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1 2007

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Przeciwnowotworowe antybiotyki enodiynowe

Boryczka S., Mól W., Jowsa A.

Wiadomości Chemiczne

2007

[Z] 61, 5-6

445-471

Naturally occurring enediyne anticancer antibiotics derived from bacterial sources are reviewed. The enediynes represent promising chemotherapeutic agents that exhibit unprecedented molecular architecture, fascinating modes of action and extremely potent anticancer activity, more potent than other anticancer drugs. The enediynes are structurally characterized by an unsaturated core with two acetylenic groups conjugated with a double bond. All these molecules contain three impor-tant functional domains: - an enediyne ring (nine-membered or ten-membered) as a highly reactive core that generates the reactive diradicals, thus providing the fragments that damage DNA, - a triggering device which after suitable activation under physiological conditions initiates the cascade of reactions that leads to the generation of diradicals, - a delivery system that is responsible for targeting DNA. The mode of action of the enediyne antibiotics is the ability to produce single--stranded or double-stranded DNA lesions by a mechanism which involves the inter-actions with duplex DNA along specific sequences within the minor groove. This is followed by the formation of a highly reactive benzenoid diradical via Bergman or Myers-Saito cyloaromatization and abstraction of hydrogen atoms from the deoxyribose of DNA leading to site-specific DNA breaks, which induces cell apoptosis. The diradical (p-benzyne) intermediates in simple prototype enediynes were postulated by Bergman in 1972 and provided the basis for the mechanism of action of the naturally occurring enediynes. Over 20 natural enediynes antibiotics are known now. They are divided into two distinct groups; those containing a nine membered enediynes chromophore non-covalently associated with a stabilizing apoprotein (neocarzinostatin 1, kedarcidin 2, lidamycin 3, maduropeptin 4, N1999A2 5) and those containing ten membered enediyne ring (calicheamicins 6, dynemicins 7, esperamicin 8, namenamicin 9, shishijimicins 10). However, the lack of selectivity for cancer cells and toxicity of natural enediynes have complicated their use in cancer chemotherapy. Several mono-clonal antibody-enediynes and polymer-enediynes conjugates have been prepared and evaluated for clinical significance as anticancer drugs. Much effort has been devoted to the design and synthesis of new, simplified, fully synthetic analogues characterized by similar mode of action.