Hydrolysis and photolysis of 4-Acetoxy-4-(benzothiazol-2-yl)-2,5-cyclohexadien-1-one, a model anti-tumor quinol ester.
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 N(3)(-) 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.
Wang
Yue-Ting
YT
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, USA.
Jin
Kyoung Joo
KJ
Myers
Lauren R
LR
Glover
Stephen A
SA
Novak
Michael
M
D000970:Antineoplastic Agents / Q000737:chemistry; D052160:Benzothiazoles / Q000737:chemistry*; D003512:Cyclohexanones / Q000737:chemistry*; D004952:Esters / Q000737:chemistry; D006868:Hydrolysis; D006873:Hydroquinones / Q000737:chemistry*; D007700:Kinetics; D010782:Photolysis; D013816:Thermodynamics
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D003512:Cyclohexanones; D004952:Esters; D006873:Hydroquinones; C471867:4-(benzothiazol-2-yl)-4-hydroxy-2,5-cyclohexadien-1-one