Maduropeptin

Maduropeptin is a complex of new chromoprotein antitumor antibiotics isolated from Ac-tinomadura madurae (ATCC 39144) in 1990 [35, 36], It exhibits potent inhibitory activity against Gram-positive bacteria and tumor cells and strong in-vivo antitumor activity in P388 leukemia and B16 melanoma implanted mice. The structure of the chromophore has been recently elucidated [36], confirming it as a member of the family of enediyne antibiotics, and will be published shortly. 

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 

THREE-MEMBERED HETEROCYCLIC RINGS AND THEIR FUSED DERIVATIVES 

The biosynthetic pathway for MDP chromophore involves the production of (i) aminosugar previously named madurose (ii) p-hydroxyacid (S)-3-(2-chloro-3-hydro xy-4-methoxyphenyl)-3-hydroxypropionic acid derived from L-a-tyrosine (iii) 6-methylsalicyl-CoA and (iv) enediyne portion and a convergent biosynthetic approach to the final MDP chromophore. 

similar to Salmonella typhimurium, catalyzes a transamination leading to madurose [12], 

The biosynthesis of maduropeptin has not been studied in detail, but an iterative type I polyketide synthase gene predicted to be responsible for forming the enediyne core structure has been identified [188]. 

---

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. 

Van Lanen, S.G., Oh, T.J., Liu, W. et al. (2007) Characterization of the maduropeptin biosynthetic gene cluster from Actinomadura madurae ATCC 39144 supporting a unifying paradigm for enediyne biosynthesis. Journal of the American Chemical Society, 129, 13082. 

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). 

Hanada M, Ohkuma H, Yonemoto T, Tomita K, Ohbayashi M, Kamei H, Miyaki T, Konishi M, Kawaguchi H, Forenza S (1991) Maduropeptin, a Complex of New Macromolecular Antitumor Antibiotics. J Antibiot 44 403... 

Schroeder DR, Colson KL, Klohr SE, Zein N, Langley DR, Lee MS, Matson JA, Doyle TW (1994) Isolation, Structure Determination, and Proposed Mechanism of Action for Artifacts of Maduropeptin Chromophore. J Am Chem Soc 116 9351... 

Suffert J, Toussaint D (1997) Synthesis of a Cyclic Dienediyne Related to the Maduropeptin Chromophore. Tetrahedron Lett 38 5507... 

Kato, N. Shimamura, S. Khan, S. Takeda, F. Kikai, Y. Hirama, M. Convergent approach to the maduropeptin chromophore aryl ether formation of (R)-3-aryl-3-hydroxypropanamide and cyclization of macrolactam. Tetrahedron 2004, 60, 3161-3172. 

Magnus, P. Carter, R. Davies, M. Elliott, J. Pitterna, T. Studies on the synthesis of the core structures of the antitumor agents neocarzinostatin, kedarcidin, C-1027 and maduropeptin. Tetrahedron 1996, 52. 6283-6306. 

Nicolaou, K.C., and Koide, K., Synthetic studies on maduropeptin chromophore. Part 1. Constmction of the aryl ether and attempted synthesis of the [7.3.0] bicyclic system. Tetrahedron Lett., 38, 3667, 1997. Corey, E.J., and Liu, K., Enantioselective total synthesis of the potent anti-HLV agent neotripterifordin. Reassignment of stereochemistry at C(16), J. Am. Chem. Soc., 119, 9929, 1997. 

Figure 2. (A) Domain organization of the MadE, NcsE, and SgcE enediyne PKSs and (B) proposed pathway for biosynthesis of a polyunsaturated intermediate (structure unknown) from the acyl CoA substrates by NcsE, MadE, or SgcE and its subsequent transformations to C-1027 (4), maduropeptin (5), or neocarzinostatin (I) by the rest of their respective biosynthetic machinery.

Figure 3.3 Proposed mechanism of action for artifacts 13-16 of maduropeptin chromophore.

---