Nucleoside‐Based Diarylethene Photoswitches and Their Facile Incorporation into Photoswitchable DNA

Abstract

The artificial control of DNA structure and function is an attractive field in chemical and synthetic biology, [1] and light is a powerful and convenient trigger: it is non-invasive, provides high spatio-temporal resolution, and offers the option of orthogonality. DNA is reactive to light: the UVlight-induced cyclodimerization of pyrimidine nucleosides is an important type of DNA damage and has been studied intensively. [2] Interestingly, this chemical property has never been exploited for the construction of DNA-based reversible photoswitches, and all published work in this field is based on the covalent functionalization of DNA with small autonomous photoactive molecules. [3] Different classes of such photoactive molecules have been studied for DNA photoregulation; [4] azobenzenes have been used most frequently and were, for example, employed for modulating oligonucleotide duplex and triplex formation and DNA transcription. [5] Other substance classes studied in this context include arylvinyl derivatives, [6] spiropyranes, [3a] and recently also diarylethenes. [3a, 7] While a certain influence of photoisomerization on the properties of the nucleic acid was always observed, these approaches share one common limitation: because an autonomous photoswitch was attached to the DNA, either as an appendage or substituting for nucleosides, the rearrangement of chemical bonds upon encountering a photon (i.e., the photochemical reaction) was strictly confined to this non-nucleosidic moiety.Recently, our lab reported a new type of diarylethene photoswitches in which one of the two aryl moieties was replaced by a nucleoside, namely 7-deaza-8-methyldeoxyadenosine (Scheme 1). [8] These photoswitches were synthesized in a convergent multi-step approach in which a substi-tuted cyclopentenyl boronic ester was reacted with protected 7-iodo-8-methyl-7-deazadeoxyadenosine by Suzuki crosscoupling, followed by deprotection. Upon irradiation with light, these compounds were found to undergo a highly efficient, reversible, electrocyclic rearrangement and the switching wavelength could be tuned by the chemical nature of substituents. Switching was found to be near-quantitative in aprotic solvents, and the compounds retained the key properties of nucleotides, such as their capability to form Watson-Crick base-pairs. Unfortunately, the photoisomerization was found to proceed with low efficiency in aqueous solvents, and the demanding synthesis involved limited the application of these photoswitches to oligonucleotides.To develop straight-forward access to truly photoswitchable DNA, we reconsidered our design approach; in contrast to 7-iodo-8-methyl-7-deazadeoxyadenosine, the 5-iodo-substituted pyrimidine nucleosides 5I-dU and 5I-dC represent oligonucleotide modifications readily available from commercial suppliers, and offer the desired reactivity for different cross-coupling reactions. [9] This could allow for the postsynthetic conversion of an iodo-modified oligonucleotide into a photoswitch, leading to the target compounds shown i...

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