Photochemical triggering of reactive enyne-allenes and enediynes for the application in anti-cancer drugs
Kuzmin, Alexander Valeryevich
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The extreme cytotoxicity of natural enediyne antibiotics is attributed to the ability of (Z)-3-ene-1,5-diyne and (Z)-1,2,4-heptatrien-6-yne fragments to undergo cycloaromatization producing DNA-damaging diradicals. The goal of this dissertation work was to develop photoactivatable precursors of reactive enediynes and enyne-allenes. To achieve this goal, we have designed compounds, which upon irradiation can efficiently generate enediyne and/or enyne-allene moiety, constrained within ten-membered ring. Thus, it was found that ten-membered ring cyclic enediynes that possess a carbonyl group in a β position with respect to the one of acetylenic termini undergo very facile cycloaromatization at ambient temperatures. Kinetic data and deuterium-labeling experiments indicate that this reaction proceeds via rate-determining tautomerization to the enyne-allene form followed by very rapid Myers—Saito cyclization. A reactive ten-membered ring enyne-allene was also developed (τ25 °C = 5–6 min). The cyclic enyne-allene is efficiently generated (Φ300 nm = 0.57) by UV irradiation of a thermally stable precursor in which a triple bond is masked as a cyclopropenone moiety. Moreover, we found that incorporation of an additional endocyclic trans double bond in a ten-membered cyclic enediyne structure increases the activation energy of the cycloaromatization reaction. The rate-limiting step of the thermal cycloaromatization of a dienediyne is apparently the trans-cis isomerization and/or 1,3-hydrogen shift, producing the isomer of dienediyne with the cis double bond. The latter isomer then undergoes facile cycloaromatization. The utility of catalyst-free azide−alkyne [3 + 2] cycloaddition for the immobilization of a variety of molecules onto a solid surface and microbeads was investigated. In this process, the surfaces are derivatized with aza-dibenzocyclooctyne (ADIBO) for the immobilization of azide-tagged substrates via a copper-free click reaction.