Molecular identification of cytotoxic compounds from a marine organism

Ola, Antonius (2009) Molecular identification of cytotoxic compounds from a marine organism. Masters (Research) thesis, James Cook University.

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Abstract

The marine world has become an important source of anticancer lead drugs with novel mechanisms of action. Many of these are in active phase I or phase II clinical trials while Yondelis in 2007 was approved for clinical use for the treatment of advanced sarcoma. This study aims to identify the molecular structure of pharmacologically active metabolites from tropical marine organisms.

The study of pharmacological activity was focused on discovering novel cytotoxic compounds with potential as anticancer agents. Cytotoxicity was assessed in vitro using the P388D1 mouse lymphoma cell line. The structural elucidation was done via 1D and 2D NMR. From the marine red alga Chondria armata, seven new halogenated triterpene polycylic ethers, armatols G-J and aplysiols C-E were isolated. The absolute stereochemistry of armatol G was determined through an X-ray structure while the stereochemistry of armatol H was proposed from acetylation of armatol G which indicated the same absolute configuration as was present in armatol G. The relative stereochemistry of armatol I and J were established via nOe experiments and by using Chem 3D and its MM2 energy minimization program to predict the lowest energy conformations. The relative stereochemistry of aplysiols C-E was determined by comparison with the very closely related structure of aplysiol B and from gradient selective NOESY experiments. Armatol J showed potent cytotoxic activity with an IC50 value of 5 μg/mL while armatol I and aplysiol C had moderate cytotoxic effects with IC50 value of 18 and 25 μg/mL respectively.

Seven known compounds were also isolated from the alga included 3 halogenated C15 acetogenins, two diterpenes [(-) angasiol and (-) angasiol acetate], a triterpene, intricatetraol and a diketopiperazine (dihydrodisamide C). (-) Angasiol acetate is the enantiomer of the diterpene reported from the sea hare Aplysia juliana and (-) pinnatifidenyne is the enantiomer of the C15 acetogenin produced by the marine red alga Laurencia pinnatifida from Canary Island. (-) Angasiol and (-) angasiol acetate were found to be inactive while intricatetraol and C15 acetogenins showed weak activity. Dihydrodisamide C was among the most potent of all the purified metabolites tested with an IC50 value of 5 μg/mL. It is probable that the collection of Chondria armata may have been contaminated by the sponge Dysidea herbacea from the substrate on which the alga was growing, or that the dihydrodysamide C was exuded by D.herbacea and absorbed into the alga.

Item ID: 8184
Item Type: Thesis (Masters (Research))
Keywords: metabolites, acetogenins, cytotoxins, marine red algae, cytotoxic compounds, pharmaceutical chemistry
Date Deposited: 09 Feb 2010 04:07
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111504 Pharmaceutical Sciences @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111506 Toxicology (incl Clinical Toxicology) @ 50%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 50%
97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 50%
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