Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3alpha, show the specific inhibition of manzamine A on GSK-3beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.

Four new manzamine-type alkaloids, 12,28-oxamanzamine E (2), 12,34-oxa-6-hydroxymanzamine E (3), 8-hydroxymanzamine B (5), and 12,28-oxaircinal A (11), were isolated from three collections of an Indonesian sponge of the genus Acanthostrongylophora together with 13 known manzamine alkaloids, ircinal A, ircinol A, xestomanzamine A, manzamines A, E, F, J, and Y, manadomanzamines A and B, neo-kauluamine, 8-hydroxymanzamine A, and manzamine A Noxide. The structures of the new compounds were elucidated by means of 1D and 2D NMR spectroscopic methods. Three of these compounds (2, 3, and 11) possess a unique manzaminetype aminal ring system generated through an ether linkage between carbons 12-28 or between carbons 12-34. In the case of manzamine B and related metabolites, carbons 11 and 12 of the typical manzamine structure have an epoxide group and add to our growing understanding of manzamine structure-activity relationships (SAR) and metabolism. The bioactivity and SAR for a number of previously reported manzamine-related metabolites against malaria, leishmania, tuberculosis, and HIV-1 are also presented. Manzamine Y (9) showed significant inhibitory activity of GSK3, an enzyme implicated in Alzheimer's disease pathology. The toxicity of manzamine A and neo-kauluamine was evaluated against both medaka fry and eggs.A common Indo-Pacific sponge, Acanthostrongylophora sp., has been shown to be a highly rich source of bioactive manzamine-related alkaloids. [1][2][3] This class of alkaloids has been reported previously to show a number of significant biological activities including cytotoxic, 4 insecticidal, 5 antibacterial, 6 anti-inflammatory, 7 anti-infective, 8 and antiparasitic 9 * To whom correspondence should be addressed. . mthamann@olemiss.edu. HHS Public AccessAuthor manuscript J Nat Prod. Author manuscript; available in PMC 2016 June 22. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript activities, with the greatest potential for possible clinical applications existing for the control of Plasmodium falciparum and Mycobacterium tuberculosis. 10 As part of our ongoing investigations to identify new manzamines and to define the SAR as well as utilize the natural products as synthetic starting materials, [1][2][3][11][12][13] extracts of the Indonesian sponge Acanthostrongylophora sp. were investigated. In an earlier investigation, this sample yielded two new manzamine alkaloids, named 12,28-oxamanzamine A and 12,28-oxa-8-hydroxymanzamine A, and a unique ircinol A analogue together with manzamines A and F and neo-kauluamine. 2 Manzamine A (1) exhibits potent in vitro bioactivity against chloroquine-sensitive (D6, Sierra Leone) and -resistant (W2, Indo-China) strains of P. falciparum. Reisolation of manzamine A for pharmacokinetic and toxicology studies as well as for preparation of analogues necessitated a major collection of Acanthostrongylophora sp., yielding four new manzamine alkaloids (2, 3, 5, and 11)together with the 13 known manzamine alkaloids, which are the subject of this re...

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