PITT RESEARCHERS MAKE LIBRARIES OF COMPOUNDS WITH ANTITUMOR PROPERTIES

PITTSBURGH, August 21 -- Based on a compound extracted from a Chinese tree, researchers at the University of Pittsburgh have created a library of compounds with potential antitumor properties in humans. The plant derivative, called camptothecin, is thought to prevent tumors by inhibiting the enzyme DNA Topoisomerase I (Topo I), which is an essential enzyme in cancer cell replication.

Ana Gabarda, a graduate student in the laboratory of Dennis Curran, distinguished professor of chemistry, Department of Chemistry, designed and prepared camptothecin-like compounds which are not found in nature via an efficient and inexpensive way. In addition to being difficult and expensive to attain, natural camptothecin in blood is rapidly converted into an inactive form, losing its antitumor properties.

"We are trying to take a compound found in nature and not only recreate it, but also modify it in a way that will allow it to function optimally in the body," said Gabarda. "You can take two houses whose design is the same, but if you make the windows larger on one of them, that one is going to get more light on the inside. "

Camptothecin with an added silicon-containing group, a silane group, and an extra carbon atom in one of the 6-membered carbon rings are called homosilatecans.

"By adding the silane group, excellent blood stability is attained. A modification enhancing antitumor properties even further is next to be discovered," says Gabarda. "We prepared over 100 different homosilatecans hoping to find an alteration that improves Topo I inhibition."

Gabarda and Curran, with Wu Du and David Bom, Department of Chemistry, created libraries of compounds with the two main alterations along with carbon additions on the silicon-containing group and on an adjacent ring. These libraries have been sent along to biologists, who will determine Topo I inhibition activity.

"The libraries are easy to prepare because they take place under mild conditions and many reactions may be run at the same time," says Gabarda. "This is the guiding principle of parallel synthesis."

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