바로가기메뉴

본문 바로가기 주메뉴 바로가기

logo

  • P-ISSN2233-4203
  • E-ISSN2093-8950

DC23, a Triazolothione Resorcinol Analogue, Is Extensively Metabolized to Glucuronide Conjugates in Human Liver Microsomes

Mass Spectrometry Letters, (P)2233-4203; (E)2093-8950
2018, v.9 no.1, pp.24-29
https://doi.org/10.5478/MSL.2018.9.1.24
Jong Cheol Shon (Kyungpook National University)
Jeongmin Joo (Daegu-Gyeongbuk Medical Innovation Foundation)
Taeho Lee (Kyungpook National University)
Nam Doo Kim (Daegu-Gyeongbuk Medical Innovation Foundation)
Kwang-Hyeon Liu (Kyungpook National University)
  • Downloaded
  • Viewed

Abstract

DC23, a triazolothione resorcinol analogue, is known to inhibit heat shock protein 90 and pyruvate dehydrogenase kinase which are up-regulated in cancer and diabetes, respectively. This study was performed to elucidate the metabolism of DC23 in human liver microsomes (HLMs). HLMs incubated with DC23 in the presence of uridine 5’-diphosphoglucuronic acid (UDPGA) and/or β-nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the formation of four metabolites, M1- M4. M1 was identified as DC23-N-Oxide, on the basis of LC-MS/MS analysis. DC23 was further metabolized to its glucuronide conjugates (M2, M3, and M4). In vitro metabolic stability studies conducted with DC23 in HLMs revealed significant glucuron- ide conjugation with a t 1/2 value of 1.3 min. The inhibitory potency of DC23 on five human cytochrome P450s was also investi- gated in HLMs. In these experiments, DC23 inhibited CYP2C9-mediated tolbutamide hydroxylase activity with an IC 50 value of 8.7 µM, which could have implications for drug interactions.

Submission Date
2018-02-08
Revised Date
2018-02-21
Accepted Date
2018-02-21

Reference

1

Sidera, K.. (2014). . Recent Pat Anticancer Drug Discov, 9, 1-.

2

Biamonte, M. A.. (2010). . J. Med. Chem., 53, 3-. http://dx.doi.org/10.1021/jm9004708.

3

Taddei, M.. (2014). . J. Med. Chem., 57, 2258-. http://dx.doi.org/10.1021/jm401536b.

4

Zhang, C.. (2017). . Eur. J. Med. Chem., 125, 315-. http://dx.doi.org/10.1016/j.ejmech.2016.09.043.

5

Sharp, S. Y.. (2012). . PLoS One, 7, e44642-. http://dx.doi.org/10.1371/journal.pone.0044642.

6

Jeong, J. H.. (2016). . Eur. J. Med. Chem., 124, 1069-. http://dx.doi.org/10.1016/j.ejmech.2016.10.038.

7

Fuhrmann-Stroissnigg, H.. (2017). . Nat. Commun., 8, 422-. http://dx.doi.org/10.1038/s41467-017-00314-z.

8

정주희. (2017). Chalcone-templated Hsp90 inhibitors and their effects on gefitinib resistance in non-small cell lung cancer (NSCLC). Archives of Pharmacal Research, 40(1), 96-105.

9

Woodhead, A. J.. (2010). . J. Med. Chem., 53, 5956-. http://dx.doi.org/10.1021/jm100060b.

10

London, C. A.. (2011). . PLoS One, 6, e27018-. http://dx.doi.org/10.1371/journal.pone.0027018.

11

Eccles, S. A.. (2008). . Cancer Res, 68, 2850-. http://dx.doi.org/10.1158/0008-5472.CAN-07-5256.

12

Sharp, S. Y.. (2007). . Mol. Cancer Ther., 6, 1198-. http://dx.doi.org/10.1158/1535-7163.MCT-07-0149.

13

Feldman, R. I.. (2009). . Chem. Biol. Drug Des., 74, 43-. http://dx.doi.org/10.1111/j.1747-0285.2009.00833.x.

14

Tso, S. C.. (2014). . J. Biol. Chem., 289, 4432-. http://dx.doi.org/10.1074/jbc.M113.533885.

15

Lee, B.. (2015). . Drug Metab. Dispos., 43, 1137-. http://dx.doi.org/10.1124/dmd.114.063016.

16

Kim, M. J.. (2005). . Rapid Commun. Mass Spectrom., 19, 2651-. http://dx.doi.org/10.1002/rcm.2110.

17

Joo, J.. (2013). . Biopharm. Drug Dispos., 34, 195-. http://dx.doi.org/10.1002/bdd.1837.

18

Walsky, R. L.. (2003). . Drug Metab. Dispos., 31, 343-. http://dx.doi.org/10.1124/dmd.31.3.343.

Mass Spectrometry Letters