Manzamines cytotoxicity

The manzamines are novel polycyclic p-carbolinealkaloids reported first by Higa and coworkers in 1986,73 from the Okinawan marine sponge Haliclona. Manzamines have been shown to have a diverse and interesting range of bioactivity including cytotoxicity and antimicrobial and insecticidal activities.74 75 Isolation ( 0.85% dry weight) and structure elucidation, aided by 15N-NMR spectroscopy, of the known manzamine A (59), and the... 

Microbial bioconversion studies of manzamine A and ent-8-hydroxymanzamine A have shown that they can be metabolized by several microbial species.76 Preparative-scale fermentation of manzamine A with Fusarium oxysporium f. gladioli ATCC 11137 resulted in the isolation of the known ircinal A (61) as a major metabolite. Preparative-scale fermentation of enf-8-hydroxymanzamine A with Nocardia sp. ATCC 11925 and Fusarium oxysporium ATCC 7601 resulted in the isolation of the new major metabolite 12,34-oxamanzamine F (62). The latter metabolite showed no cytotoxicity against different cell lines (>10 pg/ml). 

Fused tetracyclic and pentacyclic alkaloids constitute a relatively new class of natural products isolated mostly from ascidians and sponges. Cytotoxic, antimicrobial and antiviral activities have been reported for many of these compounds. The manzamine alkaloids, Fig. (33) are characterized by a complex pentacyclic diamine linked to C-l of P-carboline moiety. Manzamine have been isolated mainly from six different genera of marine sponges Haliclona, Pellina, Xestospongia, Ircinia, Pachypellin and Amphimedon. 

Further investigation of the Okinawan sponge Haliclona sp. resulted in the isolation of manzamines B-F (182-186), which show cytotoxic activity (152-154). The structures of manzamines B (182) and C (183) were based on X-ray analysis. Manzamine F (186) was found to be identical with keramamine B, the structure of which with a 1,2,3-triazacyclohexane moiety (181) was revised to structure 186 containing a hexahydro-5(2//)-azocinone ring. Total synthesis of manzamine C (183) was achieved by the... 

The most well-known group of 3-aIkylpiperidine alkaloids is the manzamines. Manzamine A (66), which is the first member of this group, was isolated from an Okinawan Haliclona sp. More than 20 manzamines have been isolated from sponges of eight different genera. Manzamine A is highly cytotoxic. 

Manzamines exhibit potent cytotoxicity (Table 1). Manzamine A (32) and its 8-hydroxy (33) and 8-methoxy derivatives are active against this HSV-II (IC50 0.05, 0.1 and 0.1 pg/mL, respectively) (48). Manzamine C (35) is an inducer of EL-4.IL-2, which is a measure of perturbation of signal transduction (204). Ircinol A (119) showed inhibition against endothelin converting enzyme (IC50 5 5 pg/mL) (91). 

In all of the different biotests performed, the cytotoxicity data are not paralleled by antibacterial or insecticidal activity (Table 5), which is rather due to different modes of action as well as specific target requirements and is apparently strongly influenced by the chemical structure of the studied compound. The insecticidal activity of the manzamine A alkaloid was not paralleled by the cytotoxicity of its N-oxide congener, while the same case... 

Evaluation of the biological properties of these compounds in the literature demonstrates a wide range of activities. For example, the manzamines and ircinals have been shown to possess antileukemic and antibacterial activity xestocyclamine A shows inhibition against the enzyme Protein Kinase C, but compounds with cytotoxicity or other activities can also be found. 

Very recently the structure of ma eganedin A (91) [104], obtained from the sponge Amphimedon sp., has been published. 91 is a new manzamine-related tetrahydro- -carboline alkaloid with a methylene carbon bridge between N-2 and N-27. The structure and absolute stereochemistry was confirmed on the basis of spectroscopic data and molecular mechanic calculations. Ma egadenin A shows antibacterial activity and a mild cytotoxic effect against murine leukemia L1210. 

Zhou B, Slebodnick C, Johnson RK, Mattem MR, Kingston DGI (2000) New cytotoxic manzamine alkaloids from aPalaun sponge. Tetrahedron 56 5781-5784... 

Mukai and co-workers used a reduction/cyclization cascade to prepare (-)-nakadomarin, a manzamine-related alkaloid with cytotoxic activity, inhibitor activity against cyclin-dependent kinase 4 (CDK-4), and anti-fungal and antibacterial activity. Treatment of the tetracyclic precursor with DIBAL-H followed by reaction with HCl led to the desired pentacyclic system in 41% yield. 

Manzamines have shown a variety of bioactivities ineluding cytotoxicity, antimicrobial, pesticidal, and anti-inflammatory properties [2] some of them demonstrated effects on HTV and AIDS opportunistic infections [2], To date, the greatest potential for the manzamine alkaloids appears to be against malaria with manzamine A showing improved aetivity over the elinieally used drugs chloroquine and artemisinin both in vitro and in vivo [2]. 

Kauluamine is an exceptional example of an asymmetrical dimer of manzamine, and was isolated from an Indonesian Prianos. Its immunosuppressive activity is moderate and it is neither cytotoxic nor antiviral. 

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