological activity screening models. Third, bioactivity screening of new compounds from marine sponges probably depends on research funding, government policy, research facilities, industrial investment, the professional knowledge of scientists, and so on. On the basis of the foregoing, more sponge-derived new natural products should be screened on a wider variety of bioassays, suggesting that effective enrichment of trace compounds and enhanced methods in bioactivity screening technologies are important.
Based on the summary above, the potential of marine sponges as prolific sources of novel bioactive compounds in marine drugs research and development is undisputed. There are still plenty of molecules with therapeutic potential to be discovered from sponges. It is worth mentioning that sponges as animal hosts are important microbial fermenters. The discovery of huge microbial diversity in sponges, the true producers of secondary metabolites, the mass production of trace amounts of compounds by symbiotic microorganisms, and the symbiotic relationship between sponge host and microorganisms make marine sponges very important and provide many interesting research opportunities.

Supplementary Information
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