title: Relationship between structure of conjugated oxime esters and their ability to cleave DNA.
abstract: The size and geometry of polycycles are critical to intercalation into DNA. This work involves the establishment of a new compound library that includes 35 O-benzoyl oxime esters with intercalators of five types. These conjugated compounds were synthesized by the condensation of substituted benzoyl chlorides (XC6H4COCl; X = H, Me, CN, F, and NO2) or naphthoyl chlorides with oximes of fluoren-9-one, 9,10-anthraquinone, xanthen-9-one, thioxanthen-9-one, and 9H-thioxanthen-9-one 10,10-dioxide to give the corresponding esters in 80-99% yields. All of these compounds could cleave DNA when photolyzed by UV light. Of these conjugates, 9,10-anthraquinone-O-9-(4-fluorobenzoyl)oxime with a binding constant of 4.49 × 10(4) M(-1) cleaved DNA most efficiently. Examination of the structure-activity relationship supports a conclusion that two factors affect DNA-cleaving potency. These are (1) the planarity of the intercalating moiety, and (2) the size and substituents of the benzoyl ring. The DNA-cleaving ability followed the order 9,10-anthraquinone > fluoren-9-one ≥ xanthen-9-one ∼ thioxanthen-9-one > 9H-thioxanthen-9-one 10,10-dioxide. The benzoyl-containing oxime ester conjugates were more active than the corresponding naphthoyl-containing conjugates. The potency that was associated with the different substituents on the benzoyl ring followed the order F > CN ≥ NO2 > Me ∼ H.
authors.affiliation: Department of Chemistry, National Tsing Hua University , No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Jih Ru
authors.initials: JR
authors.lastname: Hwu
authors.forename: Shwu-Chen
authors.initials: SC
authors.lastname: Tsay
authors.forename: Shih Chin
authors.initials: SC
authors.lastname: Hong
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Hsu
authors.forename: Chih-Fen
authors.initials: CF
authors.lastname: Liu
authors.forename: Shang-Shing P
authors.initials: SS
authors.lastname: Chou
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D053837:DNA Cleavage / Q000187:drug effects*; D004952:Esters / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
chemical_list: D004952:Esters; D010091:Oximes; D004247:DNA