Neocarzinostatine

The Parent Carbocyclic Subunit of Neocarzinostatin Chromophore A WenderTC, 1988,29,909. 

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

Myers has discovered a related reaction of the natural product neocarzinostatine 8 (simplified structure). As in the case of the Bergman cyclization a diradical intermediate is generated by a chemical activation step taking place at the reaction site, where it then can cleave DNA. Because of this feature, together with its discriminating affinity towards different DNA strands, neocarzinostatine is regarded as a potential antitumor agent. 

In the initial step, neocarzinostatine 8 (simplified structure) is converted to the cyclization precursor 9, which contains a cumulated triene unit. The reaction... 

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. 

Liu, W., Nonaka, K., Nie, L. et al. (2005) The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type I polyketide synthases. Chemistry Biology, 12, 293. 

Fig. 16 a-Diazoketones for the generation of neocarzinostatin radical chromophore under photolytic conditions... 

Several novel natural products with an intriguing system containing the cis-endiyne moiety have attracted considerable attention from chemists in recent years. Several derivatives with this characteristic skeleton have now been isolated neocarzinostatin,96 esperamicin,97 calicheamicin y. 9S and dynemicin Ai." The high antitumor activity of these compounds is based on an elegant... 

For a number of other pharmacologically active unsaturated compounds, it is assumed that a reactive allene is formed in situ by an alkyne isomerization [160] or an elimination reaction [161]. The prime example of the formation of such a highly reactive allene through chemical activation of an unsaturated precursor is the ene-diyne antibiotic neocarzinostatin (Scheme 18.57) [162],... 

Scheme 18.57 Postulated mechanism of the DNA cleavage by the neocarzinostatin chromophore 168 [162].

Since the double bond between C5 and C6 of the enynecumulene 169 is not required for the Myers-Saito cyclization, a large number of enyneallenes have been synthesized as model compounds for the neocarzinostatin chromophore and tested for DNA-cleaving activity in recent years, with the results having already been summarized extensively (cf. Chapter 20) [162]. 

Several cell lines were used to inveshgate the role of PS oxidahon in apoptosis. Preferenhal oxidahon of PS was observed in human leukemia HL-60 cells (Fabisiak et al, 1998, 2000 Kawai et al, 2000), and normal human keratinocytes (Shvedova et al, 2001). Similarly, in pheochromocytoma PC 12 cells exposed to a radical-generating anhneoplashc dmg, neocarzinostatin, extemalizahon of PS was potentiated by its selechve oxidation in whole cells (Schor et al, 1999). In contrast, this selechve PS oxidahon did not occur in liposomes prepared from mixtures of PnA-labeled phospholipids extracted from the ceUs and exposed to oxidants imder the same conditions (Fabisiak et al, 1998 Kagan et al, 2000 Shvedova et al,... 

Kumar A, Brown DT, Leno GH (2004) DNA intercalators differentially affect chromatin structure and DNA repUcation in Xenopus egg extract. Anticancer Drugs 15(6) 633—639 Kuo MT (1981) Preferential damage of active chromatin by bleomycin. Cancer Res 41(6) 2439—2443 Kuo MT, Sarny TS (1978) Effects of neocarzinostatin on mammalian nuclei release of nucleosomes. Biochim Biophys Acta 518(1) 186—190... 

Similarly, ab initio calculations on the thermal reaction of propene forming methyl-cyclopentane suggested a three-step biradical reaction with 1,4-biradical and 1,5-biradical as intermediates. Quantum-chemical calculations have been carried out for the cyclization of the neocarzinostatin chromophore cyclonona-l,2,3,5-tetraen-7-yne to 1,5-didehydroindene biradical. The degree of stereoselectivity of the Diels-Alder reaction of 2-methylfuran and maleic acid in water has been found to reduce significantly in the presence of heavy atoms. Taking into account the relatively low concentration (3.5-7 m) of heavy-atoms, and the rapid fall off of the heavy-atom effect with distance, these results show that a large portion of the Diels-Alder reaction occurs via diradical intermediates. " ... 

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