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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.
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. [1][3]. 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.
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| Aplysinopsin Derivatives | X1 | X2 | R1 | R2 | Y | Source [Ref.] | ||||||||||
| Aplysinopsin ( | 1 | ) | H | H | Me | Me | NH | Thorecta sp. sponge Great Barrier Reef Australia [1], | sp. sponge Great Barrier Reef Australia [3], | Verongia spengelli sponge Florida Keys [3], | sponge Florida Keys [4], | Dercitus sp. sponge Caribbean [4], | sp. sponge Caribbean [5], | Smenospongia aurea sponge Caribbean [5], | sponge Caribbean [24], | Astroides calycularis anthozoan Mediterranean [6] |
Table 2.
Aplysinopsins substituted at the nitrogen atom.
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| Aplysinopsin Derivatives | X | R | Sources [Ref.] | |||||||||||||||||||||||||||||||||||
| N | -propionylaplysinopsin ( | 16 | ) | H | OCCH | 2 | CH | 3 | Astroides calycularis anthozoan Mediterranean [6]. | anthozoan Mediterranean [25]. | , | anthozoan Mediterranean [25], | Tubastraea aurea Japan scleractinian coral [7], | Japan scleractinian coral [11], | Tubastraea sp. scleractinian coral Philippines [8], | sp. scleractinian coral Philippines [12], | Radianthus kuekenthali sea anemone Japan [9], | sea anemone Japan [26], | Aplysina sp. sponge Japan [10], | sp. sponge Japan [27], | Tubastraea faulkneri scleractinian coral Australia [11], | scleractinian coral Australia [13], | Tubastraea sp. scleractinian Japane [12], | sp. scleractinian Japane [14], | Smenospongia sp. sponge Indo-Pacific reefs [13], and | sp. sponge Indo-Pacific reefs [8], and | Verongula rigida sponge Florida Keys [14]. | sponge Florida Keys [9]. | ||||||||||
| Isoaplysinopsin ( | 2 | ) | H | H | ||||||||||||||||||||||||||||||||||
| 6-Bromo- | N | -propionylaplysinopsin ( | 17 | ) | BrH | Me | NMe | OCCH | 2 | CH | 3Aplysina sp. sponge Japan [10] and | sp. sponge Japan [27] and | Smenospongia aurea sponge Jamaica [15]. | sponge Jamaica [7]. | ||||||||||||||||||||||||
| 2′-de- | N | -methylaplysinopsin ( | 3 | ) | H | H | H | |||||||||||||||||||||||||||||||
| N | -methylaplysinopsin ( | 18 | Me | ) | H | Dercitus sp. sponge Caribbean [4], | sp. sponge Caribbean [5], | Tubastrea coccinea coral Hawaii [16], | coral Hawaii [10], | Phestilla melanobrachia mollusk [16], | mollusk [10], | Dendrophyllia sp. scleractinian coral Philippines [8], | sp. scleractinian coral Philippines [12], | Smenospongia aurea sponge Jamaica [15 | H | CH | 3], | Aplysina sp. sponge Japan | sponge Jamaica [7], | Verongula rigida sponge Florida Keys [14]. | sponge Florida Keys [9]. | |||||||||||||||||
| Methylaplysinopsin ( | 4 | ) | H | H | Me | Me | NMe | Aplysinopsis reticulata | sponge Australia [2] and | Smenospongia aurea sponge Jamaica [15]. | sponge Jamaica [7]. | |||||||||||||||||||||||||||
| 4′-Demethyl-3′-N-methylaplysinopsin ( | 5 | ) | H | H | Me | H | NMe | Dendrophyllia sp. scleractinian coral Philippines [8] and | sp. scleractinian coral Philippines [12] and | Smenospongia aurea sponge Jamaica [15]. | sponge Jamaica [7]. | |||||||||||||||||||||||||||
| N | -3′-ethyl-aplysinopsin ( | 6 | ) | H | H | Me | Et | NMe | Smenospongia aurea sponge Jamaica [15]. | sponge Jamaica [7]. | ||||||||||||||||||||||||||||
| 3′-Deimino-2′,4′-bis(demethyl)-3′-oxo-aplysinopsin ( | 7 | ) | H | H | H | H | O | Leptopsammia pruvoti scleractinian coral France [8]. | scleractinian coral France [12]. | |||||||||||||||||||||||||||||
| 3′-Deimino-3′oxoaplysinopsin ( | 8 | ) | H | H | Me | Me | O | Thorecta sp. sponge Great Barrier Reef Australia [1] and | sponge Great Barrier Reef Australia [3] and | Tubastraea sp. scleractinian coral Philippines [8]. | sp. scleractinian coral Philippines [12]. | |||||||||||||||||||||||||||
| 6-Bromo-2′-de- | N | -methylaplysinopsin ( | 9 | ) | Br | H | Me | H | NH | Dercitus sp. sponge Caribbean [4], | sp. sponge Caribbean [5], | Tubastrea coccinea coral Hawaii [16], | coral Hawaii [10], | Phestilla melanobrachia mollusk [16], | mollusk [10], | Dendrophyllia sp. scleractinian coral Philippines [8], | sp. scleractinian coral Philippines [12], | Tubastraea faulkneri scleractinian coral Australia [11], | scleractinian coral Australia [13], | Smenospongia aurea sponge Jamaica [15], | sponge Jamaica [7], | Hyrtios erecta sponge Japan [17]. | sponge Japan [6]. | |||||||||||||||
| [ | 10 | ] | . | sp. sponge Japan [27]. | 6-Bromoaplysinopsin ( | 10 | ) | Br | H | Me | Me | NH | Tubastrea coccinea coral Hawaii [16], | coral Hawaii [10], | Smenospongia aurea sponge Caribbean [5], | sponge Caribbean [24], | Astroides calycularis anthozoan Mediterranean [6], | anthozoan Mediterranean [25], | Radianthus kuekenthali sea anemone Japan [9], | sea anemone Japan [26], | Tubastraea faulkneri scleractinian coral Australia [11], | scleractinian coral Australia [13], | Smenospongia aurea sponge Jamaica [15], | sponge Jamaica [7], | Smenospongia aurea sponge Florida Keys [14]. | sponge Florida Keys [9]. | 6-Bromo-4′-de- | N | -methylaplysinopsin ( | 11 | ) | Br | H | H | Me | NH | Smenospongia aurea sponge Caribbean [5]. | sponge Caribbean [24]. |
| 6-Bromo-4′-demethyl- 3′- | N | -methyl-aplysinopsin ( | 12 | ) | Br | H | H | Me | NMe | Dendrophyllia sp. scleractinian coral Philippines [8]. | sp. scleractinian coral Philippines [12]. | |||||||||||||||||||||||||||
| 5,6-Dibromo-2′-demethylaplysinopsin ( | 13 | ) | Br | Br | Me | H | NH | Hyrtios erecta sponge Japan [17]. | sponge Japan [6]. | |||||||||||||||||||||||||||||
| 6-Bromo-3′-deimino-2′,4′-bis(demethyl)-3′- Oxoaplysinopsin ( | 14 | ) | Br | H | H | H | O | Smenospongia aurea sponge Caribbean [18] and | sponge Caribbean [28] and | Leptopsammia pruvoti scleractinian coral France [8]. | scleractinian coral France [12]. | |||||||||||||||||||||||||||
| 6-Bromo-3′-deimino-3′-oxoaplysinopsin ( | 15 | ) | Br | H | Me | Me | O | Astroides calycularis anthozoan Mediterranean [6] and | anthozoan Mediterranean [25] and | Tubastraea sp. scleractinian coral Philippines [8]. | sp. scleractinian coral Philippines [12]. | |||||||||||||||||||||||||||
Table 3. 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 [ | 4,27]. - Inhibit the growth of | Staphylococcus epidermidis [13]. - An inhibitor of development of fertilized sea urchin eggs at 2.5 µg/mL [7]. - Induce symbiosis between sea anemone and anemonefish [9]. | [8]. - An inhibitor of development of fertilized sea urchin eggs at 2.5 µg/mL [11]. - Induce symbiosis between sea anemone and anemonefish [26]. |
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| Isoaplysinopsin ( | 2 | ) | - Showed cytotoxic against murine lymphoma L-1210 (IC | 50 11.5 µg/mL) and human epidermoid carcinoma KJ3 (31% inhibition at 20 µg/mL) cells [10]. | 11.5 µg/mL) and human epidermoid carcinoma KJ3 (31% inhibition at 20 µg/mL) cells [27]. | |
| Methylaplysinopsin ( | 4 | ) | - Antidepressant activity by enhancing serotonin activity in the central nervous system [29][30]. - Inhibition of monoamine oxidase (MAO) [30]. - Showed cytotoxicity (IC | - Antidepressant activity by enhancing serotonin activity in the central nervous system [49,50]. - Inhibition of monoamine oxidase (MAO) [50]. - Showed cytotoxicity (IC | 50 values against L-1210 and KB cells of 3.5 and 6.7 µg/mL, respectively) [10]. | values against L-1210 and KB cells of 3.5 and 6.7 µg/mL, respectively) [27]. |
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| Aplysinopsin Derivatives | R | X | Sources [Ref.] |
| 1′,8-Dihydroaplysinopsin (19) | H | H | Tubastrea coccinea coral Hawaii [16], Radianthus kuekenthali sea anemone Japan [9], and Thorectandra sp. sponge Indo-Pacific reefs [13]. |
| 6-Bromo-1′,8-dihydroaplysinopsin (20) | Br | H | |
| 6-Bromo-1-hydroxy-1′,8-dihydroaplysinopsin (21) | Br | OH | Thorectandra sp. sponge Indo-Pacific reefs [13]. |
| 6-Bromo-1-methoxy-1′,8-dihydroaplysinopsin (22) | Br | OCH3 | |
| 6-Bromo-1-ethoxy-1′,8-dihydroaplysinopsin (23) | Br | OCH2CH3 | |
Aplysinopsin 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)BrOCH2CH3Table 4. Aplysinopsin dimers.
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| Aplysinopsin Dimers | Sources [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 B | Marine 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]. |
Aplysinopsin dimers.
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 [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) andDictazoles A and B (29)Marine Sponge Smenospongia cerebriformis, Panamanian sponge [34].
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 [25][26]. - Possess monoamine oxidase (MAO) inhibitory activity (IC | - CNS permeable scaffold for dual inhibition of cholinesterase and BACE-1 inhibition [21,47]. - Possess monoamine oxidase (MAO) inhibitory activity (IC | 50 of 5.6 nM) [27]. - Antiplasmodial activity (IC | of 5.6 nM) [19]. - Antiplasmodial activity (IC | 50: 0.43 µg/mL) [28]. - Antineoplastic activity (IC | : 0.43 µg/mL) [48]. - Antineoplastic activity (IC | 50 values against L-1210 and KB cells, respectively, 2.3 and 6.4 µg/mL [3][10]. | ||
| N | |||||||||||
| -3′-ethyl-aplysinopsin ( | |||||||||||
| 6 | ) | - Serotonin receptors modulator with Ki value 1.7 µM to the 5-HT | 2A | and 3.5 µM to 5-HT | 2C serotonin subtypes [15]. | serotonin subtypes [7]. | |||||
| 6-Bromo-2′-de- | N | -methylaplysinopsin ( | 9 | ) | - Serotonin receptors modulator (showed significant selectivity to the 5-HT | 2C | serotonin subtype over the 5-HT | 2A subtype) [15]. - Antiplasmodial. - Inhibitor of nitric oxide synthase (nNOS). | subtype) [7]. - Antiplasmodial. - Inhibitor of nitric oxide synthase (nNOS). |
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| 6-Bromoaplysinopsin ( | 10 | ) | - Serotonin receptors modulator (showed highest affinity to 5-HT | 2C with a Ki value similar to that of serotonin 0.33 µM) [15]. | with a Ki value similar to that of serotonin 0.33 µM) [7]. | ||||||
| 5,6-Dibromo-2′-demethylaplysinopsin ( | 13 | ) | - Inhibitor of nitric oxide synthase (nNOS) [17]. | - Inhibitor of nitric oxide synthase (nNOS) [6]. | |||||||
| 6-Bromo-3′-deimino-3′-oxoaply-sinopsin ( | 15 | ) | - Antiplasmodial activity [20]. | - Antiplasmodial activity [30]. | |||||||
| 1′,8-Dihydroaplysinopsin ( | 19 | ) | - Induce symbiosis between sea anemone and anemonefish [9]. | - Induce symbiosis between sea anemone and anemonefish [26]. | |||||||
| 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 [13]. | [8]. |
