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Pipobroman

Among the many DNA-damaging natural cytotoxins, leinamycin is of particular interest because it represents a new structural type of DNA-damaging agent, although it has not been clinically tested.72 Leinamycin was isolated from a strain of Streptomyces found in soil samples collected in Japan.73 Early in vitro experiments revealed that DNA damage by leinamycin is thiol-triggered and due to its unique 1,2-dithiolan-3-one-1-oxide moiety. Leinamycin is relatively stable in water; however, on entering the thiol-rich environment of the cell, a cascade of chemical reactions is initiated that leads to oxidative DNA damage (and perhaps general oxidative stress),74 as well as DNA alkylation,75 which is sequence specific.76 As shown in Fig. 5.39, the initial reaction with thiols gives intermediate 5.68, which cyclizes to 5.70 with release of hydrodisulfide 5.69 that causes oxidative DNA damage. The spatial arrangement of 5.70 allows nucleophilic attack of the alkene to the electrophilic sulfur to give the highly electrophilic episulfonium ion 5.71, which alkylates DNA at the N-7 position of guanine residues.

Hydrodisulfides are more easily oxidized than sulfides because of their higher acidity, which leads to complete ionization under physiological pH. Therefore, compound 5.69 liberated from leinomycin can transfer one electron to molecular oxygen, leading to the generation of oxygen radicals. Catalytic amounts of 5.69 are sufficient to cause oxidative DNA damage and subsequent strand breaking by this mechanism because polysulfides 5.72 are transformed back to 5.69 by reaction with thiols 5.73, which are thus depleted from the cell (Fig. 5.40).

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