Abstract2-(4-Aminophenyl)benzothiazoles related to 1 are potentially important pharmaceuticals. Metabolism apparently involves oxidation and esterification to 3. In water, hydrolysis and photolysis of 3 generates the nitrenium ion 4 that can be detected indirectly by N 3 − trapping and directly by UV-vis spectroscopy following laser flash photolysis. The transient, with λ max 570 nm, and a lifetime of 530 ns, reacts with N 3 − at a diffusion-controlled rate and generates the quinol 6 by reaction with water.Benzothiazole derivatives such as 2-(4-aminophenyl)benzothiazole, 1, are under investigation as anti-tumor, antifungal, and antibacterial agents, 1-3 and as radiopharmaceuticals for binding and in vivo imaging of Aβ-plaques, one of the earliest pathological processes in the development of Alzheimer's disease. 4 One anti-tumor derivative of 1 is currently in Phase 1 clinical trials in Great Britain. 5 The use of 1 and its derivatives as anti-tumor agents requires biological activation. 5,6 The proposed metabolism of 1 to form the active agent 3 is shown in Scheme 1, although neither 2 nor 3 had been isolated and characterized. It is presumed that 3 further decomposes into a reactive electrophile, but no direct evidence for this proposal has been presented. 7 We have succeeded in synthesizing both 2 and 3 from 2-(4-nitrophenyl)benzothiazole using procedures we previously developed for making similar derivatives of carcinogenic aromatic amines (Scheme 2). 8 Reduction of the nitro compound 9 with hydrazine hydrate in the presence novakm@muohio.edu. † Miami University § The Ohio State University Supporting Information Available Experimental details, a Table of rate constants, Figure S1, synthesis of 2 and 3, NMR spectra of 2 and 3. This material is available free of charge via the internet at http://pubs.acs.org. of 5% Pd/C catalyst generates 2 in moderate yield, while tratment of 2 with acetyl cyanide in the presence of N-ethylmorpholine provides 3 in satisfactory yield. We now report the indirect and direct detection of nitrenium ion 4 (Scheme 3) from hydrolysis and photolysis of 3. NIH Public AccessKinetics of the decomposition of 3 (2.5 × 10 −5 M) at pH 7.1 in phosphate buffer, and the formation of the major hydrolysis product 6 (Scheme 3, identified by HPLC and 1 H NMR comparison to an authentic sample 10 ) monitored by UV spectroscopy, are described by two pseudo-first-order rate constants, k o and k 1 . HPLC studies ( Figure 1A) show that the larger rate constant, k o governs the decay of 3, while the appearance of 6 is biphasic, and is fit well by a rate equation for two consecutive first-order reactions. The larger rate constant generated by the fit is equivalent in magnitude to k o measured for the disappearance of 3. The rate of appearance of 6 is limited by the smaller rate constant, k 1 . Kinetics of the appearance of 6 are consistent with its formation from a long-lived intermediate (lifetime ca. 2 h at 10 °C) that is generated by hydrolysis of 3. Steady-state photolysis of an identical aqueous soluti...

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 anti-tumor, anti-bacterial, anti-fungal, 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 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, 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.

We have developed a novel synthetic method that enables the preparation of functional derivatives of heptiptycene, i.e., cavitands with two juxtaposed cavities. The homocoupling of bicyclic dibromoalkenes is promoted by Pd(OAc)2 (10%) in dioxane (100 °C) to give cyclotrimers in 27-77% yield under optimized reaction conditions (Ph3P, K2CO3, n-Bu4NBr, N2, 4 Å MS). These dual-cavity baskets show a strong π → π* absorption at 241 nm (ε = 939,000 M(-1) cm(-1)), along with a subsequent fluorescence emission at 305 nm.

Derivatives of 2‐(4‐aminophenyl)benzothiazole, 1, are being investigated as antitumor drugs, and for other medicinal applications. Although drug development has proceeded rapidly, little is known about the basis for the activity of these drugs. We have previously shown that the putative N‐acetoxy metabolite of 1, 8, decomposes in water to generate a long‐lived nitrenium ion, 11 (530 ns at room temperature). The kinetics of reaction of 8 with monomeric purines and the pyrimidine cytosine in aqueous solution are consistent with trapping of 11 after rate limiting ionization of 8. This is equivalent to the behavior of similar metabolites of carcinogenic polycyclic arylamines that have also been shown to react with deoxyribonucleic acid bases via a nitrenium ion mechanism. Selectivities of 11 and the nitrenium ion 13, derived from the carcinogen 4‐aminobiphenyl, for individual purines and pyrimidines are comparable, with both ions showing a marked preference for reaction with 2′‐deoxyguanosine and xanthosine, and much lower selectivity for inosine, adenosine, and the pyrimidine cytosine (C). Products of the reactions of the two nitrenium ions with the individual purines are similar, although there are some notable differences. The product of the reaction of 11 with C is similar to the product of the reaction of N‐acetoxy‐3,5‐dimethylaniline with 2′‐deoxycytidine (d‐C). These results indicate that 11 is not unique among arylnitrenium ions in its reactions with deoxyribonucleic acid bases. The basis for selective antitumor activity of 1 and its derivatives is not due to an unusual property of the nitrenium ion. Copyright © 2011 John Wiley & Sons, Ltd.