Natural Products and Cancer Drug Discovery by Frank E. Koehn

Author:Frank E. Koehn
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

5.3 Current ADC Natural Product Payloads

5.3.1 Calicheamicin

The calicheamicin family of polyketide enediyne antitumor antibiotics was discovered by the Lederle group of the American Cyanamid Company, who first isolated the compounds from a fermentation broth of M. echinospora calichensis on the basis of their striking antibiotic activity and cytotoxicity (Lee et al. 1989; Maiese et al. 1989). The structure of calicheamicin (Fig. 5.3) was solved after a herculean effort to produce sufficient material (a few milligrams) for extensive spectroscopic and chemical analysis (Lee et al. 1992). Calicheamicin causes double strand scission of DNA by binding with high specificity to the minor groove followed by generation of a 1,4-­dehydrobenzene diradical ion which causes double hydrogen ion abstraction from the DNA backbone (Zein et al. 1989), an event that is triggered by the nucleophilic attack of intracellular thiol on the trisulfide moiety (Chatterjee et al. 1996) (Fig. 5.6). The initial binding is highly specific for the (T-C-C-T)·(A-G-G-A) regions, and is mediated by the sugar residues and the unique conformational preferences of the ten-member polyketide ring (Ellestad 2011). The lethality of double strand DNA lesions are what give calicheamicin its exquisite cellular potency (Elmroth et al. 2003).

Fig. 5.6Mechanism of calicheamicin

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