INTRODUCTION:

The marine environment is rich in biological and chemical diversity ^1–3. This diversity is huge, making it a fantastic resource for finding and developing new therapeutic leads. ^4–6. Due to the different physical and chemical conditions found in the ocean, practically every class of marine life contains a diverse range of molecules with distinct structural characteristics. ^7,8. Algae, fungi, plankton, plants, invertebrates, fish, marine animals, and sponges are only a few examples of marine species. ^9,10.

Sponge is one of the marine animals that makes a significant contribution to the diversity of compounds found in the ocean. ^11–13. It is a significant source of secondary metabolites with a wide range of structures and bioactivities among marine invertebrates ^14–16. The known bioactivity of sponges includes anticancer, antimicrobial and antibacterial, anti-malarial, antiviral, anti-inflammatory, and antiplasmodium ^17–22. It is strongly influenced by the phytochemistry and the diversity of compounds it has ^23–25,53.

There are over 15,000 species of marine sponges known to date, and our focus is on Hyrtios reticulatus. It is a marine sponge of the genus Hyrtios with a diverse chemical structure that includes terpenoids, particularly sesterterpenes, sesquiterpene quinones, macrolides, indoles, and -carboline alkaloids, as well as macrolides, indoles and β-carboline alkaloids ²⁶. Many of these metabolites have important biological activities ^26,27. The phytochemicals of the secondary metabolites and the bioactivity of the sponge Hyrtios reticulatus are highlighted in this review. This article discusses to the active compounds and the bioactivity of the sponge Hyrtios reticulatus

1. Secondary Metabolites of Hyrtios reticulatus:

Dark brown branches, oscules with a diameter of up to 2 mm, conules 3-4 mm conules and 1-2 mm high, and brown to orange tops of conules describe the marine sponge Hyrtios reticulatus^5,14. It has a varied range of chemicals and structures (Table 1).

H. reticulatus specimens collected in South Sulawesi contains a new derivative 1,6-dihydroxy-1,2,3,4-tetrahydro-β-carbolin (1) , serotonin (2), 6-hydroxy-1-methyl-1,2,3 , 4-tetrahydro- β -carboline (3), and 6-hydroxy-3,4- dihydro-1-oxo-β-carboline (4)²⁷ (Figure 1). Sponges obtained from Papua New Guinea contain compounds 1-imidazole-3-carboxy- 6 hydroxy-β –carboline called hyrtiocarboline (5), sacrotride A (6), and 1-O-hexadecyl - sn -glycero-3-phosphocholine (7) (Figure 2) ²⁸.

Hyrtios reticulatus collected in Vanuatu, was discovered to be a potent inhibitor of PFTase. Biogenic fractionation is used to isolate bioactive compounds known as sesterterpenes, heteronemin (8) (Figure 3) ²⁹. The sample Hyrtios reticulatus, which is collected by the National Cancer Institute in London, United Kingdom, is reported to contain puupehenone (9) ³⁰.

The marine sponge Hyrtios reticulatus, collected near the coast of Kapoposang island, Indonesia at a depth of 12 m and immediately soaked in ethanol, was found to contain the chemical compound 3-carboxy-6-hydroxy- β- carboline (10) from the biologically active butanol extract. (Figure 4) ³¹.

On the discovery for E1 inhibitors, it was found that extracts from the marine sponge Hyrtios reticulatus collected in Indonesia showed significant inhibition of E1 activity. It was reported that the isolation and structural explanation of indole alkaloid (Figure 5), hyrtioreticulins A–E (11-15) and hyrtioerectine B (16) ³². the extract also contains compounds reticulatins A (18), B (19) and hyrtioreticulin F (17) ³³.

2. Extraction and isolation of Secondary Metabolites from Marine Sponge Hyrtios reticulatus

Compound 1-4:

The sponge samples was extracted with methanol/dichloromethane 50:50. The water content of the extract was removed with dichloromethane (extract A) and dichloromethane /ethanol, 3:2 (extract B). The residual aqueous layer was dried and treated with ethanol, while the the insoluble material (extract C) was removed. The solution of ethanol was drained in order to produce (extract D). Part of D was treated with column chromatography using the mixture dichloromethane /methanol, 100:0 to 0:100, as eluent. The result served as a guide for the isolation of (2) and (1). Fractions contained a mixture of (3) and (4).

Compound 5-7:

The sponge sample was extracted with hexane, dichloromethane, and methanol. Methanol was used to extract the sponge on a large scale. The extract was fractionated into nine fractions, using column cromathography with

1 2

3 4

Figure 1. Chemical structure compound of Hyrtios reticulatus from southwest Sulawesi Indonesia.

linear gradient of methylene chloride to methanol. The column was washed with an additional methanol. The fractions obtained were combined and purified on HPLC equipped with gradient program of acetonitrile in 0.1% formic acid, to yield orange oil (5). Other fraction was purified by HPLC with gradient program of methanol in 0.1% formic acid in water, to yield (6). The fraction obtained from the methanol wash of the silica column was purified by HPLC with gradient program of acetonitrile in 0.1% formic acid in water, to yield (7).

Compound 8:

Ethanol was used to extract a freeze-dried sample. The extract was separated into hexane and methanol. The hexanic extract produced (8), was readily crystallized from pethroleum ether.

Compound 9:

A EtOAc residue has been immediately treated to multilayer coil planet centrifuge countercurrent chromatography (ccc). The ccc solvent system consisted of heptane, CHCI, CH3CN (10:3:7); the highest phase was utilized as the mobile phase. Pure (9) was delivered directly from one CCC and comprised 35% of the EtOAc residue.

Compound 10:

Specimens extracted with MeOH and the combined extracts were filtered and concentrated under decreased pressure to yield of crude extract. The residue was dissolved in H₂O and MeOH (9:1), before being sequenceled by hexane to a maximum of 300 mL. The BuOH extract was chromatographically treated to a gel filter using the MeOH eluent sephadex LH-20 column to produce 20 fractions. Fraction 10 has been submitted to semi-preparative HPLC using water and methanol with 0.5 percent TFA. This resulted in the chemical isolation.

Compound 11-16:

The marine sponge was extracted with ethanol. The concentrated aqueous residue was successively extracted with ethyl acetate and n-butanol. The n-butanol fraction was subjected to silica gel column chromatography with chloroform/methanol and chloroform/methanol/water to obtain fractions A–C.

5 7

Figure 2. Chemical structure compound of Hyrtios reticulatus from Papua New Guinea.

Fraction A eluted with chloroform/methanol/water (7:3:0.5) was purified by column chromatography (CC) with 10% and 30% acetonitrile–water followed by HPLC (Phenomenex Phenyl-hexyl (PPH) column with 10% acetonitrile–water (0.01% TFA)) to obtain (13, 14, 15) along with (16). Fraction B, which was eluted with chloroform/methanol/water (6:4:1), yielded 6 as colorless needles directly from the solution. Fraction C eluted with chloroform/methanol/water (6:4:1 and 5:5:1) was purified by ODS CC with 10% acetonitrile–water followed by HPLC (PPH column with 10% acetonitrile–water (0.05% TFA) and Cosmosil ρ-NAP column with 10% acetonitrile–water) to obtain (11 and 12).

Compound 17-19:

The marine sponge was extracted with methanol. The methanol soluble portion of the remaining aqueous fraction was subjected to ODS column chromatography with methanol/water after the concentrated aqueous residue of the ethanol extract was extracted with ethyl acetate and then n-buthanol. Fraction 1 has been cleaned by HPLC (PPH column with 5 percent acetonitrile–water (0.05 percent TFA) and Develosil C30-UG5 column with 50 percent acetonitrile–water (0.05 percent TFA)) after being eluted with 5% methanol/water. (18,19). Fraction II was purified by HPLC (Cosmosil 5C18-AR-II column with 5% acetonitrile–water) after being eluted with 10% methanol/water (17).

8 9

Figure 3. Chemical structure compound of Hyrtios reticulatus from Vanuatu.

3. Bioactivities of Sponge Hyrtios reticulatus:

a. Anticancer activity:

Sponges are marine animals that have harmfull compounds that are valuable for creating new anticancer drug discoveries ^34–37. In recent years, many therapeutic candidates are still in preclinical and early clinical development, one of which comes from sponges ³⁶. Hyrtios reticulatus is a type of sponge that has anticancer compounds, namely (1), (5) , (6), (8), (9), (10), (18), and (19).

Compound (5) compoundd from Papua New Guinea samples has been shown to have anticancer activity tested with 13 cell lines and has diverse activity (Table 1). The activity on H522-T1 cancer cell has an IC₅₀ of 1.2 µg/mL, on MDA-MB-435 cells has an IC₅₀ 3.0 µg/mL, on U937 cel line has an IC₅₀ 1.5 µg/mL, on BT-549 has an IC₅₀ 45 µg/mL, on DU-145 has an IC₅₀ 34 µg/mL , and on H460 has an IC₅₀ ranging between 17-50 µg/mL.

10 11

12 13

14 15

16 17

18 19

Figure 4. Chemical structures of compound Hyrtios reticulatus from North Sulawesi Indonesia.

However they have low activity on HCC-2998, HT-29, MCF-7 (breast), OVCAR-5, SF-539, SR, UACC-257 cancer cell, with IC₅₀ more than 50 µg/mL ²⁸. Compound (6) has anticancer activity that has been tested on cancer cells A549 cancer cells with an IC₅₀ of 10 µg/mL, SK-OV-3 with an IC₅₀ of 9.5 µg/mL, SK-MEL-2 with an IC₅₀ activity of >10µg/mL, XF498 an with IC₅₀ of 9.8 µg/mL, and HCT15 with an IC₅₀ of 9.4 µg/mL.

Compound (8) was shown to have a very strong anticancer activity on DLD-1, HCT-116, K562, T-47D cell lines with an IC₅₀ of <0.002 µM ³⁸. Meanwhile, on LNcap and PC3 cells line, it has an IC₅₀ of 1.4 µM and 2.7 µM ³⁹. Another compound with anticancer activity is (9), which has been tested on A549, H1168, PSN15, SKBR315 cancer cells with an IC₅₀ of 10 µg/mL, 7 µg/mL, 8 µg/mL, 5 µg/mL, and 15 µg/mL respectively ⁴⁰.

Table 1. Bioactivities of secondary metabolites of Hyrtios reticulatus

No.	Secondary metabolites	bioactivities	IC50 (µg/mL)	References
1	1,6-dihydroxy-1,2,3,4-tetrahydro-β-carboline	Antiproliferative and proapoptotic: - MCF7 cell line - T47D cell line	50 and 25 500 and 250	27 41
2	serotonin
3	6-hydroxy-1-methyl-1,2,3,4-tetrahydro- β -carboline
4	6-hydroxy-3,4- dihydro-1-oxo- β -carboline
5	1-imidazole-3-carboxy- 6 hydroxy-β -carboline	anticancer activity against - H522-T1 - MDA-MB-435 - U937 lymphoma	1.2 3.0 1.5	28 42
6	sacrotride A	anticancer activity against - A549 - SK-OV-3 - SK-MEL-2, - XF498, - HCT15	10 9.5 >10 9.8 9.4
7	1-O-hexadecyl-sn-glycero-3-phosphocholine	-	-
8	heteronemin	anticancer activity against - DLD-1 - HCT-116 - K562 - T-47D. - LNcap - PC 3 cells - inhibitor PFTase	0,01 µM 1.4 µM 2.7 µM 3 µM	29 38 39 29
9	puupehenone	- inhibitor of NADH oxidase activity - Candida albicans - Staphylococcus aureus - Tumor cell line BAEC - A549 - H116 8 - PSN1 5 - SKBR3 15	1.3 µM 32 64 10 7 8 5 15	30 43 40
10	3-carboxy-6-hydroxy- β- carboline	Citotoxic on PC12 and Hela Cell line	Butanol extract 50	31
11	Hyrtioreticulins A	Inhibitor (E1)	0.75	32 44 33
12	Hyrtioreticulins B		11
13	Hyrtioreticulins C		>25
14	Hyrtioreticulins D		>25
15	Hyrtioreticulins E		>25
16	hyrtioerectine B		>25
17	Hyrtioreticulins F		11
18	reticulatins A	anticancer activity on HeLa cells	5
19	reticulatins B	- anticancer activity on HeLa cells - antibacterial activity on Bacillus subtilis, Candida albicans, and Eschericia coli.	5 10

Compound (10) found in samples obtained from Kapoposang Island, Indonesia is believed to contain the active compound found in butanol extract which was then tested on hela cells with an IC₅₀ of 50μg / mL ³¹. Compound (18) and (19) have the same anticancer activity on Hella cell with an IC₅₀ of 5 µg/mL ⁴⁴.

b. Inhibitory activity against PFTase:

Compound (8) is included in marine sesterpenoid group. The structural characteristics of these marine sesterpenoids are particularly intriguing since they have a complicated structure with many functional groups, resulting in a wide range of biological activities, including PTFase inhibition. ²⁹.

A measure of [3H] farnesyl transported to [3H] farnesyl pyrophosphate GST-RAS protein are indicated the activity of PFTase ⁴⁵. The post-translational farnesylation of the cysteine residue in the carboxyl terminus tetrapeptide of the Ras oncoprotein is catalyzed by farnesyl protein transferase (FPT). This residue's prenylation is required for Ras' membrane attachment and cell-transforming actions. FPT inhibitors have been shown to impede Ras-dependent cell transformation, suggesting that they could be used as a therapeutic method for the treatment of human cancers ⁴⁶. Compound (8) showed strong PFTase inhibiting activity, with an IC₅₀ of 3 µM ²⁹.

c. Inhibition of NADH Oxidase activity:

NADH oxidase, which is continually activated in transformed cells is triggered by hormones and growth factors from the mammalian plasma membrane ^47,48. The secondary metabolite from Hyrtios reticulatus has NADH oxidase inhibitory activity, namely (9). In beef heart submitochondrial particles (SMP), puupuhenone was tested for its ability to inhibit the integrated electron transfer chain (NADH oxidase activity). It has inhibitory potency similar to that of other interesting mitochondrial respiratory chain inhibitors such as benzopyranes or stolonoxides in mammals. With IC₅₀ values of 1.3 µM, this compound was determined to be the most powerful to inhibited of NADH oxidase activity, while 100% inhibition of rotenone-sensitive NADH oxidase activity was reached at around 2 µM ⁴³.

d. Antimicrobial activity:

Based on the report, the secondary metabolites from Hyrtios reticulatus had antimicrobial activity. antimicrobial activities were evaluated against Candida albicans, Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. compound (9) was tested on Candida albicans and had antimicrobial activity with an IC₅₀ of 32 µg/mL. When tested on Staphylococcus aureus, it showed activity with an IC₅₀of 64 µg/mL ³⁰. Another compound that has been tested for antimicrobiological activity is (19), whose activity was shown to be stronger than puupuhenone. In addition, when tested on Candida albicans, Bacillus subtillis, and Eschericia coli, the IC₅₀was 10 µg/mL.

e. Inhibition of Ubiquitin-Activating Enzyme (E1):

Cell cycle control, transcription, and expansion are all biological activities that are heavily influenced by the ubiquitin-proteasome pathway of regulation of protein degradation ^49,50. The ubiquitin-proteasome pathway is made up of the ubiquitin system and the 26S proteasome, which is a 76 amino acid proteolytic engine that connects to client proteins before disintegration. Ubiquitination in the ubiquitin system necessitates the sequential action of three enzymes, namely ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), resulting in the formation of a polyubiquitin chain.⁵¹.

Western blotting with antiflag antibody was used to determine the effect of hyrtioreticulins A-E and hyrtioerectine B on the formation of E1-ubiquitin intermediates from recombinants tagged FLAG E119 and GST-ubiquitin ⁵². Compounds (11) and (12) inhibited E1-ubiquitin intermediate formation an IC₅₀ values of 0.75 and 11 µg/mL (2.4 and 35 µM), respectively. Conversely, (13–15) and (16) were inactive even at 25 µg/mL. The structure-activity relationship between (11-16) suggests that transfiguration at C-1 and the presence of an imidazole ring are required for E1 inhibition ^32,33

CONCLUSION:

Based on the available data, we can conclude that the secondary metabolites of the sponges Hyrtios reticulatus differ, depending on geographic area where they grow. Variations in the environment could explain this. It has also been identified that the sponge Hyrtios reticulatus is a rich source of secondary metabolites with a wide range of biological activities.

ACKNOWLEDGEMENT:

The authors would like to acknowledge the funding support from UGM No: 3143/UN1.P.III/DIT-LIT/PT/2021

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Received on 29.06.2021 Modified on 28.09.2021

Research J. Pharm. and Tech. 2022; 15(6):2855-2861.

DOI: 10.52711/0974-360X.2022.00477