Oxidation of adenine and adenosine derivatives by dimethyldioxirane (DMDO) using halogenated metalloporphyrins as catalysts

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Abstract

In an effort to evaluate the reactivity of nucleobases with halogenated metalloporphyrins, adenine and adenosine derivatives were oxidized by dimethyldioxirane (DMDO) as oxygen atom donor using Mn[(Cl16)TDMPP]Cl and Mn[(Cl8)TDCPP]Cl porphyrins as catalysts. The role of hydrogen bonding interactions in the selectivity of the reaction was investigated through the oxidation of adenine and adenosine derivatives bearing hydrogen bond donors on the sugar moiety or on the N-9 side chain. This procedure is a useful synthetic tool for the selective C-8 versus N-1 oxidation of purine derivatives.

Introduction

It is well established that the oxidation of purine DNA bases by oxygen free radicals, which result from the action of ionizing radiations, light and ultrasound, is one of the major forms of oxidative base damage [1], [2], [3], [4]. These modifications have important biological implications including a number of lesions that do not block DNA replication, change the structural relationship between adjacent base pairs, and are implicated in mutagenicity and aging [5], [6], [7]. There are two major products that result from the oxidation of purine nucleobases, oxopurines and purine-N-oxides. Oxopurines were detected in neoplastic liver of fish, as well as in urine samples of humans [8]. Uric acid (8-oxoxanthine) and their derivatives are used in obesity-treating pharmaceuticals, cosmetics, and antidandruff preparations [9]. Purine N-oxides show anticoccidial [10], antitumor [11], oncogenic [12], [13] and mutagenic [14] properties. Oxopurines and purine-N-oxides are mainly prepared by oxidation of the parent purines [15], [16], [17], [18], [19], [20]. Metalloporphyrins are able to selectively oxidize purine nucleobases when embedded in DNA [21], [22], [23], [24], [25]. Nevertheless, with the exception of the oxidation of adenosine-5′-monophosphate (AMP) by [Mn(Mepy)4P](OAc)5/KHSO5 [26], and the photosensitized oxidation of guanine by meso-tetrakis (1-pyrenyl)porphyrinato gold(III) acetate [27], few data are available about the selectivity of metalloporphyrins in the synthesis of oxopurines and purine-N-oxides. Metalloporphyrins containing halogenated substituents at the β-pyrrole positions of the macrocycle are of current interest since they show to be stable and efficient catalysts for the oxidation of organic substrates [28], [29], [30]. During our studies on the oxidation of uracil derivatives and pyrimidine nucleosides [31], [32], [33], we found that the hydroxyl groups of the sugar moiety on 2′-deoxyribonucleosides are suitable H-bonding donors for halogenated metalloporphyrins [34]. The selectivity observed in the epoxidation of thymidine derivatives was correlated to the presence of methoxy groups in the 2′,6′-position of the phenyl rings as H-bonding acceptors, and to the saddle-shaped conformation of the metalloporphyrin ring. Moreover, in a previous communication we briefly reported that adenine and adenosine derivatives were oxidized by dimethyldioxirane (DMDO) as oxygen atom donor using Mn[(Cl16)TDMPP]Cl and Mn[(Cl8)TDCPP]Cl porphyrins as catalysts [35].

Herein, we describe extensively these data showing that the selectivity of the oxidation, that is C-8 versus N-1 purine ring oxidation, can be switched on the basis of the structure of the catalyst, and on the position and the presence of H-bonding donors on the adenine and adenosine derivatives. Examples of affinity of metalloporphirins toward purine nucleobases by non-covalent interactions are currently available [36], [37], [38], [39], however they have not been related to the selectivity of purine ring oxidation.

Section snippets

Experimental

All commercial products were of the highest grade available and were used as such. Hydrogen peroxide was a 35% aqueous solution (Aldrich). NMR spectra were recorder on a Bruker (200 MHz). Gas chromatography and gas chromatography-mass spectroscopy (GC-MS) of the reaction products were performed after derivatization with bis-trimethylsilyl trifluoroacetamide (BSTFA) using a SPB column (25m×0.30 mm and 0.25 mm film thickness) and isothermal temperature profile of 80 °C for the first 2 min, followed by

Results and discussion

The oxidation of 9-(n-hexan-1′-yl) adenine 1, 9-[4′-(acetoxy)-n-butan-1′-yl] adenine 2, 9-[4′-(hydroxy)-n-butan-1′-yl] adenine 3, 9-[4′-(hydroxy)-n-butan-1′-yl]purine 4, 9-[3′-(hydroxy)-n-propan-1′-yl] adenine 5 and 9-[5′-(hydroxy)-pentan-1′-yl) adenine 6 has been studied. The catalysts were Mn[(Cl16)TDMPP]Cl, (catalyst A), and Mn[(Cl8)TDCPP]Cl (catalyst B) [40], [41], where (Cl16)TDMPP is the dianion of 2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetrakis-(3′,5′-dichloro-2′,6′-dimethoxyphenyl)

Conclusion

Molecular recognition processes based on hydrogen bond interactions (or other polar interactions) are probably responsible for the selectivity of the oxidation of adenine and adenosine derivatives by DMDO using catalysts A and B. As shown in Table 1, the two catalysts showed comparable oxidation efficiencies. Independently on the experimental conditions, the oxidations performed with Mn[(Cl8)TDCPP]Cl (catalyst B), lacking any acceptor of hydrogen bond, gave adenine-1-oxide derivatives in high

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