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This thesis is an investigation of the natural products deriving from marine
algae and cyanobacteria and has resulted in the discovery of eleven new secondary
metabolites. The structure elucidations of these new molecules were performed
using a variety of spectroscopic techniques.
Four new macrolides were isolated and characterized from the Madagascar
marine cyanobacterium Geitlerinema sp. These ankaraholides are structurally similar
to the potently cytotoxic swinholides and were found to have cytotoxicities ranging
from 178 nM to 354 nM against human lung cancer (NCI-H460) and mouse neuro-2a
cell lines. Since swinholide-type compounds were previously localized to the
heterotrophic bacteria of sponges, these findings raise intriguing questions about
their true metabolic source.
Geitlerinema sp. was found to be particularly rich in chemistry, and also
produced the new linear lipopeptide mitsoamide with unusual structural features
including an aminal moiety, a homolysine residue and a polyketide unit (3,7-
dimethoxy-5-methyl- nonanedioic acid) (DMNA).
A collection of the red marine alga Portieria hornemannii from the south of
Madagascar (Tolagniaro, Fort Dauphin), led to the isolation of the previously
reported halogenated monoterpene, halomon, and the discovery of three new related
metabolites. These molecules were found to inhibit DNA methyltransferase 1
(DNMT-1).
As a result of efforts to identify bioactive agents from the marine
cyanobacterium Lyngbya majuscula, tanikolide dimer, a novel SIRT2 inhibitor (IC50 =
176 nM), and tanikolide seco-acid were isolated. The depside molecular structure of
tanikolide dimer, which is likely a meso compound, was established by NMR, MS
and chiral HPLC analyses. The structure of tanikolide dimer raises a number of
intriguing configurational and biosynthetic questions for further study.
The bioassay guided fractionation of a collection of the brown marine alga
Dictyota sp. from Netherland Antilles Playa Fort, led to the identification of a novel
HDAC inhibitor with a dolastane carbon skeleton. The novel molecule was also found
to possess antimalarial activity. Other known HDAC inhibitors with interesting
antimalarial activity have been reported previously, and based on this efficacy
against malaria, HDAC appears to be a viable target for the development of
antiparasitic agents. |
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