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Pharmaceuticals

Cancer Fighters From The Sea

Natural Products: Sponge molecules isolated and synthesized for drug trials

by Bethany Halford
June 24, 2013 | APPEARED IN VOLUME 91, ISSUE 25

By scouring the oceans for disease-fighting molecules, researchers have identified two new anticancer compounds. Isolated from a sea sponge, the compounds represent a new class of the natural products called polyketides, many of which have biological activity. Because it’s not possible to extract sufficient amounts of the molecules from the sponges, the researchers also devised chemical syntheses that allowed them to make enough material to initiate clinical trials on one of the substances, known as PM060184 (J. Am. Chem. Soc. 2013,DOI: 10.1021/ja404578u).

Looking for organisms with sophisticated chemical defenses, scientists from the Spanish biopharmaceutical firm PharmaMar plucked the sea sponge Litho­plo­camia lithistoides from waters off the coast of Madagascar in 2005 and tested its extracts for cancer-fighting compounds. Two polyketides isolated from the extracts proved particularly potent at killing human cancer cells in a petri dish. The molecules appear to interfere with microtubules, which are structures that are key to cell division.

The researchers determined the structures of PM060184 and its cousin, PM050489, which has chlorine in place of hydrogen at one spot in the molecule. They developed syntheses for each one, in 33 and 35 steps, respectively, so the two compounds could be made in multigram quantities.

The syntheses construct each half of the molecules separately, so that the longest linear sequence is 18 steps. Long syntheses are not unheard of in the pharmaceutical realm. Eisai’s anticancer drug Halaven (eribulin mesylate), for example, requires 62 steps to make.

PM60184 is currently being tested in clinical trials for safety and efficacy.“When you discover a new chemical such as this, and you synthesize it and put it in clinical trials, it’s the realization of the dream of working in pharmaceutical R&D,” says Carmen Cuevas, PharmaMar’s director of R&D, who spearheaded the project.

Ian Paterson, a polyketide expert at Cambridge University, says that “while these are still early days, it is hoped that a successful anticancer drug emerges from this work and it stimulates further research in marine natural products for drug discovery.”

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