Anticancer enediyne antibiotics

Nicolaou KC, Dai W-M (1991) Chemistry and Biology of the Enediyne Anticancer Antibiotics. Angew Chem Int Ed 30 1387... 

Figure 4.14 Mechanism of action of neocarzinostatin chromophore 30 Nicolaou, K. C. Dai, W.-M. Chemistry and biology of the enediyne anticancer antibiotics, Angew. Chem. Int. Ed. Engl. 1991, 30, 1387-1416. Copyright Wiley-VCH Verlag GmbH Co. KGaA. Reproduced with permission.

Nicolaou, K.C. Zuccarello, G. Riemer, C. Estevez, V.A. Dai, W.-M. Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics. 

There are only a few naturally occurring alkynes. Examples include capillin, which has fungicidal activity, and ichthyothereol, a convulsant used by the Amazon Indians for poisoned arrowheads. A class of naturally occurring compounds called enediynes has been found to have powerful antibiotic and anticancer properties. These compounds all have a nine- or ten-membered ring that contains two triple bonds separated by a double bond. Some enediynes are currently in clinical trials. 

With their unprecedented molecular structures, fascinating mode of action, and phenomenal biological activities, the enediyne anticancer antibiotics have eccited the creative impulses and imagination of many researchers and thus established a vibrant field of investigations. Research in this rapidly evolving field spans areas from computational chemistry, chemical synthesis, molecular recognition, DNA chemistry, and medicine. 

Nicolaou, K. C., and W.-M. Dai. Chemistry and Biology of Enediyne Anticancer Antibiotics. Angewandte Chemie International Edition 30 (1991) 1387-1416. This is a review of the structural, mechanistic and medicinal properties of this recently discovered, novel class of anticancer compounds. 

Vasella has reviewed the chemistry of glycosyl carbanions, carbocations, radicals and carbenes and related work covering his own important contributions and those of others. Specific areas to have been reviewed are carba-sugars (with ring oxygen atoms replaced by carbon), the enediyne anticancer antibiotics notably calicheamycin and esperamycin (Nicolaou s synthetic work on the disaccharide component especially). ... 

The coupling reaction has widespread use in the construction of enediyne systems present in naturally occurring anticancer antibiotics[234]. The Pd-Cul catalyzed coupling reaction of the alkenyl bromides 323 and 326 with the... 

In spite of the fact that few cycloalkynes occur naturally, they gained recent attention when it was discovered that some of them hold promise as anticancer drugs. (See the boxed essay Natural and Designed Enediyne Antibiotics following this section.)... 

Gemtuzumab ozogamicin (30 Mylotarg ) Calicheamicin (31) Enediyne-type antibiotic NP-derived Microbial Anticancer DNA-cleaving 319-331... 

Golik J, Dubay G, Groenewold G, Kawaguchi H, Konishi M, Krishnan B, Ohkuma H, Saitoh K, Doyle TW. Esperamicins, a novel class of potent antitumor antibiotics. 3. Structures of esperamicins Al, A2, and Alb. J. Am. Chem. Soc. 1987 109 3462-3464. Hamann PR, Upeslacis J, Borders DB. Enediynes. In Anticancer Agents from Natural Products. Cragg GM, Kingston DGI, Newman DJ, eds. 2005. Taylor and Francis, Boca Raton, FL. pp. 451-474. 

Figure 2. A potent synthetic anticancer compound (2) derived from enediyne antibiotics.

Work in this area has been dominated by studies on the enediyne class of anticancer antibiotics which bind to the minor groove and cleave DNA through the generation of a diradical intermediate. A genoul review on the chemistry and mechanism of action of these antibiotics has appeared together with two more focused reviews on neocarzinostatin (2S7) and the... 

Neocarzinostatin, a polypeptide antibiotic from Streptomyces carzinostaticus with strong anticancer activity. Neocarcinostatin consists of an enediyne chromophore non-covalently associated to a peptide chain with 113 residues (Mr 10.7 kDa). Neocarzinostatin has potential importance for the therapy of leukemia and both stomach and pancreatic cancer [A. L. Smith, K. C. Nicolaou, J. Med. Chem. 1996, 39, 2103]. 

Aryl iodides, bromides, and inflates are used for Sonogashira coupling. But so far few smooth reactions of aryl chlorides with alkynes have been reported. On the other hand, smooth coupling takes place with alkenyl chlorides. The Pd-catalyzed reaction of 1-alkynes with alkenyl chlorides, which are inert in many other Pd-catalyzed reactions, proceeds smoothly without special activation of the chlorides. For example, cw-l,2-dichloroethylene (31) can be coupled with 1-alkynes smoothly, and the coupling has wide synthetic applications, particularly for the synthesis of enediyne structures [30]. The reaction of 31 with two different 1-alkynes is extensively used for construction of highly strained enediyne structures present in naturally occurring anticancer antibiotics such as espermicin and calichemicin [31,32]. The asymmetric (Z)-enediyne 34 can be prepared by a one-pot reaction of 31 with two different 1-alkynes 32 and 33. Similarly the asymmetric ( )-enediyne 37 was obtained in a one-pot reaction of 1-alkynes 33 and 23 with 1,2-dichloroethylene 35. 

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