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Title: Hydrolysis and Photolysis of 4-Acetoxy-4-(benzothiazol-2-yl)-2,5-cyclohexadien-1-one, a Model Anti-Tumor Quinol Ester
Contributor(s): Wang, Yue-Ting (author); Jin, Kyoung Joo (author); Myers, Lauren R (author); Glover, Stephen  (author)orcid ; Novak, Michael (author)
Publication Date: 2009
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Abstract: 4-Acetoxy-4-(benzothiazol-2-yl)-2,5-cyclohexadien-1-one, 1, a quinol derivative that exhibits significant anti-tumor activity against human breast, colon, and renal cancer cell lines, undergoes hydrolysis in aqueous solution to generate an oxenium ion intermediate, 3, that is selectively trapped by N3 - in an aqueous environment. The 4-(benzothiazol-2-yl) substituent slows the rate of ionization of 1 compared to analogues with 4-phenyl or 4-(p-tolyl) substituents, 4a or 4b. However, once generated, 3 is somewhat more selective than the 4-phenyl-substituted cation 5a. Calculations performed at the B3LYP/6-31G(d) level agree that the 4-(benzothiazol-2-yl) substituent does significantly stabilize 3. The structure of the major isolated azide adduct, 4-(6-azidobenzothiazol-2-yl)phenol, 9, confirms that the positive charge is highly delocalized in 3. The results of hydrolysis of 1 show that the 4-(benzothiazol-2-yl) substituent has a significant inductive electron-withdrawing effect as well as a significant resonance effect that is electron-donating. Photolysis of 1 in aqueous solution generates the quinol 2 as one of several photolysis products. The presence of the quinol suggests that photolysis also leads, in part, to generation of 3, but photoionization of 1 is significantly less efficient than is the case for the esters 4a and 4b. This study proves that 3 is generated by ionization of 1 in an aqueous environment. A significant number of other 2-benzothiazole derivatives that are not quinols, including ring-substituted derivatives of 2-(4-aminophenyl)benzothiazole 15, are under development as anti-tumor agents as well. The possible generation of the reactive intermediate 17 by hydrolysis of the putative metabolite 16 is under investigation.
Publication Type: Journal Article
Source of Publication: Journal of Organic Chemistry, 74(12), p. 4463-4471
Publisher: American Chemical Society
Place of Publication: United States of America
ISSN: 1520-6904
Field of Research (FOR): 030799 Theoretical and Computational Chemistry not elsewhere classified
030505 Physical Organic Chemistry
030401 Biologically Active Molecules
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
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