6-Thiopurine (6TP) is a drug that has been used to treat Acute Lymphocytic Leukemia (ALL) and non-Hodgkin’s leukemia since the early 1950s. This drug has the ability to mimic the guanosine nucleotide, which incorporates into the cancer cell’s DNA causing its death. Unfortunately, toxic effects have been reported from its use, such as hepatotoxicity, severe vomiting, jaundice, and even death. These side effects come from the enzymatic inhibition of UDP-glucose dehydrogenase (UDPGDH) who is responsible of the solubility and excretion of bilirubin in the body. 6TP metabolites can inhibit UDPGDH causing high concentrations of bilirubin, preventing it from becoming soluble and excreted. The drug metabolites arrive because 6TP oxidation of carbons two (C2) and eight (C8) by the enzyme xanthine oxidase. 6TP being the lesser inhibitor metabolite and 6-thiouric acid (oxidation in both carbon) the greater inhibitor. Upon discovery of C2/8 oxidation is responsible for enzymatic inhibition, efforts were undertaken for the construction of 6TP analogs, substituted at the C8 position. We looked to measure their inhibition in the UDPGDH enzyme, by avoiding oxidation in hopes to decrease or eliminate 6TP’s off-target toxicity while retaining therapeutic efficacy. Installation of groups such as bromine, fluorine, chlorine, deuterium and hydrocarbons were considered for the analogs. Characterization of the synthesized analogs was done by HNMR and CNMR. Half maximal inhibitory concentration (IC50) was measure, for synthesized compounds, cultivating ALL cell lines REH for 48 hours using Alamar Blue Assay. Finally, inhibition constant (KI) respect to the UDPGDH was calculated. Brominated, chlorinated, and fluorinated 6TP was successfully synthesized with an overall percent yield of 28%, 16%, and 2%, respectively. 6TP showed an IC50 of 2.94 µm (+/- 0.484) with an Ki of 288 µm, fluorinated 6TP with 4.71 µm (+/- 1.40) and 215 µm, chlorinated 6TP with 3.95 µm (+/- 1.94) and 163 µm , and brominated 6TP with 9.54 µm (+/- 0.970) and 192 µm. Results have shown that structural modifications can retain cytotoxicity and decrease inhibition towards UDPGDH. It is anticipated that with a decrease in toxicity of new 6TP analogs, an increase in dosage can be administered, resulting in further increase of therapeutic properties of 6TP treatment.

Efforts in redesigning the antileukemic drug 6-thiopurine: Decreasing toxic side effects while maintaining efficacy

2019 Spring National Meeting

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