Synthesis of 2-amino-alpha-carboline and analogues relevant for structural investigations of the corresponding dna adducts

Matthew Blake, University of Rhode Island


In rational drug design, the most effective targets are identified when a mechanism-based understanding of a disease state’s proliferation and persistence is available. 2-amino-?-carboline (2-A?C) is a heterocyclic aromatic amine (HAA), which upon metabolic activation in vivo, can covalently bind to the C8-position of guanine. This modification elicits a response from the Nucleotide Excision Repair (NER) system but, if left unrepaired, may result in mutations. The metabolites of 2-A?C are significantly more reactive towards adduct formation than those of 4-aminobiphenyl (4-ABP), a confirmed human bladder carcinogen. Furthermore, 2-A?C is found in cigarette smoke at concentrations 1000 times greater than 4-ABP. 2-A?C has been implicated in hepatocellular carcinoma and cancers of the gastrointestinal tract, potentially explaining the increased incidence of liver cancer in smokers. The cause of cancers and many other diseases is attributed to DNA mutations caused by failure of a cell’s natural DNA repair mechanisms. NER is a major human repair system among many, all part of a complex network consisting of hundreds of proteins that target different types of damage. The overlapping systems making up this network are dependent on molecular recognition and signaling pathways. Structural and thermodynamic investigations of abnormal DNA duplexes have yielded valuable mechanism-based information for use in drug discovery. To perform these studies, the DNA lesion in question must be readily available. Despite powerful implications regarding the role of 2-A?C in cancer, efficient synthetic protocols are not available for 2-A?C or the corresponding adducts. Inefficient biomimetic production of C8-(2-A?C)-guanine adducts has been reported, but is limited by scale and sequence context. This project outlines a more efficient synthesis of 2-A?C and novel analogs necessary for certain structural investigations. Attempts to synthesize a C8-(2-A?C)-guanine oligonucleotide are also described to provide a starting point for future investigations. ^

Subject Area

Chemistry|Pharmaceutical sciences|Biophysics

Recommended Citation

Matthew Blake, "Synthesis of 2-amino-alpha-carboline and analogues relevant for structural investigations of the corresponding dna adducts" (2015). Dissertations and Master's Theses (Campus Access). Paper AAI1605365.