Chromoprotein antitumor antibiotic

Process Developments in the Isolation of Largomycin F-II, a Chromoprotein Antitumor Antibiotic... 

Figure 4. Non-chemical representation of the production and isolation of the chromoprotein antitumor antibiotic, largomycin F-Il. The person with a lighted lantern is the biologically active form of largomycin F-II.

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. 

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. 

Largomycin F-II is a chromoprotein. Like the protein antitumor antibiotics neocarzinostatin (JtD an< macromomycin (10-12), the chromophore is probably responsible for the biological activity. 

The chromoproteine antibiotic C-1027 [108] from Streptomyces globisporus has antitumor activity, unfortunately correlated with strong cytotoxicity that hampers the use of this lead structure class as a drug which is a general problem in cancer drug development (Scheme 1.5.10). The labile chromophor 61 (C-1027-Chr) con-... 

Neocarzinostatin (NCS) is an enediyne chromoprotein antibiotic secreted by Streptomyces macromomyceticus with potent antibacterial and antitumor activities. NCS is composed of the NCS chromophore (Scheme 57.16) and a carrier apoprotein. Enantiopure tra s-4,5-dioxygenated cyclopent-2-enone (—)-63 can be used as a building block... 

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