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Exploiting Cortistatins' Essence

Simple analogs of a complex natural product may protect against loss of vision

by Carmen Drahl
June 8, 2009 | A version of this story appeared in Volume 87, Issue 23

Marine natural product cortistatin A (left) and a potent cortistatin analog (right).
Marine natural product cortistatin A (left) and a potent cortistatin analog (right).

By making simplified versions of cortistatins, marine natural products that halt new blood vessel growth, researchers can treat excessive vessel growth in mice with macular degeneration. The analogs may inspire a new class of medications for the disease, which is a leading cause of vision loss.

Cortistatins A and J are potent blockers of angiogenesis, or new blood vessel growth, but the natural supply is scarce and chemical syntheses of the cortistatins haven't produced enough material for animal testing. Chemists Barbara Czakó, László Kürti, and E. J. Corey at Harvard University decided to study analogs instead.

"What distinguishes cortistatins are two basic groups at opposite ends of a steroidlike scaffold that are important for bioactivity," Corey says. His team incorporated those essential groups, a dimethylamino and an isoquinoline group, on opposite ends of an easy-to-build steroid and made refinements to optimize anti-angiogenic activity in cells. In collaboration with vascular biologists Akiko Mammoto and Donald E. Ingber of Harvard Medical School, they found that some of their compounds blocked angiogenesis in a mouse model of macular degeneration but did not show signs of toxicity in cellular assays (J. Am. Chem. Soc., DOI: 10.1021/ja902601e).

The most effective pharmaceutical treatment for macular degeneration is administered by injection into the eye, Corey notes. All of his team's most potent analogs are water soluble and could lead to an eye-drop-based treatment, he says.

Chemist Samuel J. Danishefsky of Memorial Sloan-Kettering Cancer Center and Columbia University praised the work, saying that Corey's team "has increased the scope of the cortistatins by weaving them into a steroid setting which provided a doable terrain for chemical synthesis."

"In terms of an exercise in blending intuition and rational discovery, this paper could emerge as a classic," Danishefsky adds.

Studies from other groups suggest that inhibitors of the particular angiogenesis pathway that the cortistatin analogs target may lead to side effects, cautions David A. Cheresh, who studies tumor angiogenesis at the University of California, San Diego. Nonetheless, the analogs "represent exciting new leads in the search for the next class of anti-angiogenic agents" and should be studied further, he adds.

Corey tells C&EN that the cortistatin analogs are effective in mice at very low doses of less than 1 mg and would also be locally administered. Therefore, the amount of drug that the rest of the body would see is likely to be essentially zero, vastly reducing the potential for side effects, he says.

In related work, independent teams led by Hiromasa Kiyota at Tohoku University in Japan and Phil S. Baran at Scripps Research Institute have tested simplified cortistatins in cells, but neither team has reported animal studies (Biosci. Biotechnol. Biochem. 2008, 72, 2992; Angew. Chem. Int. Ed., DOI: 10.1002/anie.200901116).



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