Dactylospongia elegans as A Promising Drug Source

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Sabrin R. M. Ibrahim	--	1533	2022-03-30 12:10:31	\|
2	format change	Peter Tang	-9 word(s)	1524	2022-03-31 03:30:25	\|

Dactylospongia elegans as A Promising Drug Source

This entry is adapted from the peer-reviewed paper 10.3390/md20040221

Dactylospongia elegans Thiele (Thorectidae) is a wealth pool of various classes of sesquiterpenes, including hydroquinones, quinones, and tetronic acid derivatives. These metabolites possessed a wide array of potent bioactivities such as antitumor, cytotoxicity, antibacterial, and anti-inflammatory.

sponges Dactylospongia elegans sesquiterpenes bioactivities biosynthesis

1. Introduction

The marine environment is extraordinarily rich in diverse species of organisms that represent an enormous source of biometabolites, many of which have unique chemical entities not present in terrestrial sources ^[1]^[2]^[3]. The molecular diversity and exceptional complexity of marine metabolites have been highlighted in many studies ^[4]^[5]. The marine environment investigations have greatly been limited to subtropical and tropical regions, in addition, the exploration has been recently extended to colder regions. However, it is fact that many of these unique marine resources have barely been investigated.

Sponges (filter feeders, phylum Porifera) are evolutionarily ancient metazoans that occur in marine benthic, quasi-terrestrial, deep-sea, and fresh-water ecosystems ^[6]^[7]. They represent one of the important members of marine communities that have potential biotechnological and ecological roles ^[8]^[9]. They are sessile multicellular invertebrates, having an enormous amount of tiny pores on their surfaces that allow entrance and circulation of water through canals where organic particles and microorganisms are filtered out and eaten ^[10]. Calcarea, Demospongiae, Homoscleromorpha, and Hexactinellida are the four main classes of sponges ^[11]. It is noteworthy that the secondary metabolites distribution among these four different classes of sponges is greatly varied as shown in Table 1.

Table 1. Reported secondary metabolites from the four main class of sponges ^[12].

Sponge Class	Compounds Classes
Calcarea	C₂₇ to C₂₉ ∆^5,7,9(11),22 and C₂₇ to C₂₉ ∆^5,7,22 sterols Amino alcohols
Hexactinellida	5α(H)-Cholestan-3β-ol/cholest-5-en-3β-ol Ceramide glycosides
Homoscleromorpha	Steroidal alkaloids Peroxy-polyketides
Demospongiae	Pyrroloquinoline, azetidine, pyrrole-2-aminoimidazole, and pentacyclic guanidine alkaloids Norditerpene and norsesterterpene peroxides Tetramic acids Steroidal saponins and glycosides Isomalabaricane triterpenoids Bengamide and bengazoles Hydroxyimino- and 3β-hydroxymethyl-A-nor-sterols 3-Alkylpyridines/3-alkylpiperidines Renieramycins and polyacetylenes Pentacyclic hydroquinones/polyprenylated benzoquinones Adenine- and cyanthiwigin diterpenes Hypotaurocyamine (Sesquiterpene derivatives) Diterpene thio/iso/cyanides and formamides Sesquiterpene thio/iso/cyanides and formamides Aaptamines and bromotyrosines Suberitane-derived sesterterpenes Diterpene, sesquiterpene, and sesterterpenefurans/lactones Scalarane sesterterpenes/sesterterpene hydroquinones Thiazole polyketides Polybrominated diphenyl ethers

∆: Double bond.

Sponges are devoid of any physical capacity for defense; therefore, they need to develop specific means and adaptive responses for self-protection ^[13]. They produce diverse secondary metabolites as defense ways against pathogenic fungi, algae, bacteria, and other predators, also to modulate and/or enable cellular communication ^[14]. Sponges have been known as a fertile field for the discovery of bioactive metabolites with diverse structural features that have been proven to have a beneficial potential for humans as agricultural medicines, drugs, health foods, and cosmetics ^[14]^[15].

2. Secondary Metabolites of D. elegans

Phytochemical studies of D. elegans from 1992 until 2022, revealed that 101 metabolites have been separated and characterized from D. elegans. These metabolites are grouped according to their chemical classes into sesquiterpenes, sesterterpenes, diterpenes, sterols, pregnanes, and other metabolites which are consequently discussed.

Figure 1. Structures of compounds 1–12.

Figure 2. Structures of compounds 13–24.

Figure 3. Structures of compounds 25–36.

Figure 4. Structures of compounds 37–48.

Figure 5. Structures of compounds 49–60.

Figure 6. Structures of compounds 61–70.

Figure 7. Structures of compounds 71–80.

Figure 8. Structures of compounds 81–91.

Figure 9. Structures of compounds 92–101.

3. Biosynthetic Pathways of D. elegans Metabolites

Several studies reported the biosynthetic pathways of the reported sesquiterpenes from this sponge. In this work, the reported postulated pathways were summarized. It was reported that the observed differences in stereochemistry among the marine sesquiterpene metabolites could be inferred from the precursor binding preferences within a single cyclase enzyme active site ^[16]. Additionally, this may be due to the existence of various synthase enzymes, whereas each individual enzyme can create a range of diverse metabolites, as well as presumably the potential to change the stereochemical outcomes, relying on the provided substrate nature. Thus, the possibility of enantiomeric metabolites should be considered that emphasize the significance of reporting [α]_D values for these terpenes in cases where they are utilized as a reference in the stereochemical determination ^[17]^[18].

Boufridi et al. hypothesized that the biosynthetic process of 1 and 2 started with the farnesylation of the aromatic ring, which is the quinone moiety’s precursor to obtain I. This involves the initial folding of I within the active site of a specific terpene cyclase (Scheme 1). Successively, two carbocationic intermediates II and III are resulted from peri-planar Wagner–Meerwein hydrogen and methyl shifts. Finally, III may undergo two pathways (A or B) for the formation of 1 and 2 through the loss of a proton from carbocations IV and V, respectively ^[19].

Scheme 1. Postulated biosynthetic pathway for 1 and 2 ^[19].

Yong et al. postulated that 13, 15, 16, 19, 20, and 22 may be originated from the cationic intermediate (I) (Scheme 2). The introduction of double bond yields 16. The cyclization of 16 (pathway A), or hydride migration with subsequent cyclization forming 22 and its related cyclic intermediate ent-cyclospongiaquinone-2 (II), then the formation of double bond yields 19 and 20 (pathway B). Finally, the hydride migration and loss of a proton from the cationic site adjacent methyl form 13 with a cyclopropyl ring (pathway C) ^[17].

Scheme 2. Postulated biosynthetic pathways for 13, 15, 16, 19, 20, and 22 ^[17].

Scheme 3 shows that the farnesyl precursor (I) initial cyclization gives II (enantiomeric cation) that undergoes a loss of a proton to give 16 and 21. On the other side, cation II’s hydride and methyl migrations yield compounds 1, 14, and 18 ^[17].

Scheme 3. Postulated biosynthetic pathways for 1, 14, 16, 18, and 21 ^[17].

Diacetoxydolabella-2,7-dien-6-one (89) was proposed to be the biogenetic precursor of 88. (+)-Eleganstone A (88) may be originated from diacetoxydolabella-2,7-dien-6-one (89) through intramolecular [2 + 2] cycloaddition. The coupling of Δ^7,8 and Δ^2,3 in 89 via the endo-cycloaddition generates 88 (Scheme 4) ^[20]^[21].

Scheme 4. Proposed biosynthetic pathway for 88 ^[20].

4. Synthesis of D. elegans Metabolites

Some of the reported metabolites from this sponge possessed fascinating bioactivities, such as anticancer. Nevertheless, further biological investigation is limited due to the not enough isolated metabolites. Therefore, research interests have been directed towards synthesis and structural modification of these metabolites to improve the bioactivities and study structural/activity relations, which could help in drug development and discovery. Some of these studies have been highlighted here.

Kotoku et al. synthesized several analogs of furospinosulin-1 (92) and assessed their selective hypoxia inhibitory potential (Scheme 5) ^[22].

Scheme 5. Synthesis of furospinosulin-1 (92) analogues ^[22].

It was found that only the analog (FA) with desmethyl near to the furan ring had an excellent hypoxia-specific growth inhibitory potential such as furospinosulin-1 (92) and displayed greater in vivo antitumor potential in oral administration (doses 1–10 µM) versus DU145 cells, as well as lower toxicity in normal conditions (dose 300 µM) ^[22]. Therefore, this analog might be better than furospinosulin-1 for drug candidates.

Kotoku et al. reported that the modifications of 92 structure such as elongating the methyl group close to the furan ring, changing the aromatic ring, and side-chain truncation led to a remarkable loss of selective hypoxia growth inhibition capacity, obviously revealing that the entire structure was substantial for the binding with the target molecule ^[23]; whilst the analog had a longer side chain partially retained hypoxia-selective inhibitory potential. Therefore, Kotoku et al. synthesized and assessed various furospinosulin-1 (92) tail-modified analogs (Scheme 6)

Scheme 6. Synthesis of tail-modified analogues of furospinosulin-1 (92) ^[23].

The analog X was found to be much more potent than furospinosulin-1 as it possessed hypoxia-selective growth-inhibitory potential (Conc. 1–300 µM) and had powerful in vivo antitumor effectiveness after oral administration (doses 5–25 mg/kg) without side effects ^[23].

Additionally, in 2015, Sumii et al. assessed the structure–activity relationship of (+)-dictyoceratin A (49) and (+)-dictyoceratin C (52) through the synthesis of structural-modified derivatives of (+)-dictyoceratin C (52) and testing their in-vivo antitumor potential ^[24]. Thus far, the only methyl ester substitution in 52 with propargyl amide (DA) had an excellent hypoxia-selective growth prohibition potential at 30 µM relative to 52 (Scheme 7). Thus, it could be efficient for probe molecules synthesis for target identification of 49 and 52 ^[24].

Scheme 7. Synthesis of potent structurally modified analog of 52 ^[24].

Pelorol (64), sesquiterpene hydroquinone having C8–C21 cyclization had a potent and selective SHIP1 (Src homology 2-containing inositol 5-phosphatase 1) activating potential ^[25]. However, this compound had catechol moiety that can be either enzymatic or chemically oxidized to orthoquinones, forming covalent linkages with proteins resulting in losing the activity. Additionally, it is highly water-insoluble, which limits its in vivo bioactivity as a SHIP1 activator. Meimetis et al. synthesized more water-soluble amino analogs ent-PA or (±)-PA (Scheme 8). Synthesis of (±)-PA characterized by generating a tetracyclic ring system through a cation-initiated polyene cyclization ^[26]. Then, 3,5-Dimethoxybromobenzene lithiation subsequent alkylation with farnesyl bromide produced the 3,5-dimethoxybenzene prenylated intermediate. A racemic epoxide was produced utilizing m-chloroperbenzoic acid with subsequent steps giving (±)-PA. Repeating the same procedure using ent-Shi catalyst produced ent-PA analog. These analogs in vitro activated SHIP1, prohibited Akt phosphorylation and had potent in vivo anti-inflammation potential (ED50 0.1 mg/kg, oral gavage) using passive cutaneous anaphylaxis mouse model ^[26]. The results suggested that ent-PA or (±)-PA pelorol analogs are promising candidates for further in vivo preclinical investigation as SHIP1-activating therapeutics for treating hematopoietic illnesses, involving aberrant PI3K cell signaling activation.

Scheme 8. Synthesis of SHIP1-activating analogs of pelorol (64) ^[26].

5. Activities of D. elegans Extracts and Fractions

BACE1 (β-site of amyloid precursor protein cleaving enzyme) is an enzyme involved in Alzheimer’s disease pathogenesis. The 75% and 100% MeOH C8 fractions of D. elegans obtained from the coast of Kauai had significant in vitro BACE1 inhibition (%inhibition 66% and 73%, respectively, at Conc. 30 μg/mL) ^[27]. Li et al. revealed that the CH₂Cl₂/MeOH extract possessed marked IL-6 and TNF-α inhibitory potential ^[28]. Additionally, the antioxidant potential testing revealed that D. elegans hexane extract exhibited significant antioxidant potential in comparison to the ascorbic acid ^[29].

References

Kobayashi, J. Search for new bioactive marine natural products and application to drug development. Chem. Pharm. Bull. 2016, 64, 1079–1083.
Omar, A.M.; Mohamed, G.A.; Ibrahim, S. Chaetomugilins and chaetoviridins-promising natural metabolites: Structures, separation, characterization, biosynthesis, bioactivities, molecular docking, and molecular dynamics. J. Fungi 2022, 8, 127.
Radjasa, O.K.; Vaske, Y.M.; Navarro, G.; Vervoort, H.C.; Tenney, K.; Linington, R.G.; Crews, P. Highlights of marine invertebrate-derived biosynthetic products: Their biomedical potential and possible production by microbial associants. Bioorg. Med. Chem. 2011, 19, 6658–6674.
Gerwick, W.H.; Moore, B.S. Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chem. Biol. 2012, 19, 85–98.
Mohamed, G.A.; Ibrahim, S.R.M. Untapped potential of marine-associated Cladosporium species: An overview on secondary metabolites, biotechnological relevance, and biological activities. Mar. Drugs 2021, 19, 645.
Gao, Z.M.; Zhou, G.W.; Huang, H.; Wang, Y. The Cyanobacteria-dominated sponge Dactylospongia elegans in the South China Sea: Prokaryotic community and metagenomic insights. Front. Microbiol. 2017, 8, 1387.
Hentschel, U.; Hopke, J.; Horn, M.; Friedrich, A.B.; Wagner, M.; Hacker, J.; Moore, B.S. Molecular evidence for a uniform microbial community in sponges from different oceans. Appl. Environ. Microbiol. 2002, 68, 4431–4440.
Esposito, R.; Ruocco, N.; Viel, T.; Federico, S.; Zupo, V.; Costantini, M. Sponges and their symbionts as a source of valuable compounds in cosmeceutical field. Mar. Drugs 2021, 19, 444.
Bell, J.J. The functional roles of marine sponges. Estuar. Coast. Shelf Sci. 2008, 79, 341–353.
Lee, Y.K.; Lee, J.H.; Lee, H.K. Microbial symbiosis in marine sponges. J. Microbiol. 2001, 39, 254–264.
Thomas, T.R.; Kavlekar, D.P.; LokaBharathi, P.A. Marine drugs from sponge-microbe association-a review. Mar. Drugs 2010, 8, 1417–1468.
Galitz, A.; Nakao, Y.; Schupp, P.J.; Wörheide, G.; Erpenbeck, D. A soft spot for chemistry–current taxonomic and evolutionary implications of sponge secondary metabolite distribution. Mar. Drugs 2021, 19, 448.
Sladić, D.; Gasić, M.J. Reactivity and biological activity of the marine sesquiterpene hydroquinone avarol and related compounds from sponges of the order Dictyoceratida. Molecules 2006, 11, 1–33.
Sagar, S.; Kaur, M.; Minneman, K.P. Antiviral lead compounds from marine sponges. Mar. Drugs 2010, 8, 2619–2638.
Wada, Y.; Fujioka, H.; Kita, Y. Synthesis of the marine pyrroloiminoquinone alkaloids, discorhabdins. Mar. Drugs 2010, 8, 1394–1416.
Butler, M.S.; Capon, R.J. Beyond polygodial: New drimane sesquiterpene from a Southern marine sponge, Dysidea sp. Aust. J. Chem. 1993, 46, 1255–1267.
Yong, K.W.L.; Jankam, A.; Hooper, J.N.A.; Suksamrarn, A.; Garson, M.J. Stereochemical evaluation of sesquiterpene quinones from two sponges of the genus Dactylospongia and the implication for enantioselective processes in marine terpene biosynthesis. Tetrahedron 2008, 64, 6341–6348.
Poigny, S.; Huor, T.; Guyot, M.; Samadi, M. Synthesis of (−)-hyatellaquinone and revision of absolute configuration of naturally occurring (+)-hyatellaquinone. J. Org. Chem. 1999, 64, 9318–9320.
Boufridi, A.; Lachkar, D.; Erpenbeck, D.; Beniddir, M.A.; Evanno, L.; Petek, S.; Debitus, C.; Poupon, E. Ilimaquinone and 5-epi-ilimaquinone: Beyond a simple diastereomeric ratio, biosynthetic considerations from NMR-based analysis. Aust. J. Chem. 2017, 70, 743–750.
Yu, H.-B.; Gu, B.-B.; Wang, S.-P.; Cheng, C.-W.; Yang, F.; Li, H.-W. New diterpenoids from the marine sponge Dactylospongia elegans. Tetrahedron 2017, 73, 6657–6661.
Liang, L.-F.; Kurtán, T.; Mándi, A.; Yao, L.-G.; Li, J.; Zhang, W.; Guo, Y.-W. Unprecedented diterpenoids as a PTP1B inhibitor from the Hainan soft coral Sarcophyton trocheliophorum Marenzeller. Org. Lett. 2012, 15, 274–277.
Kotoku, N.; Fujioka, S.; Nakata, C.; Yamada, M.; Sumii, Y.; Kawachi, T.; Arai, M.; Kobayashi, M. Concise synthesis and structure activity relationship of furospinosulin-1, a hypoxia-selective growth inhibitor from marine sponge. Tetrahedron 2011, 67, 6673–6678.
Kotoku, N.; Nakata, C.; Kawachi, T.; Sato, T.; Guo, X.H.; Ito, A.; Sumii, Y.; Arai, M.; Kobayashi, M. Synthesis and evaluation of effective photoaffinity probe molecule of furospinosulin-1, a hypoxia-selective growth inhibitor. Bioorg. Med. Chem. 2014, 22, 2102–2112.
Sumii, Y.; Kotoku, N.; Fukuda, A.; Kawachi, T.; Sumii, Y.; Arai, M.; Kobayashi, M. Enantioselective synthesis of dictyoceratin-A (smenospondiol) and -C, hypoxia-selective growth inhibitors from marine sponge. Bioorg. Med. Chem. 2015, 23, 966–975.
Yang, L.; Williams, D.E.; Mui, A.; Ong, C.; Krystal, G.; van Soest, R.; Andersen, R.J. Synthesis of pelorol and analogues: Activators of the inositol 5-phosphatase SHIP. Org. Lett. 2005, 7, 1073–1076.
Meimetis, L.G.; Nodwell, M.; Yang, L.; Wang, X.; Wu, J.; Harwig, C.; Stenton, G.R.; Mackenzie, L.F.; MacRury, T.; Patrick, B.O.; et al. Synthesis of SHIP1-activating analogs of the sponge meroterpenoid pelorol. Eur. J. Org. Chem. 2012, 2012, 5195–5207.
Goedert, M.; Spillantini, M.G. A century of Alzheimer’s disease. Science 2006, 314, 777–781.
Li, J.; Wu, W.; Yang, F.; Liu, L.; Wang, S.P.; Jiao, W.H.; Xu, S.H.; Lin, H.W. Popolohuanones G–I, dimeric sesquiterpene quinones with IL-6 inhibitory activity from the marine sponge Dactylospongia elegans. Chem. Biodivers. 2018, 15, e1800078.
Rivera, A.P.; Uy, M.M. In vitro antioxidant and cytotoxic activities of some marine sponges collected off misamis oriental coast, Philippines. E-J. Chem. 2012, 9, 354–358.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Marine & Freshwater Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Sabrin Ibrahim

Sana Fadil

Hossam Abdallah

Gamal Mohamed

View Times: 501

Update Date: 31 Mar 2022

Table of Contents

Video Upload Options

Confirm