Chemical Structures and Biological Activities of of Aplysinopsins: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Eslam El-Sawy.

Marine products are among the most promising sources of biologically active molecules. Aplysinopsins, tryptophan-derived marine natural products, were isolated from different natural marine sources including sponges, stony corals (hard corals) especially genus scleractinian, as well as sea anemone, in addition to one nudibranch. Aplysinopsins were reported to be isolated from different marine organisms related to various geographic areas such as Pacific, Indonesia, Caribbean, and Mediterranean regions.

  • aplysinopsin
  • sources
  • synthesis
  • bioactivity

1. Different Sources and Chemical Structures of Aplysinopsins

The chemical backbone of the natural aplysinopsins include a simple configuration of monomeric aplysinopsin-type structures and their brominated derivatives at the A ring, variation in the structure of the C ring, the presence and configuration of the C-8-C-1′ double bond, the oxidation state of the 2-aminoimidazoline fragment and N-alkylated at the B ring (Figure 1), in addition to the aplysinopsin dimers form.
Marinedrugs 21 00268 g001 550
Figure 1. The chemical configuration of monomeric aplysinopsin-type structures shows detailed segmentation of the rings, carbon numbering, and type of bonds.
Aplysinopsin, (E)-5-((1H-indol-3-yl)methylene)-2-imino-1,3-dimethylimidazo-li-din-4-one (1), was first isolated from the sponge genus Thorecta of the Australian Great Barrier Reef by Kazlauskas et al. [3][1]. Sequentially, aplysinopsin and its derivatives have been reported in many other marine organisms from various geographic areas (Table 1, Table 2, Table 3 and Table 4) [2].
Table 1.
Monomeric aplysinopsin-type structures and their brominated derivatives.
Marinedrugs 21 00268 i001
Aplysinopsin Derivatives X1 X2 R1 R2 Y Source [Ref.]
Aplysinopsin (1)
Table 2.
Aplysinopsins substituted at the nitrogen atom.
Marinedrugs 21 00268 i002
Aplysinopsin Derivatives X R Sources [Ref.]
H
N-propionylaplysinopsin (16) HH Me Me OCCH2CH3 Astroides calycularis anthozoan Mediterranean [25]. anthozoan Mediterranean [6]NH .Thorecta sp. sponge Great Barrier Reef Australia [3], sp. sponge Great Barrier Reef Australia [1], Verongia spengelli sponge Florida Keys [4], sponge Florida Keys [3], Dercitus sp. sponge Caribbean [5], sp. sponge Caribbean [4], Smenospongia aurea sponge Caribbean [24], sponge Caribbean [5], Astroides calycularis anthozoan Mediterranean [25], anthozoan Mediterranean [6], Tubastraea aurea Japan scleractinian coral [11], Japan scleractinian coral [7], Tubastraea sp. scleractinian coral Philippines [12], sp. scleractinian coral Philippines [8], Radianthus kuekenthali sea anemone Japan [26], sea anemone Japan [9], Aplysina sp. sponge Japan [27], sp. sponge Japan [10], Tubastraea faulkneri scleractinian coral Australia [13], scleractinian coral Australia [11], Tubastraea sp. scleractinian Japane [14], sp. scleractinian Japane [12], Smenospongia sp. sponge Indo-Pacific reefs [8], and sp. sponge Indo-Pacific reefs [13], and Verongula rigida sponge Florida Keys [9]. sponge Florida Keys [14].
Isoaplysinopsin (2) H H H Me NMe Aplysina sp. sponge Japan [27] and sp. sponge Japan [10] and Smenospongia aurea sponge Jamaica [7]. sponge Jamaica [15].
6-Bromo-N-propionylaplysinopsin (17) Br OCCH2CH3 2′-de-N-methylaplysinopsin (3) H H H Me H
N-methylaplysinopsin (18)Dercitus sp. sponge Caribbean [5], sp. sponge Caribbean [4], Tubastrea coccinea coral Hawaii [10], coral Hawaii [16], Phestilla melanobrachia mollusk [10], mollusk [16], Dendrophyllia sp. scleractinian coral Philippines [12], sp. scleractinian coral Philippines [8], Smenospongia aurea sponge Jamaica [7], sponge Jamaica [15], Verongula rigida sponge Florida Keys [9]. sponge Florida Keys [14].
H CH3 Methylaplysinopsin

(		4) H H Me Me NMe Aplysinopsis reticulata sponge Australia [2] and Smenospongia aurea sponge Jamaica [7]. sponge Jamaica [15].
4′-Demethyl-3′-N-methylaplysinopsin (5) H H Me H NMe Dendrophyllia sp. scleractinian coral Philippines [12] and sp. scleractinian coral Philippines [8] and Smenospongia aurea sponge Jamaica [7]. sponge Jamaica [15].
N-3′-ethyl-aplysinopsin (6) H H Me Et NMe Smenospongia aurea sponge Jamaica [7]. sponge Jamaica [15].
3′-Deimino-2′,4′-bis(demethyl)-3′-oxo-aplysinopsin (7) H H H H O Leptopsammia pruvoti scleractinian coral France [12]. scleractinian coral France [8].
3′-Deimino-3′oxoaplysinopsin

(		8) H H Me Me O Thorecta sp. sponge Great Barrier Reef Australia [3] and sponge Great Barrier Reef Australia [1] and Tubastraea sp. scleractinian coral Philippines [12]. sp. scleractinian coral Philippines [8].
6-Bromo-2′-de-N-methylaplysinopsin

(		9) Br H Me H NH Dercitus sp. sponge Caribbean [5], sp. sponge Caribbean [4], Tubastrea coccinea coral Hawaii [10], coral Hawaii [16], Phestilla melanobrachia mollusk [10], mollusk [16], Dendrophyllia sp. scleractinian coral Philippines [12], sp. scleractinian coral Philippines [8], Tubastraea faulkneri scleractinian coral Australia [13], scleractinian coral Australia [11], Smenospongia aurea sponge Jamaica [7], sponge Jamaica [15], Hyrtios erecta sponge Japan [6]. sponge Japan [17].
.
Aplysina sp. sponge Japan [27]. sp. sponge Japan [10]. 6-Bromoaplysinopsin (10) Br H Me Me NH Tubastrea coccinea coral Hawaii [10], coral Hawaii [16], Smenospongia aurea sponge Caribbean [24], sponge Caribbean [5], Astroides calycularis anthozoan Mediterranean [25], anthozoan Mediterranean [6], Radianthus kuekenthali sea anemone Japan [26], sea anemone Japan [9], Tubastraea faulkneri scleractinian coral Australia [13], scleractinian coral Australia [11], Smenospongia aurea sponge Jamaica [7], sponge Jamaica [15], Smenospongia aurea sponge Florida Keys [9]. sponge Florida Keys [14] 6-Bromo-4′-de-N-methylaplysinopsin (11) Br H H Me NH Smenospongia aurea sponge Caribbean [24]. sponge Caribbean [5].
6-Bromo-4′-demethyl-

3′-		N-methyl-aplysinopsin (12) Br H H Me NMe Dendrophyllia sp. scleractinian coral Philippines [12]. sp. scleractinian coral Philippines [8].
5,6-Dibromo-2′-demethylaplysinopsin (13) Br Br Me H NH Hyrtios erecta sponge Japan [6]. sponge Japan [17].
6-Bromo-3′-deimino-2′,4′-bis(demethyl)-3′-

Oxoaplysinopsin (		14) Br H H H O Smenospongia aurea sponge Caribbean [28] and sponge Caribbean [18] and Leptopsammia pruvoti scleractinian coral France [12]. scleractinian coral France [8].
6-Bromo-3′-deimino-3′-oxoaplysinopsin

(		15) Br H Me Me O Astroides calycularis anthozoan Mediterranean [25] and anthozoan Mediterranean [6] and Tubastraea sp. scleractinian coral Philippines [12]. sp. scleractinian coral Philippines [8].
Table 3. Aplysinopsins with a single C-8-C-1′ bond.
Aplysinopsins with a single C-8-C-1′ bond.
- Inhibit the growth of
values against L-1210 and KB cells, respectively, 2.3 and 6.4 µg/mL [3][10].

- Inhibit the growth of 		Staphylococcus epidermidis [8].

- An inhibitor of development of fertilized sea urchin eggs at 2.5 µg/mL [11].

- Induce symbiosis between sea anemone and anemonefish [26].		 [13].

- An inhibitor of development of fertilized sea urchin eggs at 2.5 µg/mL [7].

- Induce symbiosis between sea anemone and anemonefish [9].
Isoaplysinopsin (2) - Showed cytotoxic against murine lymphoma L-1210 (IC50 11.5 µg/mL) and human epidermoid carcinoma KJ3 (31% inhibition at 20 µg/mL) cells [27]. 11.5 µg/mL) and human epidermoid carcinoma KJ3 (31% inhibition at 20 µg/mL) cells [10].
Methylaplysinopsin (4) - Antidepressant activity by enhancing serotonin activity in the central nervous system [49,50].

- Inhibition of monoamine oxidase (MAO) [50].

- Showed cytotoxicity (IC		- Antidepressant activity by enhancing serotonin activity in the central nervous system [29][30].

- Inhibition of monoamine oxidase (MAO) [30].

- Showed cytotoxicity (IC		50 values against L-1210 and KB cells of 3.5 and 6.7 µg/mL, respectively) [27]. values against L-1210 and KB cells of 3.5 and 6.7 µg/mL, respectively) [10
Marinedrugs 21 00268 i003
Aplysinopsin DerivativesRXSources [Ref.]
1′,8-Dihydroaplysinopsin (19)HHTubastrea coccinea coral Hawaii [16], Radianthus kuekenthali sea anemone Japan [9], and Thorectandra sp. sponge Indo-Pacific reefs [13].
6-Bromo-1′,8-dihydroaplysinopsin (20)BrH
6-Bromo-1-hydroxy-1′,8-dihydroaplysinopsin (21)BrOHThorectandra sp. sponge Indo-Pacific reefs [13].
6-Bromo-1-methoxy-1′,8-dihydroaplysinopsin (22)BrOCH3
6-Bromo-1-ethoxy-1′,8-dihydroaplysinopsin (23)BrOCH2CH3
Marinedrugs 21 00268 i003Aplysinopsin DerivativesRXSources [Ref.]1′,8-Dihydroaplysinopsin (19)HHTubastrea coccinea coral Hawaii [10], Radianthus kuekenthali sea anemone Japan [26], and Thorectandra sp. sponge Indo-Pacific reefs [8].6-Bromo-1′,8-dihydroaplysinopsin (20)BrH6-Bromo-1-hydroxy-1′,8-dihydroaplysinopsin (21)BrOHThorectandra sp. sponge Indo-Pacific reefs [8].6-Bromo-1-methoxy-1′,8-dihydroaplysinopsin (22)BrOCH36-Bromo-1-ethoxy-1′,8-dihydroaplysinopsin (23)BrOCH2CH3
Table 4. Aplysinopsin dimers.
Aplysinopsin dimers.
Marinedrugs 21 00268 i004
Aplysinopsin DimersSources [Ref.]
Cycloaplysinopsin (24)Scleractinian corals of the family Dendrophylliidae from Comoro islands and hard coral Tubastraea sp., from the Great Hanish in the Archipelago of the Hanish Islands, Yemen, tropical Indo-Pacific (Comoros, Philippines) scleractinian corals of the family Dendrophylliidae [19][20].
Tubastrindoles A–C (25)Stony Coral, Tubastraea sp. scleractinian Japane [12].
Tubastrindole B (26)Australian Marine Sponge, a specimen of the sponge Ianthella cf. flabelliformis [21].
Tubastrindoles D–H (27)Stony Coral, Tubastraea aurea Odomari area, Kagoshima Prefecture, Japan [22].
Dictazolines A and BMarine Sponge Smenospongia cerebriformis, Hospital Point on Solarte Isle, Boca del Toro, on the northwest coast of Panama [23].
Dictazolines C–E (28) and

Dictazoles A and B (29)		Marine Sponge Smenospongia cerebriformis, Panamanian sponge [24].
Marinedrugs 21 00268 i004Aplysinopsin DimersSources [Ref.]Cycloaplysinopsin (24)Scleractinian corals of the family Dendrophylliidae from Comoro islands and hard coral Tubastraea sp., from the Great Hanish in the Archipelago of the Hanish Islands, Yemen, tropical Indo-Pacific (Comoros, Philippines) scleractinian corals of the family Dendrophylliidae [29,30].Tubastrindoles A–C (25)Stony Coral, Tubastraea sp. scleractinian Japane [14].Tubastrindole B (26)Australian Marine Sponge, a specimen of the sponge Ianthella cf. flabelliformis [31].Tubastrindoles D–H (27)Stony Coral, Tubastraea aurea Odomari area, Kagoshima Prefecture, Japan [32].Dictazolines A and BMarine Sponge Smenospongia cerebriformis, Hospital Point on Solarte Isle, Boca del Toro, on the northwest coast of Panama [33].Dictazolines C–E (28) and

Dictazoles A and B (29)Marine Sponge Smenospongia cerebriformis, Panamanian sponge [34].

2. Biological Activity

2. Biological Activity
Aplysinopsins possess an array of biological activities (Table 5).
Table 5.
Biological activities of aplysinopsins.
Aplysinopsin Derivatives Activity [Ref.]
Aplysinopsin (1) - CNS permeable scaffold for dual inhibition of cholinesterase and BACE-1 inhibition [21,47].

- Possess monoamine oxidase (MAO) inhibitory activity (IC		- CNS permeable scaffold for dual inhibition of cholinesterase and BACE-1 inhibition [25][26].

- Possess monoamine oxidase (MAO) inhibitory activity (IC		50 of 5.6 nM) [19].

- Antiplasmodial activity (IC		 of 5.6 nM) [27].

- Antiplasmodial activity (IC		50: 0.43 µg/mL) [48].

- Antineoplastic activity (IC		: 0.43 µg/mL) [28].

- Antineoplastic activity (IC		50 values against L-1210 and KB cells, respectively, 2.3 and 6.4 µg/mL [4,27].

]
.
N-3′-ethyl-aplysinopsin (6) - Serotonin receptors modulator with Ki value 1.7 µM to the 5-HT2A and 3.5 µM to 5-HT2C serotonin subtypes [7]. serotonin subtypes [15].
6-Bromo-2′-de-N-methylaplysinopsin (9) - Serotonin receptors modulator (showed significant selectivity to the 5-HT2C serotonin subtype over the 5-HT2A subtype) [7].

- Antiplasmodial.

- Inhibitor of nitric oxide synthase (nNOS).		 subtype) [15].

- Antiplasmodial.

- Inhibitor of nitric oxide synthase (nNOS).
6-Bromoaplysinopsin (10) - Serotonin receptors modulator (showed highest affinity to 5-HT2C with a Ki value similar to that of serotonin 0.33 µM) [7]. with a Ki value similar to that of serotonin 0.33 µM) [15].
5,6-Dibromo-2′-demethylaplysinopsin (13) - Inhibitor of nitric oxide synthase (nNOS) [6].- Inhibitor of nitric oxide synthase (nNOS) [17].
6-Bromo-3′-deimino-3′-oxoaply-sinopsin (15) - Antiplasmodial activity [30].- Antiplasmodial activity [20].
1′,8-Dihydroaplysinopsin (19) - Induce symbiosis between sea anemone and anemonefish [26].- Induce symbiosis between sea anemone and anemonefish [9].
6-Bromo-1′,8-dihydroaplysinopsin (20)

6-Bromo-1-hydroxy-1′,8-dihydroaplysinopsin (		21)

6-Bromo-1-methoxy-1′,8-dihydroaplysinopsin (		22)

6-Bromo-1-ethoxy-1′,8-dihydroaplysinopsin (		23) - Inhibit the growth of Staphylococcus epidermidis [8]. [13].

References

  1. Kazlauskas, R.; Murphy, P.T.; Quinn, R.J.; Wells, R.J. Aplysinopsin, a new tryptophan derivative from a sponge. Tetrahedron Lett. 1977, 18, 61–64.
  2. Bialonska, D.; Zjawiony, J.K. Aplysinopsins—Marine Indole Alkaloids: Chemistry, Bioactivity and Ecological Significance. Mar. Drugs 2009, 7, 166.
  3. Kh, H.; Fj, S. Aplysinopsin: Antineoplastic Tryptophan Derivative from the Marine Sponge Verongia Spengelii. Lloydia 1977, 40, 479–481.
  4. Djura, P.; Faulkner, D.J. Metabolites of the marine sponge Dercitus species. J. Org. Chem. 1980, 45, 735–737.
  5. Tymiak, A.A.; Rinehart, K.L.; Bakus, G.J. Constituents of morphologically similar sponges: Aplysina and Smenospongia Species. Tetrahedron 1985, 41, 1039–1047.
  6. Fattorusso, E.; Lanzotti, V.; Magno, S.; Novellino, E. Tryptophan Derivatives from a Mediterranean Anthozoan, Astroides calycularis. J. Nat. Prod. 1985, 48, 924–927.
  7. Fusetani, N.; Asano, M.; Matsunaga, S.; Hashimoto, K. Bioactive marine metabolites—XV. Isolation of aplysinopsin from the Scleractinian coral Tubastrea aurea as an inhibitor of development of fertilized sea urchin eggs. Comp. Biochem. Physiol. Part B Comp. Biochem. 1986, 85, 845–846.
  8. Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Novel Aplysinopsin-Type Alkaloids from Scleractinian Corals of the Family Dendrophylliidae of the Mediterranean and the Philippines. Configurational-assignment criteria, stereospecific synthesis, and photoisomerization. Helvetica Chim. Acta 1988, 71, 773–782.
  9. Murata, M.; Miyagawa-Kohshima, K.; Nakanishi, K.; Naya, Y. Characterization of Compounds That Induce Symbiosis Between Sea Anemone and Anemone Fish. Science 1986, 234, 585–587.
  10. Kondo, K.; Nishi, J.; Ishibashi, M.; Kobayashi, J. Two New Tryptophan-Derived Alkaloids from the Okinawan Marine Sponge Aplysina sp. J. Nat. Prod. 1994, 57, 1008–1011.
  11. Koh, E.G.; Sweatman, H. Chemical warfare among scleractinians: Bioactive natural products from Tubastraea faulkneri Wells kill larvae of potential competitors. J. Exp. Mar. Biol. Ecol. 2000, 251, 141–160.
  12. Iwagawa, T.; Miyazaki, M.; Okamura, H.; Nakatani, M.; Doe, M.; Takemura, K. Three novel bis(indole) alkaloids from a stony coral, Tubastraea sp. Tetrahedron Lett. 2003, 44, 2533–2535.
  13. Segraves, N.L.; Crews, P. Investigation of Brominated Tryptophan Alkaloids from Two Thorectidae Sponges: Thorectandra and Smenospongia. J. Nat. Prod. 2005, 68, 1484–1488.
  14. Kochanowska, A.J.; Rao, K.V.; Childress, S.; El-Alfy, A.; Matsumoto, R.R.; Kelly, M.; Stewart, G.S.; Sufka, K.J.; Hamann, M.T. Secondary Metabolites from Three Florida Sponges with Antidepressant Activity. J. Nat. Prod. 2008, 71, 186–189.
  15. Hu, J.-F.; Schetz, J.A.; Kelly, M.; Peng, J.-N.; Ang, K.K.H.; Flotow, H.; Leong, C.Y.; Ng, S.B.; Buss, A.D.; Wilkins, S.P.; et al. New Antiinfective and Human 5-HT2 Receptor Binding Natural and Semisynthetic Compounds from the Jamaican Sponge Smenospongia aurea. J. Nat. Prod. 2002, 65, 476–480.
  16. Okuda, R.K.; Klein, D.; Kinnel, R.B.; Li, M.; Scheuer, P.J. Marine natural products: The past twenty years and beyond. Pure Appl. Chem. 1982, 54, 1907–1914.
  17. Aoki, S.; Ye, Y.; Higuchi, K.; Takashima, A.; Tanaka, Y.; Kitagawa, I.; Kobayashi, M. Novel Neuronal Nitric Oxide Synthase (nNOS) Selective Inhibitor, Aplysinopsin-Type Indole Alkaloid, from Marine Sponge Hyrtios erecta. Chem. Pharm. Bull. 2001, 49, 1372–1374.
  18. Djura, P.; Stierle, D.B.; Sullivan, B.; Faulkner, D.J.; Arnold, E.V.; Clardy, J. Some metabolites of the marine sponges Smenospongia aurea and Smenospongia (Ident.Polyfibrospongia) echina. J. Org. Chem. 1980, 45, 1435–1441.
  19. Mancini, I.; Guella, G.; Zibrowius, H.; Pietra, F. On the origin of quasi-racemic aplysinopsin cycloadducts, (bis)indole alkaloids isolated from scleractinian corals of the family Dendrophylliidae. Involvement of enantiodefective Diels–Alderases or asymmetric induction in artifact processes involving adventitious catalysts? Tetrahedron 2003, 59, 8757–8762.
  20. Meyer, M.; Delberghe, F.; Liron, F.; Guillaume, M.; Valentin, A.; Guyot, M. An antiplasmodial new (bis)indole alkaloid from the hard coral Tubastraea sp. Nat. Prod. Res. 2009, 23, 178–182.
  21. Balansa, W.; Islam, R.; Gilbert, D.F.; Fontaine, F.; Xiao, X.; Zhang, H.; Piggott, A.M.; Lynch, J.W.; Capon, R.J. Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator. Bioorganic Med. Chem. 2013, 21, 4420–4425.
  22. Iwagawa, T.; Miyazaki, M.; Yokogawa, Y.; Okamura, H.; Nakatani, M.; Doe, M.; Morimoto, Y.; Takemura, K. Aplysinopsin Dimers from a Stony Coral. Tubastraea aurea. Heterocycles 2008, 75, 2023.
  23. Dai, J.; Jiménez, J.I.; Kelly, M.; Barnes, S.; Lorenzo, P.; Williams, P. Dictazolines A and B, Bisspiroimidazolidinones from the Marine Sponge Smenospongia cerebriformis. J. Nat. Prod. 2008, 71, 1287–1290.
  24. Dai, J.; Jiménez, J.I.; Kelly, M.; Williams, P.G. Dictazoles: Potential Vinyl Cyclobutane Biosynthetic Precursors to the Dictazolines. J. Org. Chem. 2010, 75, 2399–2402.
  25. Nuthakki, V.K.; Yadav Bheemanaboina, R.R.; Bharate, S.B. Identification of aplysinopsin as a blood-brain barrier permeable scaffold for anti-cholinesterase and anti-BACE-1 activity. Bioorganic Chem. 2021, 107, 104568.
  26. Nuthakki, V.K.; Sharma, A.; Kumar, A.; Bharate, S.B. Identification of embelin, a 3-undecyl-1,4-benzoquinone from Embelia ribes as a multitargeted anti-Alzheimer agent. Drug Dev. Res. 2019, 80, 655–665.
  27. Lewellyn, K.; Bialonska, D.; Loria, M.J.; White, S.W.; Sufka, K.J.; Zjawiony, J.K. In vitro structure–activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety–depression model. Bioorganic Med. Chem. 2013, 21, 7083–7090.
  28. Passemar, C.; Saléry, M.; Soh, P.N.; Linas, M.-D.; Ahond, A.; Poupat, C.; Benoit-Vical, F. Indole and aminoimidazole moieties appear as key structural units in antiplasmodial molecules. Phytomedicine 2011, 18, 1118–1125.
  29. Wells, R.J.; Murphy, P.T. 5-(Indol-3-Ylmethylene)-1,3-Dimethyl-2-Methylamino-4-Imidazolidinone. U.S. Patent US4195179A, 25 March 1980.
  30. Baird-Lambert, J.; Davis, P.A.; Taylor, K.M. Methylaplysinopsin: A natural product of marine origin with effects on serotonergic neurotransmission. Clin. Exp. Pharmacol. Physiol. 1982, 9, 203–212.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback