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Chemistry of ring-substituted 4-(benzothiazol-2-yl)phenylnitrenium ions from antitumor 2-(4-aminophenyl)benzothiazoles.

ABSTRACT: Ring-substituted derivatives of 2-(4-aminophenyl)benzothiazole, 1a, 1b-g, are under development as antitumor agents. One derivative, 1f, has reached phase 1 clinical trials as the prodrug 2f, Phortress (NSC 710305). These amines are activated by CYP450 1A1, apparently into hydroxylamines 8a-g that are likely metabolized into esters that ionize into nitrenium ions responsible for cellular damage. Previously we showed that 9a, the acetic acid ester of 8a, generates the long-lived (530 ns) nitrenium ion 11a by hydrolysis or photolysis in water. In this study, azide trapping shows that 9b-g generate 11b-g via rate-limiting N-O heterolysis. Ion lifetimes, estimated from azide/solvent selectivities, range from 250 to 1150 ns with identical lifetimes for 11a and 11f. Differences in biological activity of the amines are likely not due to differences in the chemistry of the cations but to differences in metabolic activation/deactivation of individual amines. Unlike the nitrenium ions, lifetimes of the esters are strongly dependent on the 3'-Me substituent. Esters containing 3'-Me (9b, 9f, 9g) have lifetimes of 5-10 s compared to 400-800 s for esters without 3'-Me (9a, 9c, 9d, 9e). This restricts 3'-Me esters to cells/tissues in which activation occurs, concentrating their effects in tumor cells if metabolism is restricted to those cells.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3740366 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Chemistry of ring-substituted 4-(benzothiazol-2-yl)phenylnitrenium ions from antitumor 2-(4-aminophenyl)benzothiazoles.

Zhang Yang Y Chakraborty Mrinal M Cerda-Smith Christian G CG Bratton Ryan N RN Maurer Natalie E NE Senser Ethan M EM Novak Michael M

The Journal of organic chemistry 20130701 14

Ring-substituted derivatives of 2-(4-aminophenyl)benzothiazole, 1a, 1b-g, are under development as antitumor agents. One derivative, 1f, has reached phase 1 clinical trials as the prodrug 2f, Phortress (NSC 710305). These amines are activated by CYP450 1A1, apparently into hydroxylamines 8a-g that are likely metabolized into esters that ionize into nitrenium ions responsible for cellular damage. Previously we showed that 9a, the acetic acid ester of 8a, generates the long-lived (530 ns) nitreniu ...[more]

PMID: 23786256

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Project description: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, k(az)/k(s), is also nearly equivalent to that of 12. A minor product of the reaction of 11 with N(3)(-), 21, contains no azide functionality but may be generated by a process in which N(3)(-) attacks 11 at the nitrenium ion center with loss of N(2) to generate a diazene 25 that subsequently decomposes into 21 with loss of another N(2). The adduct derived from attack of 2'-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, k(d-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 N(3)(-) 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.

Project description:A series of N(1),N(1),N(3)-tri-substituted benzamidrazones of the general formula [PhC(NHR)=NNMe(2)] (R = Me, n-Pr, i-Pr, n-Bu, Bn, Ph; 1a-f) was synthesized via condensation of 1,1-dimethylhydrazine with the corresponding imidoyl chloride, [PhC(Cl)=NR]. Multinuclear NMR data, and zero-point energy DFT calculations conducted with the B3LYP functional and 6-31G+(d,p) basis set, suggest that these compounds exist as a single tautomer in solution; possessing a weak intramolecular hydrogen bond and a structure dominated by the localised resonance structure ArC(NHR)=N-NMe(2). An X-ray crystallographic study upon PhC(NHPh)=NNMe(2) (1f) demonstrated that this compound adopts an identical tautomer in the solid state. Reactions of [PhC(NHMe)=NNMe(2)] (1a) with [LMCl(2)](2) (M = Ru, L = cymene; M = Rh, Ir, L = Cp*) results in the stoichiometric formation of products of the formula [LM{PhC(=NMe)NHNMe(2)}Cl](+)Cl(-) (2a-c) in which the amidrazone chelates the metal in a ?(2)-N(1),N(3)-coordination mode. Formation of this five-membered chelate occurs with a concomitant tautomerisation of the amidrazone ligand to an alternative tautomer, i.e. [PhC(=NMe)NHNMe(2)], the latter tautomer is expected to be readily energetically accessible based upon the aforementioned DFT calculations. This series of salts may be deprotonated with lithium hexamethyldisilazide to form the corresponding charge neutral complexes [LM{PhC(NMe)=NNMe(2)}] (3a-c). In contrast, the reaction of N(1),N(1),N(3)-tri-substituted benzamidrazones with [(cymene)RuCl(2)](2) in the presence of NaOAc yielded a mixture of cyclometallation (C-H activation) and amidrazone chelation/deprotonation (N-H activation) products. Reaction of 1a yielded an inseparable mixture of products, whilst the reaction of 1c resulted in formation of the cyclometallated product [LM{C(6)H(5)C(=N(i)Pr)NHNMe(2)}] (L = cymene, M = Ru; 4a) in a modest 62% yield. This latter complex could be isolated as a crystalline orange solid, full characterisation including single crystal X-ray diffraction demonstrated that the amidrazone coordinates in a ?(2)-N(2),C-coordination mode.

Dataset Information

Chemistry of ring-substituted 4-(benzothiazol-2-yl)phenylnitrenium ions from antitumor 2-(4-aminophenyl)benzothiazoles.

Publications

Chemistry of ring-substituted 4-(benzothiazol-2-yl)phenylnitrenium ions from antitumor 2-(4-aminophenyl)benzothiazoles.

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