Secondary Metabolites from the Marine Sponge Genus Phyllospongia

Phyllospongia, one of the most common marine sponges in tropical and subtropical oceans, has been shown to be a prolific producer of natural products with a broad spectrum of biological activities. This review for the first time provides a comprehensive overview of secondary metabolites produced by Phyllospongia spp. over the 37 years from 1980 to 2016.


Introduction
Marine sponges, as very primitive animals, are widely distributed in the oceans from tropic to polar regions. Growing evidence indicates that these animals are the most prolific source of natural products as pharmaceutical leads [1][2][3]. Marine sponges possess a large variety of secondary metabolites with diverse chemical structures, such as terpenoids [4], macrolides [5], and sterols [6]. Therefore, it has greatly attracted the attention of natural product chemists and pharmaceutical experts around the world to carry out chemical research for the new drug discovery.
Phyllospongia (Porifera, Demospongiae, Dictyoceratida, Thorectidae) is one of the most common marine sponges in tropical and subtropical areas, including the Indian Ocean, the Great Barrier Reef, Papua New Guinea, the South China Sea, the South Pacific, and the Red Sea. Chemical investigation of Phyllospongia spp. has been extensively carried out and has given rise to a great array of bioactive secondary metabolites. In order to better understand and rationally exploit the marine sponge genus Phyllospongia, relevant research references reported between 1980 and 2016 are summarized in this review for the first time.

Phyllospongia (syn. Carteriospongia) foliascens
Marine sponge P. foliascens is the most productive maker of secondary metabolites among all known Phyllospongia spp. Chemical investigation indicates that most of these compounds belong to scalarane sesterterpenoid. P. foliascens grows in many marine areas, such as Okinawa, the South China Sea, Papua New Guinea, Indonesia, the South Pacific near Vanuatu, and the Great Barrier Reef. Interestingly, the same species of marine sponge collected from different areas possesses various scalarane sesterterpenoids.

Phyllospongia (syn. Carteriospongia) foliascens
Marine sponge P. foliascens is the most productive maker of secondary metabolites among all known Phyllospongia spp. Chemical investigation indicates that most of these compounds belong to scalarane sesterterpenoid. P. foliascens grows in many marine areas, such as Okinawa, the South China Sea, Papua New Guinea, Indonesia, the South Pacific near Vanuatu, and the Great Barrier Reef. Interestingly, the same species of marine sponge collected from different areas possesses various scalarane sesterterpenoids.

Phyllospongia (syn. Carteriospongia) foliascens
Marine sponge P. foliascens is the most productive maker of secondary metabolites among all known Phyllospongia spp. Chemical investigation indicates that most of these compounds belong to scalarane sesterterpenoid. P. foliascens grows in many marine areas, such as Okinawa, the South China Sea, Papua New Guinea, Indonesia, the South Pacific near Vanuatu, and the Great Barrier Reef. Interestingly, the same species of marine sponge collected from different areas possesses various scalarane sesterterpenoids.

Phyllospongia madagascarensis
To the best of our knowledge, only three natural products (93-95) (Chart 6) have been found in the marine sponge P. madagascarensis, which was grown near the northwest coast of Madagascar [35]. Interestingly, the chemical structure of 94 possesses seven-membered oxacycle.

Phyllospongia papyracea
Ten small molecules (96-105) (Chart 7) were isolated from P. papyracea collected on Hainan Island in the South China Sea, Papua New Guinea, and Sangihe Island in the Indonesian Sea [36][37][38]. Cytotoxic tests suggested that compound 96 had an in vitro cytotoxic effect on the leukemia cancer cell line P388 with an IC50 value of 5 μg/mL, and 99-104 were inactive against the β-catenin and transcription factor 4 (Tcf4) complex. Phyllactone H (105) was found in the marine sponge derived from Sangihe Island and possessed in vitro moderate cytotoxicities against cell lines A549, MCF-7, and HeLa with IC50 values of no more than 25 μM.

Phyllospongia madagascarensis
To the best of our knowledge, only three natural products (93-95) (Chart 6) have been found in the marine sponge P. madagascarensis, which was grown near the northwest coast of Madagascar [35]. Interestingly, the chemical structure of 94 possesses seven-membered oxacycle.

Phyllospongia madagascarensis
To the best of our knowledge, only three natural products (93-95) (Chart 6) have been found in the marine sponge P. madagascarensis, which was grown near the northwest coast of Madagascar [35]. Interestingly, the chemical structure of 94 possesses seven-membered oxacycle.

Phyllospongia papyracea
Ten small molecules (96-105) (Chart 7) were isolated from P. papyracea collected on Hainan Island in the South China Sea, Papua New Guinea, and Sangihe Island in the Indonesian Sea [36][37][38]. Cytotoxic tests suggested that compound 96 had an in vitro cytotoxic effect on the leukemia cancer cell line P388 with an IC50 value of 5 μg/mL, and 99-104 were inactive against the β-catenin and transcription factor 4 (Tcf4) complex. Phyllactone H (105) was found in the marine sponge derived from Sangihe Island and possessed in vitro moderate cytotoxicities against cell lines A549, MCF-7, and HeLa with IC50 values of no more than 25 μM.

Phyllospongia papyracea
Ten small molecules (96-105) (Chart 7) were isolated from P. papyracea collected on Hainan Island in the South China Sea, Papua New Guinea, and Sangihe Island in the Indonesian Sea [36][37][38]. Cytotoxic tests suggested that compound 96 had an in vitro cytotoxic effect on the leukemia cancer cell line P388 with an IC 50 value of 5 µg/mL, and 99-104 were inactive against the β-catenin and transcription factor 4 (Tcf4) complex. Phyllactone H (105) was found in the marine sponge derived from Sangihe Island and possessed in vitro moderate cytotoxicities against cell lines A549, MCF-7, and HeLa with IC 50 values of no more than 25 µM.

Phyllospongia madagascarensis
To the best of our knowledge, only three natural products (93-95) (Chart 6) have been found in the marine sponge P. madagascarensis, which was grown near the northwest coast of Madagascar [35]. Interestingly, the chemical structure of 94 possesses seven-membered oxacycle.

Phyllospongia papyracea
Ten small molecules (96-105) (Chart 7) were isolated from P. papyracea collected on Hainan Island in the South China Sea, Papua New Guinea, and Sangihe Island in the Indonesian Sea [36][37][38]. Cytotoxic tests suggested that compound 96 had an in vitro cytotoxic effect on the leukemia cancer cell line P388 with an IC50 value of 5 μg/mL, and 99-104 were inactive against the β-catenin and transcription factor 4 (Tcf4) complex. Phyllactone H (105) was found in the marine sponge derived from Sangihe Island and possessed in vitro moderate cytotoxicities against cell lines A549, MCF-7, and HeLa with IC50 values of no more than 25 μM.

Carteriospongia (syn. Phyllospongia) flabellifera
The marine sponge C. (syn. P.) flabellifera is usually distributed in a wide corridor of the Indo-Pacific Ocean. A chemical study of the marine sponge collected in the South Pacific Ocean led to the isolation of two new small molecules, flabelliferins A (106) and B (107) [39]. Compound 106 had a rare 25-homocheilanthane carbon skeleton, and 107 exhibited inhibitory effect on the human colon tumor cell lines KM12 and COLO205. A new sesterterpenoid derivative (108) was also characterized from C. flabellifera collected around the Great Barrier Reef [40] (Chart 8).  [42]. Compounds 120-127 [43] and phylloamide A (128) [44] were also isolated from the South China Sea sponge. Carteriosulfonic acids A-C (129-131) [45] and 132 [46] were respectively isolated from two specimens collected at Philippines and Fiji. Bioassay results suggested that 128-130 had an inhibitory effect on the growth of glycogen synthase kinase-3β (GSK-3β), with IC50 values of 12.5, 6.8, and 6.8 μM, respectively.

Carteriospongia (syn. Phyllospongia) flabellifera
The marine sponge C. (syn. P.) flabellifera is usually distributed in a wide corridor of the Indo-Pacific Ocean. A chemical study of the marine sponge collected in the South Pacific Ocean led to the isolation of two new small molecules, flabelliferins A (106) and B (107) [39]. Compound 106 had a rare 25-homocheilanthane carbon skeleton, and 107 exhibited inhibitory effect on the human colon tumor cell lines KM12 and COLO205. A new sesterterpenoid derivative (108) was also characterized from C. flabellifera collected around the Great Barrier Reef [40]

Carteriospongia (syn. Phyllospongia) flabellifera
The marine sponge C. (syn. P.) flabellifera is usually distributed in a wide corridor of the Indo-Pacific Ocean. A chemical study of the marine sponge collected in the South Pacific Ocean led to the isolation of two new small molecules, flabelliferins A (106) and B (107) [39]. Compound 106 had a rare 25-homocheilanthane carbon skeleton, and 107 exhibited inhibitory effect on the human colon tumor cell lines KM12 and COLO205. A new sesterterpenoid derivative (108) was also characterized from C. flabellifera collected around the Great Barrier Reef [40] (Chart 8). Up to 24 secondary metabolites (109-132) (Chart 9) were isolated and identified from other unclassified Phyllospongia spp. Compounds 109-114 from an Indonesian marine sponge displayed 30%-95% inhibition of the growth of KB cells at 10 μg/mL [41]. Compounds 115-119 were produced by the Phyllospongia sp. collected from Northern Madagascar. Compounds 115, 116, and 119 possessed strong in vitro cytotoxic activities against human ovarian cancer cell line A2780 with IC50 values of 0.26, 0.28, and 0.65 μM, respectively, while 117 and 118 had moderate activities with IC50 values of 4.5 and 8.7 μM, respectively. Compound 116 exhibited a strong inhibitory effect on the human lung non-small cell line H522-T1 with an IC50 value of 0.61 μM [42]. Compounds 120-127 [43] and phylloamide A (128) [44] were also isolated from the South China Sea sponge. Carteriosulfonic acids A-C (129-131) [45] and 132 [46] were respectively isolated from two specimens collected at Philippines and Fiji. Bioassay results suggested that 128-130 had an inhibitory effect on the growth of glycogen synthase kinase-3β (GSK-3β), with IC50 values of 12.5, 6.8, and 6.8 μM, respectively. Up to 24 secondary metabolites (109-132) (Chart 9) were isolated and identified from other unclassified Phyllospongia spp. Compounds 109-114 from an Indonesian marine sponge displayed 30%-95% inhibition of the growth of KB cells at 10 µg/mL [41]. Compounds 115-119 were produced by the Phyllospongia sp. collected from Northern Madagascar. Compounds 115, 116, and 119 possessed strong in vitro cytotoxic activities against human ovarian cancer cell line A2780 with IC 50 values of 0.26, 0.28, and 0.65 µM, respectively, while 117 and 118 had moderate activities with IC 50 values of 4.5 and 8.7 µM, respectively. Compound 116 exhibited a strong inhibitory effect on the human lung non-small cell line H522-T1 with an IC 50 value of 0.61 µM [42]. Compounds 120-127 [43] and phylloamide A (128) [44] were also isolated from the South China Sea sponge. Carteriosulfonic acids A-C (129-131) [45] and 132 [46] were respectively isolated from two specimens collected at Philippines and Fiji. Bioassay results suggested that 128-130 had an inhibitory effect on the growth of glycogen synthase kinase-3β (GSK-3β), with IC 50 values of 12.5, 6.8, and 6.8 µM, respectively.

Carteriospongia (syn. Phyllospongia) flabellifera
The marine sponge C. (syn. P.) flabellifera is usually distributed in a wide corridor of the Indo-Pacific Ocean. A chemical study of the marine sponge collected in the South Pacific Ocean led to the isolation of two new small molecules, flabelliferins A (106) and B (107) [39]. Compound 106 had a rare 25-homocheilanthane carbon skeleton, and 107 exhibited inhibitory effect on the human colon tumor cell lines KM12 and COLO205. A new sesterterpenoid derivative (108) was also characterized from C. flabellifera collected around the Great Barrier Reef [40] (Chart 8). Up to 24 secondary metabolites (109-132) (Chart 9) were isolated and identified from other unclassified Phyllospongia spp. Compounds 109-114 from an Indonesian marine sponge displayed 30%-95% inhibition of the growth of KB cells at 10 μg/mL [41]. Compounds 115-119 were produced by the Phyllospongia sp. collected from Northern Madagascar. Compounds 115, 116, and 119 possessed strong in vitro cytotoxic activities against human ovarian cancer cell line A2780 with IC50 values of 0.26, 0.28, and 0.65 μM, respectively, while 117 and 118 had moderate activities with IC50 values of 4.5 and 8.7 μM, respectively. Compound 116 exhibited a strong inhibitory effect on the human lung non-small cell line H522-T1 with an IC50 value of 0.61 μM [42]. Compounds 120-127 [43] and phylloamide A (128) [44] were also isolated from the South China Sea sponge. Carteriosulfonic acids A-C (129-131) [45] and 132 [46] were respectively isolated from two specimens collected at Philippines and Fiji. Bioassay results suggested that 128-130 had an inhibitory effect on the growth of glycogen synthase kinase-3β (GSK-3β), with IC50 values of 12.5, 6.8, and 6.8 μM, respectively.