Synthesis and biological evaluation of manzamine analogues

[Structure: see text] The synthesis and biological evaluation of a series of analogues of manzamine A, representing partial structures of the pentacyclic ABCDE diamine core, is described. All new compounds were screened against Plasmodium falciparum and demonstrated attenuated antimalarial activity relative to that of manzamine A.     

New manzamine alkaloids with potent activity against infectious diseases.

The isolation of the new enantiomers of 8-hydroxymanzamine A (1), manzamine F (2), along with the unprecedented manzamine dimer, neo-kauluamine from an undescribed genus of Indo-Pacific sponge (family Petrosiidae, order Haplosclerida) is reported. The relative stereochemistry of neo-kauluamine was established through detailed analysis of NOE-correlations combined with molecular modeling. The significance of the manzamines as in vivo antimalarial agents with superior activity to the clinically used drugs artemisinin and chloroquine is discussed along with the activity in vitro against the AIDS-opportunistic infectious diseases tuberculosis and toxoplasmosis. Reexamination of the sponges identified as Prianos, and Pachypellina, in earlier publications has confirmed that these are members of the same genus as the sponge described here, but differ at the species level.     

Neuritogenic activity-guided isolation of a free base form manzamine A from a marine sponge, Acanthostrongylophora aff. ingens (Thiele, 1899)

Two manzamine-class alkaloids, manzamine A (1) and 8-hydroxymanzamine (2) were isolated from a Japanese marine sponge Acanthostrongylophora aff. ingens, together with three known alkaloids manzamine E (3), manzamine F (4), and manzamine X (5). The spectral features of 1 and 2 were different from the reported data. Detailed structure analysis using 2D NMR revealed the structure of 1 and 2 as a free base form of hydrochloric salt. These manzamine-class alkaloids showed neuritogenic activity against Neuro 2a cells.     

Zamamidine C, 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A, and 3,4-dihydromanzamine J N-oxide, new manzamine alkaloids from sponge Amphimedon sp.

New manzamine alkaloids, zamamidine C (1), 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2), and 3,4-dihydromanzamine J N-oxide (3), have been isolated from an Okinawan marine sponge Amphimedon species. The structures and stereochemistries of 1-3 were elucidated from the spectroscopic data and chemical derivatization. Zamamidine C (1) is a new manzamine alkaloid possessing a second β-carboline ring via an ethylene unit at N-2 of manzamine D, while 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2) is the first manzamine alkaloid possessing an epoxide ring at C-10 and C-11. Zamamidine C (1) showed significant antitrypanosomal activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and antimalarial activity against Plasmodium falciparum, the causative agent of malaria in vitro.     

Stereoselective furan-iminium cation cyclization in the construction of the core structure of manzamine A

[reaction: see text] A new type of furan-iminium cation cyclization was developed and used to construct the ABC ring of manzamine A. The cyclization proceeded at the 2-position with complete regio- and stereoselectivity to give a spiro-center. The product was efficiently converted to the highly substituted core structure of manzamine A.     

The first total synthesis of nakadomarin A

(-)-Nakadomarin A is a member of manzamine alkaloid isolated from a marine sponge and have a unique hexacyclic structure. The first total synthesis of (+)-nakadomarin A, an enantiomer of natural product, has been accomplished from stereochemically defined 4-oxopiperidin-3-carboxylic acid derivative. The synthesis established the structure of nakadomarin A including absolute configuration.     

Antimalarial natural products of marine and freshwater origin

This review highlights recently discovered antimalarial natural products from marine and freshwater sources described in the literature from 2006 to 2008. The structures as well as bioactivities of compounds against the malaria parasites such as Plasmodium falciparum are discussed, including, for example, agelasine, xestoquinone, alisiaquinone, crambescidin, venturamide, dragomabin, gragonamide, viridamide, salinosporamide, chaetoxanthone, nodulisporacid, tumonoic acid, girolline, oroidin, nostocarboline, aerucyclamide, and microcylamide 7806 and its revised structure. Synthetic derivatives of natural products are presented including plakortin, isoaaptamine, curcuphenol, pseudopyronine, manzamine, and nostocarboline. Consequences of these discoveries for the development of novel natural product agents against malaria are discussed. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 187–198; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900001     

Synthetic strategies directed to the antitumour alkaloids sesbanimide A and manzamine A

Synthons derived from nature's chiral pool have been utilized in developing strategies aimed at the syntheses of the alkaloids sesbanimide A and manzamine A. The route designed for sesbanimide A has provided the naturally occurring alkaloid and a facile access to several analogues for structure-activity relationship studies. The approach to the synthesis of manzamine A has led to a strategically functionalized chiral tricyclic intermediate possessing the absolute stereochemistry of the natural product. Recent results on the synthesis of sesbanimide analogues and the progress towards the total synthesis of manzamine A is described.     

A new cyclostellettamine from sponge Amphimedon compressa

A new compound,8,8′-dienecyclostellettamine,was isolated from the marine sponge Amphimedon compressa.Its structure was elucidated by spectroscopic methods including ID and 2D NMR,UV,IR,ESI-MS,MALDI-MS techniques.It is probably an important precursor of the manzamine alkoids,and also showed vigorous antibacterial activities.     

The biocatalytic conversion of 8-hydroxymanzamine A to manzamine A

The selective dehydroxylation of 8-hydroxymanzamine A (1) to form manzamine A (2) can be completed by fermentation with Fusarium solani or Streptomyces seokies. This unique biocatalytic conversion is important due to the fact that manzamine A has more desirable biological activity when assayed in a murine model against malaria.     

Synthetic modification of manzamine A via Grubbs metathesis. Novel structures with enhanced antibacterial and antiprotozoal properties

A strategy for the structural modification of biologically important alkene-containing natural products via ring-opening olefin metathesis is described. Exposure of manzamine A 1 to the second-generation Grubbs catalyst in the presence of ethylene leads to the formation of 2 and 4. The antibacterial activity of the novel manzamine analogue 2 (IC50=0.10 nM) against Mycobacterium intracellulare is ca. 2-fold more potent than that of ciprofloxacin (IC50=0.18 nM), a drug that is frequently used against antibiotic-resistant infections.     

Enantioselective total syntheses of manzamine a and related alkaloids

As a prelude to undertaking the total syntheses of the complex manzamine alkaloids, a series of model studies were conducted to establish the scope and limitations of intramolecular [4 + 2] cycloadditions of N-acylated vinylogous ureas with the trienic substrates 17a,b, 28a,b, and 34. These experiments clearly demonstrated that the geometry of the internal double bond and the presence of an electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation of the desired cycloadducts. The enantioselective syntheses of the manzamine alkaloids ircinol A (75), ircinal A (5), and manzamine A (1) were then completed by employing a convergent strategy that featured a novel domino Stille/Diels-Alder reaction to construct the tricyclic ABC ring core embodied in these alkaloids. Thus, the readily accessible chiral dihydropyrrole 58 was first converted in a single chemical operation into the key tricyclic intermediate 60. Two ring-closing metathesis reactions were then used to form the 13- and 8-membered rings leading to Z-72 and 74, the latter of which was quickly elaborated into ircinal A (5) via ircinol A (75). The synthetic 5 thus obtained was converted into manzamine A (1) following literature precedent. This concise synthesis of ircinal A required a total of 24 operations from commercially available starting materials with the longest linear sequence being 21 steps.     

Enantioselective total synthesis of marine alkaloids,manzamine A and related compounds

A review of our studies toward the enantioselective total synthesis of ircinal A, manzamine A and related compounds is presented in detail.     

From a biogenetic scenario to a synthesis of the ABC ring of manzamine A

On the basis of a biogenetic proposal for explaining the biogenesis of manzamine A, the cycloaddition of dihydropyridinium salt 26 with diene derivative 5 leads to adducts 27. These adducts, as well as their related and previously described analogues 9, are now shown to be precursors of diene derivatives such as 10, 13, and 28. Treatment of diene 32 with sodium azide resulted in a one-step formation of the tricyclic imino derivative 34. This key intermediate was further transformed into tricyclic derivative 40, which possesses the essential features of the ABC ring of manzamine A.     

Synthetic study on efficient stereoselective construction of tricyclic core skeleton of manzamine A

Tricyclic core skeleton of manzamine A was constructed stereoselectively from the fused nitrogen-containing bicyclic enone 3 via a novel and efficient strategy including sequential stereoselective Diels-Alder reaction, Curtius rearrangement, and intramolecular lactam formation reaction.     

1,2,3,4-tetrahydro-8-hydroxymanzamines, alkaloids from two different haplosclerid sponges

The isolation and characterization of two new sponge alkaloids, 1,2,3,4-tetrahydro-2-N-methyl-8-hydroxymanzamine A (2) and 1,2,3,4-tetrahydro-8-hydroxymanzamine A (3), is described. These compounds were obtained from Papua New Guinea sponges of the genera Petrosia and Cribochalina, which are in different families of the order Haplosclerida. These new manzamines are close in structure to 8-hydroxymanzamine (4) recently reported from Pachypellina, a Haplosclerid sponge belonging to a different family than that of the two preceding sponges. The cytotoxicity of 2 is described and the biogenetic relationship of 2 or 3 to manzamine A (1) and to nine other related polycyclic diamine and one monoamine type alkaloids is described.     

Total synthesis of haliclamine A, a macrocyclic marine alkaloid related to the key biogenetic intermediate of manzamines

The first total synthesis of haliclamine A (1), a macrocyclic marine alkaloid closely related to the key bisdihydropyridine intermediate 3 of the biogenetically unique manzamine family, has been efficiently achieved via stepwise inter- and intramolecular N-alkylations of 3-alkylpyridine derivatives 26 and 28.     

Manzamine B and C,two novel alkaloids from the sponge haliclona sp.

The title compounds were isolated from a marine sponge collected off Okinawa. Their structures were determined by X-ray and shown to be 1-β-carbolines. Manzamine C was the 2-ethyl-N-azacycloundec-6-ene derivative, whereas manzamine B was more complex being the epoxy isomer of the free base of dihydromanzamine A.     

Simulation of intramolecular hydrogen bond dynamics in manzamine A as a sensitive test for charge distribution quality

Subtle balance of inter- and intramolecular hydrogen bond strength in aqueous solutions often governs the structure and dynamics of molecular species used as potential drugs and in supramolecular applications. In silico molecular dynamics study of water solution of manzamine A has been performed with different atomic charges in order to investigate the influence of charge distribution choice on predicting qualitative and quantitative features of the simulated systems. Various well known charge schemes (MK-ESP, RESP, Mulliken, AMI-BCC, Gasteiger-Hückel, Gasteiger-Marsili, MMFF94, and Dynamic Electronegativity Relaxation - DENR) led to qualitatively different pictures of dynamic behavior of the intramolecular hydrogen bond. The reported calculation framework represents a relatively rare case where differences in charge distributions lead to noticeable differences in simulated properties, thus providing a useful test case for force field and charge distribution development, provided high quality experiments are conducted to use as references.     

Interaction of manzamine A with glycogen synthase kinase 3β: a molecular dynamics study

The search for the possible binding site of manzamine A to glycogen synthase kinase 3β(GSK-3β) was performed by molecular docking followed by molecular dynamics simulation and calculations of the Gibbs free energy of inhibitor—kinase binding. The cavity between the glycine-rich loop, the loop C, and the activation loop is the most likely site of interaction.