Motuporamines, anti-invasion and anti-angiogenic alkaloids from the marine sponge Xestospongia exigua (Kirkpatrick): isolation, structure elucidation, analogue synthesis, and conformational analysis.
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.
Williams
David E
DE
Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
Craig
Kyle S
KS
Patrick
Brian
B
McHardy
Lianne M
LM
van Soest
Rob
R
Roberge
Michel
M
Andersen
Raymond J
RJ
D000470:Alkaloids / Q000737:chemistry* / Q000302:isolation & purification; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control; D019906:Nuclear Magnetic Resonance, Biomolecular; D011161:Porifera / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014961:X-Ray Diffraction
D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C409087:motuporamine A; C409086:motuporamine B; C409085:motuporamine C