Please use this identifier to cite or link to this item: https://hdl.handle.net/1959.11/6687
Title: Characterization of 4-(Benzothiazol-2-yl)phenylnitrenium Ion from a Putative Metabolite of a Model Antitumor Drug
Contributor(s): Chakraborty, Mrinal (author); Jin, Kyoung Joo (author); Glover, Stephen (author)orcid ; Novak, Michael (author)
Publication Date: 2010
DOI: 10.1021/jo101275y
Handle Link: https://hdl.handle.net/1959.11/6687
Abstract: The 4-(benzothiazol-2-yl)phenylnitrenium ion 11 is generated from hydrolysis or photolysis of O-acetoxy-N-(4-(benzothiazol-2-yl)phenyl)hydroxylamine 8, a model metabolite of 2-(4-aminophenyl) benzothiazole 1 and its ring-substituted derivatives that are being developed for a variety of medicinal applications, including antitumor, antibacterial, antifungal, and imaging agents. Previously, we showed that 11 had an aqueous solution lifetime of 530 ns, similar to the 560 ns lifetime of the 4-biphenylylnitrenium ion 12 derived from the well-known chemical carcinogen 4-aminobiphenyl. We now show that the analogy between these two cations extends well beyond their lifetimes. The initial product of hydration of 11 is the quinolimine 16, which can be detected as a long-lived reactive intermediate that hydrolyzes in a pH-dependent manner into the final hydrolysis product, the quinol 15. This hydrolysis behavior is equivalent to that previously described for a large number of ester metabolites of carcinogenic arylamines, including 4-aminobiphenyl. The major azide trapping product (90% of azide products) of 11, 20, is generated by substitution on the carbons 'ortho' to the nitrenium ion center of 11. This product is a direct analogue of the major azide adducts, such as 22, generated from trapping of the nitrenium ions of carcinogenic arylamines. The azide/solvent selectivity for 11, 'kaz/ks', is also nearly equivalent to that of 12. A minor product of the reaction of 11 with N₃‾, 21, contains no azide functionality but may be generated by a process in which N₃‾ attacks 11 at the nitrenium ion center with loss of N₂ to generate a diazene 25 that subsequently decomposes into 21 with loss of another N₂. The adduct derived from attack of 20-deoxyguanosine (d-G) on 11, 28, is a familiar C-8 adduct of the type generated from the reaction of d-G with a wide variety of arylnitrenium ions derived from carcinogenic arylamines. The rate constant for reaction of d-G with 11, kd-G, is very similar to that observed for the reaction of d-G with 12. The similar lifetimes and chemical reactivities of 11 and 12 can be rationalized by B3LYP/6-31G(d) calculations on the two ions that show that they are of nearly equivalent stability relative to their respective hydration products. The calculations also help to rationalize the different regiochemistry observed for the reaction of N₃‾ with 11 and its oxenium ion analogue, 13. Since 8 is the likely active metabolite of 1 and a significant number of derivatives of 1 are being developed as pharmaceutical agents, the similarity of the chemistry of 11 to that of carcinogenic arylnitrenium ions is of considerable importance. Consideration should be given to this chemistry in continued development of pharmaceuticals containing the 2-(4-aminophenyl) benzothiazole moiety.
Publication Type: Journal Article
Source of Publication: Journal of Organic Chemistry, 75(15), p. 5296-5304
Publisher: American Chemical Society
Place of Publication: United States of America
ISSN: 0022-3263
1520-6904
Field of Research (FOR): 030505 Physical Organic Chemistry
030405 Molecular Medicine
030799 Theoretical and Computational Chemistry not elsewhere classified
030401 Biologically Active Molecules
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
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