Marine alkaloids cytotoxic activity

A new bromopyrrole alkaloid 15 along with racemic 16 was isolated from the Japanese marine sponge Homaxinellct sp. They exhibit weak cytotoxic activity against P-388 lymphocytic leukemia cells with ED50 values of 21.5 pg/ml and 30 pg/ml, respectively [34]. 

Scheme A was employed in the multi-step synthesis of the marine sponge alkaloid makaluvamine C 65 that displays cytotoxic activity (98JOC9846, 98SL845).

Two new indolocarbazole alkaloids, 4 -A -Methyl-5 -hydroxystaurosporine 12 and 5 -hydroxystaurosporine 13, were isolated from the culture broth of a marine Micromonospora sp. (strain L-31-CLCO-002) both showed cytotoxic activities against various tumor cell lines. 

For the above classes of marine alkaloids the antimalarial activity is several orders of magnitude higher than the cytotoxic activity and thus, although their mechanism of action has not been determined, it should be likely ascribed to a specific action on Plasmodium. 

Heptyl prodigiosin (43) [Fig. (13)] is another antimalarial alkaloid isolated from a tunicate. Precisely, this pigment was purified from a culture of a-proteobacteria isolated from a marine tunicate and showed an antimalarial activity similar to that of quinine against the chloroquine -sensitive strain P. falciparum 3D7 with an in vitro activity that was about 20 times the in vitro cytotoxic activity against mouse lymphocytes. When this molecule was tested in vivo, a single administration of 5 mg/Kg significantly extended the survival of P. berghei ANKA strain-infected mice but, unfortunately, the same dose caused sclerotic lesions at the site of injection [62],... 

An enantioselective total synthesis of (+)-ptilocaulin (79), a marine alkaloid with high antimicrobial and cytotoxic activity, was reported by Schmalz (Scheme 14) [40, 41]. The synthesis starts from anisole-Cr(CO)3, which is converted to the planar-chiral building block 74 with >99% ee by enantioselective deprotonation/silylation [42] and subsequent recrystallization. After attachment of a 2-butenyl side-chain ( 75) [43], nucleophilic addition of 2-lithio-l,3-... 

Another interesting application is the synthesis of a model tricyclic core of the cylindrospermopsin alkaloids 66-68 (Fig. 9.6) reported by Murphy s group following a Biginelli reaction as a key step of the process (Scheme 9.26) [77], These alkaloids are marine natural products that exhibit diverse cytotoxic activities [78], and they have been the focus of a different total synthesis. 

Pla, D., Mardial, A., Olsen, C.A., Francesch, A., Cuevas, C Alberido, F., and Ivarez, M. (2006) Synthesis and stmcture-activity relationship study of potent cytotoxic analogues of the marine alkaloid lamellarin D. J. Med. Chem., 49, 3257—3268. 

Xynas and Capon reported aplysamine 2 (172) from an Australian marine sponge Aplysina sp. in 1989 (44). Aplysamines 3 (173), 4 (174), and 5 (175) were isolated from the Hawaiian sponge Psammaplysilla purpurea by Scheuer s group (118). All of these alkaloids exhibited cytotoxic activity, while aplysamine 3 and 4 showed mild antibacterial activity against Staphylococcus aureus. Alkaloids 176 and 177 were isolated from the sponge P. purpurea collected in Okinawa by an Indian group (119,120). 

There are numerous examples of intramolecular Heck reactions,151 such as in Entries 10 to 14. Entry 11 is part of a synthesis of the antitumor agent camptothecin. The Heck reaction gives an 11 1 endocyclic-exocyclic mixture. Entries 12-14 are also steps in syntheses of biologically active substances. Entry 12 is part of a synthesis of maritidine, an alkaloid with cytotoxic properties the reaction in Entry 13 is on a route to galanthamine, a potential candidate for treatment of Alzheimer s disease and Entry 14 is a key step in the synthesis of a potent antitumor agent isolated from a marine organism. 

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