Enediyne chromophore

Another DNA-damaging antitumor agent is kedarcidin from an actinomycete which consists of an apoprotein and an enediyne chromophore (189) with a chloropyridine moiety [151,152]. 

Otani T, Yoshida K, Sasaki T, Minami Y (1999) C-1027 Enediyne Chromophore Presence of Another Active Form and Its Chemical Structure. J Antibiot 52 415... 

Ando T, Ishii M, Kajiura T, Kameyama T, Miwa K, Sugiura Y (1998) A New Non-Protein Enediyne Antibiotic N1999A2 Unique Enediyne Chromophore Similar to Neocarzinosta-tin and DNA Cleavage Feature. Tetrahedron Lett 39 6495... 

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]. 

Sugiura Y, Matsumoto T. Some characteristics of DNA strand scission by macromo-lecular antitumor antibiotic C-1027 containing a novel enediyne chromophore. Biochemistry. 1993 32 5548-5553. 

Maduropeptin (MDP) 17, isolated in 1991 from the broth filtrate of Actinomadura madurae, consists of a 1 1 complex of an acidic water-soluble carrier apoprotein (32 kDa) and a labile enediyne chromophore, and showed potent antibacterial and antitumor activities [7]. The MDP apoprotein represented at that time a new protein class showing no sequence homology to the related chromoproteins neocarzistatin, auromomycin, actinoxanthin, C-1027, or kedarcidin, which were all in the 11.5-kDa... 

Figure 3.1 Nine-membered enediyne chromophores whose structures have been elucidated neocarzinostatin (3.405), kedarcidin (3.406), C-1027 (3.407), maduropeptin (3.408), and N1999A2 (3.409).

The nine-membered enediyne chromophores require activation. Most biological pathways of activation involve the collapse of diradicals that are generated from thiol groups, although other chemical routes, as well as photochemical activation, are able to initiate the electronic rearrangement of the chromophore. It is noted that C-1027 is the most labile of the explored free enediyne chromophores of the nine-membered subfamily. 

The concept of activation of enediyne antibiotics by photolysis of an enediyne chromophore has been developed using a diazo compound. Irradiation of 11-membered enediynes containing an a-diazo-p,p-dicarbonyl fragment leads, via the Wolff rearrangement, to reactive 10-membered structures. Thus, photolysis of 2-diazo-6,7-benzocycloundeca-4,8-diyn-l,3-dione produced the ketoester 3.479 which via enolization undergoes fast cycloaromatization to the reactive diradical 3.480, which in the presence of hydrogen donors produces dihydroanthracene (Scheme 3.17) [245]. 

Konig, B., Schofield, E., Bubenitschek, P. and Jones, P.G. (1994) Synthesis and photoinduced cis-trans isomerization of diaryl enediyne chromophores. Journal of Organic Chemistry, 59(23), 7142-7143. 

Enediynes with ethylene carbonate fragment in the synthesis of dienediyne models of the biradical-forming and DNA-cleaving natural neocarzinostatin chromophore 99SL657. 

The tightly bound chromophore could be extracted from the protein with methanol [186], and the major component of the extract was determined to have the enediyne structure 116 (Figure 11.21), related to chromophores of other chromoprotein antitumor agents such as neocarzinostatin. Additional minor components were extracted, variously containing an OH group instead of OMe attached to the enediyne core, with Cl instead of OMe when chloride was present in the buffer salt, or with OEt instead of OMe when ethanol was used for the extraction. Another byproduct was isolated in the form of structure 117, consistent with a facile cy-doaromatization reaction as observed for all other enediyne antibiotics. Surprisingly, 117 also displayed antibiotic and antitumor activity, perhaps due to alkylation of DNA or protein by the aziridine. The interpretation of these results was that 116 and the other enediyne byproducts were merely artifacts of the extraction procedure and that the true structure of the maduropeptin chromophore is the aziridine 118. 

The previously known kedarcidin chromophore (7) is revised to CCC (7559), and the mechanism of action of this enediyne has been studied (1560). The new maduropeptin chromophore 1601 was isolated from Actinomadura madurae, which is associated with a protein of 14 amino acids (1561-1563). The non-protein associated enediyne N1999A2 (1602) was characterized from Streptomyces sp. AJ 9493 (1564), and confirmed by synthesis (1565,1566). 

Usuki T, Inoue M, Akiyama K, Hirama M (2005) ESR Studies on DNA Cleavage Induced by Enediyne C-1027 Chromophore. Bioorg Med Chem 13 5218... 

Figure 3.4 Mechanism of action of the neocarzinostatin chromophore. Thiol addition initiates conversion to an allenic intermediate, which undergoes cyclisation to form a diradical intermediate. Formation of this diradical in a DNA-bound state leads to radical abstraction and subsequent strand cleavage. The star notes the location of the reactive enediyne functionality of the neocarzinostatin chromophore.

These novel, extremely potent antibiotics all possessed one very unusual chemical structural feature an enediyne fragment within a ring. The first discovered was neocarzinostatin (NSC), which was found to be composed of a protein (NSC apoprotein) and the neocarzinostatin chromophore 30 in a 1 1 complex. The biological activity is associated with the NSC chromophore. However, it took until the discovery of the calichaemicin " 31 and esperamicin 32 families in 1987 to really gamer the broad attention of chemists. Other enediyne antibiotics include the dynemicin family, the kedarcidin chromophore, namenamicin, the C-1027 chromophore,and uncialamycin. " ... 

Unlike the other naturally occurring enediyne molecnles, neocarzinostatin chromophore (30) is activated into an enyne-butatriene. This unusual cumulene 57 undergoes a cyclization analogous to the Bergman cyclization, proposed concurrently by Myers and Saito. This cyclization, now referred to as Myers-Saito cyclization, produces the diradical 58 that can abstract hydrogen atoms from DNA. Thus, neocarzinostatin s bioactivity is remarkably similar to calichaemicin (Figure 4.14). 

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.

Yoshida, K. Minami, Y Azuma, R. Saeki, M. Otani, T. Structure and cycloarom-atization of a novel enediyne, C-1027 chromophore, Tetrahedron Lett. 1993, 34, 2637-2640. 

Vuljanic, T, Kihlberg, J, Somfai, P, Diastereoselective synthesis of methyl a-kedarosaminide, a carbohydrate moiety of the enediyne antitumor antibiotic kedaricidin chromophore. Tetrahedron Lett., 35, 6937-6940, 1994. 

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