Romano G et al. (2013), Design and synthesis of pro-apoptotic compounds...

ECB-ART-43119

Mar Drugs 2013 Nov 13;1111:4527-43. doi: 10.3390/md11114527.

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Design and synthesis of pro-apoptotic compounds inspired by diatom oxylipins.

Romano G , Manzo E , Russo GL , d'Ippolito G , Cutignano A , Russo M , Fontana A .

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Oxylipins are a large and diverse family of fatty acid derivatives exhibiting different levels of oxidation of the carbon chain. They are involved in many biological functions in mammals, plants and diatoms. In this last group of organisms, they are suggested to play a role in the reproductive failure of copepod predators, showing clear pro-apoptotic effects on newborn nauplii. In this work, these compounds were tested for the ability to induce mitotic arrest in sea urchin embryos. We show for the first time that oxylipins have an increased efficacy in their corresponding methylated form. Natural oxylipins were also used as an inspiration for the rational design and synthesis of stable chemical analogs with apoptotic activity against tumor cell lines. This approach led to the synthesis of the linear C15-ketol (22) that was shown to induce apoptosis in human leukemia U-937 cells. These results are proof of the concept of the use of eco-physiological considerations as a platform to guide the search for novel drug candidates.

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Genes referenced: LOC100887844 LOC100893907 LOC115919910 LOC115925415

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References [+] :

Adolph, Cytotoxicity of diatom-derived oxylipins in organisms belonging to different phyla. 2004, Pubmed

	Figure 1. Percentage of first cleavage occurrence in sea urchin embryos treated with increasing concentrations of (a) 15S-hydroxyeicosapentaenoic acid (15(S)-HEPE) (#1), 15(S)-HEPE methyl ester (#2), eicosapenataenoic acid (EPA) (#3) and EPA methyl ester (#4) and of (b) natural oxylipins #5aâ€“#8a. Compound numbering is according to the structure reported in Scheme 1. Values (means Â± S.D.; N = 600) are the results of three different experiments.
	Scheme 1. Structures of typical diatom oxylipins.
	Scheme 2. Synthetic strategy for preparation of C18-analogs of diatom oxylipins.
	Figure 2. Cleavage inhibition in sea urchin embryos treated with increasing concentrations of (a) C18-fatty acid synthetic derivatives and (b) synthetic C15-alkyl derivatives. Compound numbering is according to the structure reported in Scheme 2 and Scheme 3. Values (means Â± S.D.; N = 600) are the results of three different experiments.
	Scheme 3. Synthetic scheme for preparation of compounds 18â€“25.
	Figure 3. Z-projections of confocal images of sea urchin eggs stained with TUNEL 70 min after fertilization: (a) control and (b) eggs treated with 10 ÂµM of 22. Arrows indicate positive nuclei that appear fluorescent and arrowhead indicates blebbing on egg surface.
	Figure 4. Compound 22 is cytotoxic in U-937 cell line. Cells were treated with different doses of 22, as indicated. Cytotoxicity was measured by neutral red assay and reported as a percentage of DMSO treated control cells, as described in Methods. Data points represent the mean of three experiments (Â±S.E.).