2. Academic Validation
  3. Synthesis of Mitomycin C and decarbamoylmitomycin C N6 deoxyadenosine-adducts

Synthesis of Mitomycin C and decarbamoylmitomycin C N6 deoxyadenosine-adducts

  • Bioorg Chem. 2019 Nov:92:103280. doi: 10.1016/j.bioorg.2019.103280.
Maggie Zheng 1,  Seokjin Hwang 2,  Timothy Snyder 3,  Jake Aquilina 4,  Gloria Proni 5,  Manuel M Paz 6,  Padmanava Pradhan 7,  Shu-Yuan Cheng 8,  Elise Champeil 9
Affiliations

Affiliations

  • 1 John Jay College of Criminal Justice, New York, 524 West 59(th) Street, New York, NY 10019, USA. Electronic address: maggie.zheng@jjay.cuny.edu.
  • 2 John Jay College of Criminal Justice, New York, 524 West 59(th) Street, New York, NY 10019, USA. Electronic address: seokjin.hwang@jjay.cuny.edu.
  • 3 John Jay College of Criminal Justice, New York, 524 West 59(th) Street, New York, NY 10019, USA. Electronic address: timothy.snyder@jjay.cuny.edu.
  • 4 John Jay College of Criminal Justice, New York, 524 West 59(th) Street, New York, NY 10019, USA. Electronic address: jake.aquilina@jjay.cuny.edu.
  • 5 John Jay College of Criminal Justice, New York, 524 West 59(th) Street, New York, NY 10019, USA. Electronic address: gproni@jjay.cuny.edu.
  • 6 Departamento de Química Orgánica, Facultade de Química, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address: manuel.paz@usc.es.
  • 7 The City College, 138th Street at Convent Avenue, New York, NY 10031, USA. Electronic address: ppradhan@ccny.cuny.edu.
  • 8 John Jay College of Criminal Justice, New York, 524 West 59(th) Street, New York, NY 10019, USA. Electronic address: shcheng@jjay.cuny.edu.
  • 9 John Jay College of Criminal Justice, New York, 524 West 59(th) Street, New York, NY 10019, USA; The Graduate Center of the City University of New York, New York, NY 10016, USA. Electronic address: echampeil@jjay.cuny.edu.
PMID: 31539740 DOI: 10.1016/j.bioorg.2019.103280
Abstract

Mitomycin C (MC), an anti-cancer drug, and its analog, decarbamoylmitomycin C (DMC), are DNA-alkylating agents. MC is currently used in the clinics and its cytotoxicity is mainly due to its ability to form Interstrand Crosslinks (ICLs) which impede DNA replication and, thereby, block Cancer cells proliferation. However, both MC and DMC are also able to generate monoadducts with DNA. In particular, we recently discovered that DMC, like MC, can form deoxyadenosine (dA) monoadducts with DNA. The biological role played by these monoadducts is worthy of investigation. To probe the role of these adducts and to detect them in enzymatic digests of DNA extracted from culture cells treated by both drugs, we need access to reference compounds i.e. MC and DMC dA-mononucleoside adducts. Previous biomimetic methods used to generate MC and DMC mononucleoside adducts are cumbersome and very low yielding. Here, we describe the diastereospecific chemical synthesis of both C-1 epimers of MC and DMC deoxyadenosine adducts. The key step of the synthesis involves an aromatic substitution reaction between a 6-fluoropurine 2'-deoxyribonucleoside and appropriately protected stereoisomeric triaminomitosenes to form protected-MC-dA adducts with either an S or R stereochemical configuration at the adenine-mitosene linkage. Fluoride-based deprotection methods generated the final four reference compounds: the two stereoisomeric MC-dA adducts and the two stereoisomeric DMC-dA adducts. The MC and DMC-dA adducts synthesized here will serve as standards for the detection and identification of such adducts formed in the DNA of culture cells treated with both drugs.

Keywords

DNA-adducts; Deoxyadenosine; Mitomycin C; Nucleophilic aromatic substitution; Stereoisomers.

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