NEWS OF THE WEEK
EXPLOITING CORTISTATINS MEDICINAL CHEMISTRY: Accessible analogs of a complex natural product may protect against loss of vision
B
Y 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 of 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, 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 and 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-dropbased treatment, he says.
Chemist Samuel J. Danishefsky of Memorial SloanKettering 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.” Studies from other groups suggest that inhibitors of the particular angiogenesis pathway that the cortistatin analogs target may lead to side LOOK-ALIKE Marine natural product cortistatin A effects, cau(left) and a potent tions David A. cortistatin analog N N Cheresh, who (right). studies tumor angiogenesis at the University HO of California, H H O San Diego. H HO Nonetheless, H H (CH3)2N the analogs (CH3)2N H “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).— CARMEN DRAHL
ECONOMIC DOWNTURN Major Japanese petrochemical producers mull merger of operations As part of an effort to improve the profitability of their struggling petrochemical businesses, Mitsubishi Chemical and Asahi Kasei will study whether to merge their olefins facilities at the Mizushima complex in southern Japan. Both companies’ petrochemical businesses lost money in the fiscal year that ended on March 31. At Mizushima, each company operates a 450,000-metric-ton-per-year ethylene cracker and a series of downstream facilities. A Mitsubishi spokesman tells C&EN that no decision has been made concerning the closure of either one of
the crackers, as has been speculated in the Japanese business media. Japan’s total ethylene capacity is about 7.5 million metric tons. Ryota Hamamoto, a senior executive adviser at the consulting firm Accenture, in Tokyo, says the Mizushima site clearly has too much ethylene capacity. He adds that the pending merger of the refiners Shin Nikko and Shin Nihon Sekiyu, raw material suppliers to Asahi and Mitsubishi, respectively, likely “further motivated” the decision to consolidate at the site. In related moves, Mitsubishi announced that it will withdraw from mak-
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ing styrene and caprolactam, a nylon raw material. The decision will entail the closure in Japan of a 370,000-metric-ton styrene facility and a 60,000-metric-ton caprolactam plant. Earlier this year, the company said it would stop producing purified terephthalic acid in Japan. Mitsubishi has also agreed to swap its nylon business in exchange for DSM’s polycarbonate business. Both businesses enjoy annual sales of about $130 million. Hamamoto says the restructuring at Mitsubishi, Japan’s largest chemical maker, is perhaps overdue but is still “better late than never.”—JEAN-FRANÇOIS TREMBLAY
