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  • br Acknowledgments br The design of polyaromatic

    2021-04-07


    Acknowledgments
    The design of polyaromatic molecules able to bind to DNA is of significant importance for the development of anticancer and fluorescent imaging agents. Among them, 1,8-naphthalimide derivatives have received significant attention and have been extensively investigated for their potent antitumor activity., , , , Moreover their photophysical properties make them interesting candidates to detect DNA by fluorescence. Due to its tricyclic planar ring structure, 1,8-naphthalimide () interacts with DNA and its anticancer activity was discovered 20 years ago. A large variety of 1,8-naphthalimide derivatives has been designed and synthesized in order to improve the interaction with DNA and has been studied as anticancer and fluorescent imaging agents ()., , , Synthetic strategies such as functionalization of the imide nitrogen atom, substitution at the 3 and 4 positions and ring expansion, have provided access to a wide range of 1,8-naphthalimide derivatives with various chemical and photophysical properties. The position and nature of the substituents significantly influence the behavior of these derivatives in terms of DNA binding and fluorescence properties., Interestingly, the aromatic fused derivative azonafide () which contains an anthracene unit, displays a larger affinity for DNA than its parent compound amonafide with a naphthalene unit. This result can be explained by the increased planar surface of the chromophore, thereby increasing the π-stacking interactions between the aromatic rings and the IL-4, murine recombinant pairs of DNA. The heteroaromatic fused derivatives with furan or thiophene developed by Brañas and co-workers demonstrate increased antitumor activity. In fact, heteroaromatic rings likely contribute to additional interactions such as Van der Waals forces. Qian and co-workers have described a novel family of naphthalimide derivatives, thiazonaphthalimides, in which the naphthalene ring has been fused with a thiazole moiety ( – and ). According to their study, the angular isomer and the linear isomer of the aminothiazole derivative (R = NH) were both obtained and interact with calf-Thymus DNA (ct-DNA) with an affinity in the range of 10 M. Following these promising early results, new angular and linear thiazonaphthalimide derivatives were reported by the same team and binding constants to DNA in the range of 10 M were achieved. The photophysical and DNA-binding properties of thiazonaphthalimide derivatives make them ideal candidates for the design of luminescent DNA probes. In particular their insertion into lanthanide complexes would afford DNA-binding long-lived luminescent probes, as previously reported for lanthanide-binding peptides grafted with proflavine or naphthalimide., Non-substituted thiazo compounds were chosen (, R = H) for their large affinity for DNA and their similar fluorescence properties to naphthalimide, which is known to efficiently sensitize the lanthanide europium ion. An acidic group was introduced by the reaction with glycine for efficient coupling to the -terminus of peptides. The two angular and linear derivatives ( and respectively; ) were targeted in order to compare their behaviors with DNA. However, we report herein that cyclisation occurs exclusively in positions 3 and 4 of the naphthalimide moiety affording the angular isomer only, contrary to what was described in previous reports that did not demonstrate unambiguous proof of the regioselectivity. DNA binding studies indicate that the aromatic moiety found in the angular regioisomer has promising DNA binding properties with a large fluorescence quenching upon binding and an affinity of 10 M. The angular thiazonaphthalimide derivative was obtained in five steps with an overall yield of 8%, starting from the commercially available compound 3-nitro-1,8-naphthalic anhydride (). Detailed experimental conditions for each step and compound characterization are given in the . The key step of this synthesis is the formation of the aminothiazole ring starting from amino derivative . Compound was obtained by reduction of the nitro group to the corresponding amine, using tin chloride salts in acetic acid at reflux, as described in the literature., The formation of the aminothiazole moiety was then carried out by the treatment of with potassium thiocyanate and bromine in acetic acid., This synthesis involved a two-step reaction with the initial formation of an aryl-thiocyanate. Indeed, it has been demonstrated that aromatic hydrocarbons bearing strong electron-donating groups such as –NH can react with thiocyanogen to afford aryl-thiocyanates in or in positions. Thiocyanogen is formed from KSCN and Br according to the method developed by Soderback. The thiocyanate moiety can then react with the amine, leading to the formation of an aminothiazole ring. Regardless of the number of equivalents of bromine and potassium thiocyanate, the order or even the duration of addition for each reagent, only one regioisomer was obtained and isolated, with yields ranging from 60 to 95%. The experimental conditions leading to the highest efficiency are described in the and gave compound in 95% yield. Compound displays limited stability and was therefore quickly engaged in the following step, which consists of deamination involving a diazonium ion. The treatment of with phosphoric acid, sodium nitrite and hypophosphorous acid affords the crude product in 36% yield. Compound was then engaged in a condensation reaction with glycine methyl ester hydrochloride, leading to stable compound in 44% yield after purification on a silica gel column. Finally, saponification with lithium hydroxide provides the desired compound in 52% yield. The full characterization of stable compound by H and C NMR, ESI-MS and microanalysis is reported in the .