Date of Award


Document Type

Honors Thesis (Open Access)


Colby College. Chemistry Dept.


Kevin P. Rice

Second Advisor

Julie T. Millard


Sulfonylhydrazines are a class of DNA alkylating drugs which also produce carbamoylating activity in situ. The carbamoylating species is of significance because it has shown to inhibit important thiol-containing enzymes such as glutathione reductase (GR) and thioredoxin reductase (TrxR). TrxR catalyzes dithiol-disulfide exchange reactions on thioredoxin (Trx), which in turn catalyzes other reductive processes such as deoxyribonucleotide biosynthesis. In this study, we demonstrate that TrxR activity is strongly inhibited by the anticancer prodrug Cloretazine both in purified form and in leukemia cell lysates. This inhibition is specific to the carbamoylating activity of methylisocyanate (MiC). In contrast, another important oxidoreductase, glutathione reductase (GR), was inhibited in purified form, but showed little susceptibility to Cloretazine in the cellular context. These results suggest the mode of inhibition against TrxR and GR differs inside of cells. Due to the overexpression of TrxR in cancer cells and its role in DNA metabolism, inhibiting TrxR may be important to the activity of the anticancer agent Cloretazine.


Cloretazine, Antineoplastic agents, Thioredoxin

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Chemistry Commons