Motuporamines, Anti-Invasion and Anti-Angiogenic Alkaloids from the Marine Sponge Xestospongia exigua (Kirkpatrick):  Isolation, Structure Elucidation, Analogue Synthesis, and Conformational Analysis

Abstract

Extracts of the sponge Xestospongia exigua collected in Papua New Guinea were positive in a new assay for anti-invasion activity. Bioassay-guided fractionation led to the identification of the three known motuporamines A (1), B (2), and C (3) along with the new motuporamines D (4), E (5), and F (6) and a mixture of G, H, and I (15). Motuporamines A (1), B (2), and C (3) and the mixture of G, H, and I (15) were responsible for the anti-invasion activity of the crude extract. Motuporamine C (3) has also been found to be anti-angiogenic. A series of analogues of the motuporamines have been synthesized and evaluated for anti-invasive activity. These SAR results revealed that a saturated 15-membered cyclic amine fused to the natural motuporamine diamine side chain (13) represented the optimal structure for anti-invasive activity in this family. Single-crystal X-ray diffraction analysis of one of the analogues 20 showed that in the solid state its 16-membered macrocyclic amine fragment adopted the [4444] quadrangular conformation predicted by calculations to be the lowest energy conformation for the corresponding cycloalkane, cyclohexadecane. These data along with literature X-ray data and conformational analysis for derivatives of azacyclotridecane have been used as precedents for predicting the lowest energy ring conformations of other motuporamines. The SAR data from the natural and synthetic motuporamines have been combined with the conformational analyses to provide an outline of the functionality and shape required for activity in this family of alkaloids and to design a new analogue 49 that showed good anti-invasion activity.

Chemical and bioactive diversities of marine sponge <i>Neopetrosia</i>

“…Eight motuporamines including motuporamine A (36), B (37) and C (38) , D(39), E (40) and F (41) and a mixture of G, H, and I (42) were obtained from N. exigua (Xestospongia exigua) collected from Papua New Guinea yielded (Williams et al, 1998;Williams et al, 2002). Two phenethyl-guanidine derivatives, 7,8-dihydrotubastrine (43) and 4-deoxy-7,8-dihydrotubastrine (44), were isolated from the from the Indo-Pacific sponge N. contignata (Petrosia cf.…”

Mechanism Targeted Discovery of Antitumor Marine Natural Products

“…Using a three-step screening assay for inhibitors of tumor cell invasion, motuporamines A, B, C, and an unresolved mixture of motuporamines G, H, and I, were isolated from the marine sponge Xestospongia exigua and found to inhibit the invasion of tumor cells into basement membranes [31,32]. The structures of the motuporamines are shown in Fig.…”

“…In addition to inhibiting tumor cell invasion, the most potent compound, motuporamine C also inhibits endothelial sprout formation in vitro (complete inhibition at 10 μM) and angiogenesis in vivo (CAM assay with 30 ng/mL VEGF stimulated angiogenesis, complete inhibition at 10 μM). Structure-activity studies on a series of natural and synthetic motuporamine analogues revealed that the maximum anti-invasion activity of this alkaloid family requires a saturated monocyclic amine with a ring size of 13, 14, or 15, fused to a linear side chain with two basic nitrogen atoms, each separated by three methylene carbons [32].…”

Antiamoebic Activity of Marine Sponge Spongia officinalis var. ceylonensis Dendy

“…Sponges are utilized as therapeutic agents. A literature search revealed that few compounds have been reported from S. officinalis, including alkaloids and steroids (Lin et al, 2003;Lin et al, 2001;Thale et al, 2002;Orabi et al, 2002;Edrada et al, 2002;Williams et al, 2002;Bohlin et al, 1980).…”