Design, synthesis, and evaluation of N-aroyloxy-2-thiopyridones as DNA photocleaving reagents.
N-Benzoyloxy-2-thiopyridone (12) was shown to induce single-strand nicks in duplex DNA upon irradiation with visible light (lambda&350 nm). This finding led to the design of a series of compounds, in which an acridinyl nucleus was covalently linked to the N-benzoyloxy-2-thiopyridone unit. These conjugates (15, 16, 17 and 18) were synthesized and evaluated as novel DNA photocleaving reagents. Optimal photocleaving activity was observed for conjugate 16, in which a flexible polymethylene spacer of 4 carbons was used to connect the aminoacridine entity to the thiopyridone. This compound was shown to cleave DNA at low microM concentrations and was approximately two-orders of magnitude more efficient than the parent N-benzoyloxy-2-thiopyridone (12). Furthermore, the DNA cleavage ladders induced by 16 and 12 were found to be identical and of no significant sequence selectivity. These data suggest that the N-aroyloxy-2-thiopyridones can be used for the design of new DNA photocleaving reagents with potential use as 'photofootprinting agents' or as 'site-directed photonucleases'.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla 92093, USA.
P
P
Blom
A X
AX
Xiang
D
D
Kao
E A
EA
Theodorakis
D001345:Autoradiography; D010584:Bacteriophage phi X 174 / Q000187:drug effects; D004247:DNA / Q000187:drug effects*; D004262:DNA Restriction Enzymes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D006863:Hydrogen-Ion Concentration; D008027:Light; D008956:Models, Chemical; D011725:Pyridines / Q000138:chemical synthesis*; D013696:Temperature
D011725:Pyridines; D004247:DNA; D004262:DNA Restriction Enzymes; C029347:2-thiopyridine