Cancer wars: natural products strike back

Abstract

Natural products have historically been a mainstay source of anticancer drugs, but in the 90's they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many solid tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, 12 novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery.

Keywords: cancer; drug discovery; molecular targets; natural products; pharmacognosy; privileged structures.

Figure 1

Structures of podophyllotoxin, etoposide, and teniposide.

Figure 2

Chemical structures of representative natural compounds that stabilize microtubule assemblies.

Scheme 1

Synthesis of vinflunine from vinorelbine (Fahy et al., 1997).

Scheme 2

DNA Alkylation by ecteinascidin 743.

Figure 3

Structure of galeterone.

Figure 4

Structures of cytotoxic Cephalotaxus alkaloids.

Scheme 3

Proposed mechanism of alkylation of the proteasome by epoxomicin.

Figure 5

Structures of epoxomicin, YU-101, carfilzomib.

Figure 6

Structures of 12-O-tetradecanoylphorbol-13-acetate and ingenol mebutate.

Figure 7

Structures of marketed immunoconjugates.

Figure 8

Structure of vintafolide and mechanism of release of the payload in the endosome.

Scheme 4

Combination of biotechnology and organic synthesis for the synthesis of ansamitocin derivatives (Taft et al., 2008).