Hydrogen atom abstraction reactions of charged polyaromatic sigma-radicals related to the active intermediates of the enediyne antitumor drugs.
Polar effects are demonstrated to play an important role in controlling the reactivity of polyaromatic sigma-radicals that are structurally related to the active intermediates of the enediyne anticancer type antibiotics. This was accomplished by measuring the rate constants of hydrogen atom abstraction for novel, charged dehydroquinolines, dehydroisoquinolines, dehydrobenzenes, and dehydronaphthalenes in the gas phase by using Fourier-transform ion cyclotron resonance mass spectrometry. The reactivity trends observed for these radicals upon hydrogen atom abstraction from tetrahydrofuran and 2-methyltetrahydrofuran, simple models of deoxyribose, do not reflect differences in reaction exothermicities, radical sizes, exact location of the radical site in the ring system, or heteroatom-radical site distances. However, the reactivity trends match the trend in the calculated electron affinities of the radicals. The radicals' different electrophilicities result in variations in the reaction barrier due to different extents of polarization of the transition state. Generally, the reaction efficiencies are the greatest when the formally charged heteroatom is contained within the same ring system as the radical site. In this case, polar effects have the greatest influence on radical reactivity. Hence, insertion of a basic heteroatom (which gets protonated in biological systems) into specific locations in the polyaromatic ring system of the sigma-biradicals, which ultimately cause cleavage of DNA exposed to the enediyne antitumor drugs, should allow tuning of the reactivity of these radicals.
Petucci
Chris
C
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393, USA.
Nyman
Marianne
M
Guler
Leo
L
Kenttämaa
Hilkka
H
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005583:Fourier Analysis; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D006859:Hydrogen / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000970:Antineoplastic Agents; D005609:Free Radicals; D009281:Naphthalenes; D011725:Pyridines; D011804:Quinolines; D006859:Hydrogen