Biomimetic One-Pot Route to Acridine Epoxides Margarida Linhares, Susana L. H. Rebelo,* Krzysztof Biernacki, Alexandre L. Magalha ̃ es, and Cristina Freire REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciê ncias, Universidade do Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal *S Supporting Information ABSTRACT: The first direct epoxidation of acridine on the edge positions is reported. The reaction proceeds under mild conditions using a biomimetic catalytic system based on a Mn(III) porphyrin. The successive oxyfunctionalization to mono-, di-, and tetraepoxy derivatives is accomplished using hydrogen peroxide as a green oxidant at room temperature. Computed optimized geometries showed only slight shifts to the base planarity upon dearomatiza- tion by epoxidation, which is an important feature for DNA intercalation and bioactivity. NMR studies and comparison with theoretical values allowed the assignment of the stereochemistry of the anti- and syn-diepoxy and -tetraepoxy derivatives as well as compounds resulting from epoxide ring opening, exemplified by epoxydiol. The diepoxide is formed in an anti:syn ratio of ∼4, and the attack by nucleophiles, exemplified by ethylaniline, occurs selectively and with full conversion, using a microwave process with acetonitrile reflux for 10 min. Finally, studies of the electrostatic potential allowed the mechanisms of the formation of 4-hydroxyacridine and the regioselective reaction of diepoxyacridine with nucleophiles to be rationalized. ■ INTRODUCTION Acridine derivatives are an important class of bioactive compounds that have been widely studied for their antibacterial 1 and antimalarial 2 activities, while the more recent research has mainly focused on their use as potential therapeutic agents for cancer 3−5 and Alzheimers’s disease. 6 A key feature of these molecules is the planar base structure, which allows strong but reversible intercalation into DNA chains between nitrogen bases 7 and inhibition of topoisomerase enzymes. 8 More recently, the antibacterial activity has been ascribed to their activity as amphiphilic membrane disruptors. 9 The most recent studies considered platinum−acridine hybrid agents showing synergistic metalating−intercaling properties and very promising activity for the treatment of chemoresistant cancers. 10,11 The understanding of the mode of action of these compounds and the existence of different biological targets has stimulated the synthesis of new acridine derivatives. In addition, substituted acridine chromophores have found extensive applications as luminescent probes, essentially chemilumines- cent and fluorescent. 12−14 Despite the many studies developed for the preparation of compounds based on the acridine structure, direct substitution on the acridine backbone occurs only at the most reactive meso position (position 9, opposite to the nitrogen atom; see Scheme 1 for atom numbering) or by nucleophilic attack at the central N-pyridyl site. 15 Consequently, acridines carrying substituents on the peripheral aromatic rings commonly result from addition and cyclization reactions of lower-mass compounds. These type of reactions often require several steps with the formation of significant amounts of secondary products and the demand for high temperatures and long reaction times in the individual steps. 16 Cytochrome P450 enzymes play a key role in metabolic pathways, as they are responsible for a wide range of selective oxygenation reactions, 17 and they promote the activation of green oxidants such as molecular oxygen and hydrogen peroxide. 18,19 One of the most unusual reactions mediated by P450 is the direct epoxidation of aromatic rings, which is ultimately associated with the mutagenic properties of polycyclic aromatic compounds due to the reaction of the epoxide rings with DNA bases. 20,21 Since aromatic epoxidation by chemical systems is not common, the development of efficient pathways to new and potential useful derivatives can be inspired by biomimetic processes. After epoxidation at peripheral positions and convenient derivatization of the epoxides, several stable acridine derivatives can be obtained. These compounds have very promising bioactivities 22,23 due to the possibility of intercala- tion and reversible binding to DNA. On the basis of the prosthetic center of cytochrome P450, an iron(III) protoporphyrin IX with a cysteine as the axial ligand, synthetic metalloporphyrins carrying electron-withdrawing substituents have been increasingly and successfully used in the oxidation of various organic substrates. Novel processes have been described for the oxidation of, e.g., alkenes, 24 inert Received: October 14, 2014 Article pubs.acs.org/joc © XXXX American Chemical Society A dx.doi.org/10.1021/jo5023525 | J. Org. Chem. XXXX, XXX, XXX−XXX