Читать книгу Successful Drug Discovery, Volume 5 - Группа авторов - Страница 20

In 1952, the National Advisory Cancer Council discussed the promise of chemotherapy for curing cancer and came to the conclusion that the available knowledge was not sufficient to support establishment of a specific funding program for drug discovery for cancer chemotherapy. However, in 1955, the Congress of the United States approved foundation of the Cancer Chemotherapy National Service Center (CCNSC) [33] and an associated budget of US$ 5 million for research on cancer. US$ 4.2 million were dedicated to grants supporting specific research proposals, while US$ 800 000 were reserved for acquisition and testing of new compounds. As a consequence, dedicated profiling laboratories were set up and a large compound collection was compiled. This effort was even strengthened in 1960, when the National Cancer Institute (NCI) partnered with the US Department of Agriculture (USDA) to collect plant and animal samples in search for natural products with potential anticancer activities. This alliance turned out to be very productive. Between 1960 and 1981, a total of 30 000 compounds was screened, and many pharmaceutically interesting structures were identified. At one of the involved profiling laboratories, the newly founded Research Triangle Park in North Carolina, chemists Monroe Elliot Wall and Mansukh C. Wani reported, among many others, the structure and activity of the natural product called camptothecin (Figure 1.6) [34].

Camptothecin, isolated from bark and stem of the Chinese Happy Tree (Camptotheca), was first chemically derived through total synthesis by Stork and Schultz [35] (Cornell University) in 1971, quickly followed by syntheses by the Danishefsky [36] (University of Pittsburgh) and Winterfeldt (University of Hanover) laboratories [37]. Camptothecin was identified as an inhibitor of topoisomerase I, acting through binding to the covalent topoisomerase‐DNA complex [38]. It is particularly toxic for cells in the S‐phase of mitosis. Albeit camptothecin itself proved too toxic to be used as a chemotherapeutic agent in patients, it served as a valuable lead structure for the approved drugs topotecan (Hycamtin™, approved in 1996 for treatment of ovarian cancer, in 2006 for cervical cancer, and 2007 for treatment of small‐cell lung carcinoma) and irinotecan (Camptosar™, a prodrug of topotecan approved in 1996 and used for treatment of colon cancer and small‐cell lung cancer) (Figure 1.6). Both derivatives are derived through semisynthesis.

Figure 1.6 Camptothecin and approved derivatives.