Development of Anticancer Agents Based on Photochemical DNA-Cleavage

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Various acyclic (Z)-1, 2, 4-heptatrien-6-ynes, which undergo cycloaromatization to produce reactive dehydrotoluene biradicals, have been investigated as chemical models for a class of potent antitumor antibiotics, neocarzinostatin (NCS). The preparation of enyne-allene models possessing characteristic triggering devices which initiate the generation of dehydrotoluene biradicals is a challenging current problem. For the development of this class of molecules, we designed various models which produce carbon-biradicals via Myers-Saito-type cyclization. For typical examples, we synthesized the naphthoate esters having the α-hydroxy naphthoate moiety in NCS and demonstrated the biradical formation reactions in acidic media.For the elucidation of these cascade reaction mechanisms and development of biologically active substances, the preparation of thermally stable carboxylic acid derivatives, which cycloaromatize under mild conditions, is essential. For this purpose, we designed novelα-alkynylacetic acid derivatives. A series of decarboxylative cycloaromatization reactions under various conditions were carried out. The reaction rates in MeOH were relatively slow and the reactions in the absence or presence of a radical scavenger (O_2 or 1, 4-cyclohexadiene) produced the products in similar yields, respectively. These results suggest that the cycloaromatization proceeded via an ionic cyclization pathway but not via the biradical intermediate.In order to prevent the ionic pathway during the cyclization reaction, the molecules possessing electron-withdrawing groups which destabilize the cationic carbon center were synthesized. The reactions of these compounds in acidic media produced predominantly or exclusively the products via biradical intermediates. Some of them showed relatively potent DNA-damaging activity. Studies on the analogues of this class of compounds and development of bio-active enediynes are continuing.