ABSTRACT
The world market for antifungal agents in 2002 was estimated to be $4 billion with growth of this sector estimated at 10% annually [1]. Growth in the antifungal market is due to a dramatic increase in life-threatening fungal diseases (e.g., candidiasis and aspergillosis), mostly as a result of opportunistic fungal pathogens infecting immunocompromised patients. In addition, a number of the currently used antifungal drugs are acutely toxic (e.g., amphotericin B) or are ‘‘static’’ agents (e.g., azoles) that depend on the immune system to clear the existing fungal infection. Moreover, the azoles are ineffective against Aspergillus spp. because of natural resistance. These issues have motivated the discovery and development of antifungal agents that affect novel intracellular targets. The fungal cell wall is such a target, because it is essential for growth of the fungus and is absent from the mammalian host [2]. Cancidas (Merck & Co.; caspofungin acetate, aka MK0991) has fungicidal activity against pathogens of clinical significance and recently has been approved for the treatment of life-threatening infections [3,4]. This ‘‘first-in-class’’ fungicidal agent is a potent inhibitor of glucan synthesis, a component of the fungal cell wall actively deposited at the hyphal ends during fungal growth. By comparison, the azoles,
Figure 1 Structures of pneumocandin B0 and Cancidas (represented as the acetate salt, i.e., caspofungin acetate). The chemical modifications (in bold) made to the natural product inlcude the reduction of the primary amide of the hydroxyglutamine residue to an amine and the substitution of the hydroxyl group of the dihydroxyorntithine residue with an ethylenediamine moiety.
