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Synthesis of Oligonucleotides containing the cis-Interstrand Crosslink Produced by Mitomycins in their Reaction with DNA |
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| Authors: | William Aguilar Owen Zacarias Marian Romaine Prof. Gloria Proni Prof. Ana G. Petrovic Prof. Dr. Rinat Abzalimov Dr. Manuel M. Paz Prof. Elise Champeil |
| Affiliation: | 1. Science Department, John Jay College of Criminal Justice, 524 West 59th street, New York, NY, 10019 USA These authors contributed equally to this work.;2. Science Department, John Jay College of Criminal Justice, 524 West 59th street, New York, NY, 10019 USA;3. New York Institute of Technology, 1855 Broadway, EGGC 405A, New York, NY, 10023 USA;4. City University of New York, Advanced Research Center, 85 St Nicholas Terrace, New York, NY, 10031 USA Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, 10016 USA;5. Departamento de Química Orgánica, Facultad de Química, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, 15782 Spain |
| Abstract: | Mitomycin C (MC) an antitumor drug and decarbamoylmitomycin C (DMC), a derivative of MC lacking the carbamoyl moiety, are DNA alkylating agents which can form DNA interstrand crosslinks (ICLs) between deoxyguanosine residues located on opposing DNA strands. MC forms primarily deoxyguanosine adducts with a 1“-R stereochemistry at the guanine-mitosene bond (1”-α, trans) whereas DMC forms mainly adducts with a 1“-S stereochemistry (1”-β, cis). The crosslinking reaction is diastereospecific: trans-crosslinks are formed exclusively at CpG sequences, while cis-crosslinks are formed only at GpC sequences. Until now, oligonucleotides containing 1“-β-deoxyguanosine adducts or ICL at a specific site could not be synthesized, thus limiting the investigation of the role played by the stereochemical configuration at C1′′ in the toxicity of these compounds. Here, a novel biomimetic synthesis to access these substrates is presented. Structural proof of the adducted oligonucleotides and ICL were provided by enzymatic digestion to nucleosides, high resolution mass spectral analysis, CD spectroscopy and UV melting temperature studies. Finally, a virtual model of the 25-mer 1”-β ICL synthesized was created to explore the conformational space and structural features of the crosslinked duplex. |
| Keywords: | biomimetic synthesis conformational studies interstrand crosslink mitomycin site-specific alkylation |