Abstract
Deuterium substitution has been widely known that can improve the pharmacokinetic profiles due to isotope effect. Herein, a series of deuterated sorafenib derivatives have been synthesized and characterized by 1H NMR, 13C NMR and MS. Their antitumor activities were evaluated in vitro against human hepatoma cell line HepG2 and human cervical carcinoma cell line HeLa. The LogP values were detected by high-performance liquid chromatography. Subsequently, the metabolic stability and pharmacokinetics study were assessed in vitro and in vivo.
Similar content being viewed by others
References
Urey HC, Brickwedde FG, Murphy GM (1932) A hydrogen isotope of mass 2. Phys Rev 39:164–165. https://doi.org/10.1103/PhysRev.39.164
Gant TG (2014) Using deuterium in drug discovery: leaving the label in the drug. J Med Chem 57:3595–3611. https://doi.org/10.1021/jm4007998
Halford B (2016) The deuterium swithcheroo. Chem Eng News 94:32–36. https://doi.org/10.1021/cen-09427-cover
Mullard A (2017) FDA approves first deuterated drug. Nat Rev Drug Discov 16:305. https://doi.org/10.1038/nrd.2017.89
Radajewski S, Ineson P, Parekh NR, Murrell JC (2000) Stable-isotope probing as a tool in microbial ecology. Nature 403:646–649. https://doi.org/10.1038/35001054
Foster AB (1984) Deuterium isotope effects in studies of drug metabolism. Trends Pharmacol Sci 5:524–527. https://doi.org/10.1016/0165-6147(84)90534-0
Krumbiegel P (2011) Large deuterium isotope effects and their use: a historical review. Isot Environ Health Stud 47:1–17. https://doi.org/10.1080/10256016.2011.556725
Nelson SD, Trager WF (2003) The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab Dispos 31:1481–1498. https://doi.org/10.1124/dmd.31.12.1481
Sharma R, Strelevitz TJ, Gao H, Clark AJ, Schildknegt K, Obach RS, Ripp SL, Spracklin DK, Tremaine LM, Vaz ADN (2012) Deuterium isotope effects on drug pharmacokinetics. I. System-dependent effects of specific deuteration with aldehyde oxidase cleared drugs. Drug Metab Dispos 40:625–634. https://doi.org/10.1124/dmd.111.042770
Kushner DJ, Baker A, Dunstall TG (1999) Pharmacological uses and perspectives of heavy water and deuterated compounds. Can J Physiol Pharma 77:79–88. https://doi.org/10.1139/y99-005
Tung R (2010) The development of deuterium-containing drugs. Innov Pharm Technol 32:24–28. https://doi.org/10.1177/0963721414547414
Howland RH (2015) Deuterated drugs. J Psychosoc Nurs Men 53:13–16. https://doi.org/10.3928/02793695-20150821-55
Bruix J, Gores GJ, Mazzaferro V (2014) Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 63:844–855. https://doi.org/10.1136/gutjnl-2013-306627
Tejeda-Maldonado J, García-Juárez I, Aguirre-Valadez J, González-Aguirre A, Vilatobá-Chapa M, Armengol-Alonso A, Escobar-Penagos F, Torre A, Sánchez-Ávila JF, Carrillo-Pérez DL (2015) Diagnosis and treatment of hepatocellular carcinoma: an update. World J Hepatol 7:362–376. https://doi.org/10.4254/wjh.v7.i3.362
Dutta R, Mahato R (2017) Recent advances in hepatocellular carcinoma therapy. Pharmacol Ther 173:106–117. https://doi.org/10.1016/j.pharmthera.2017.02.010
Keating GM, Santoro A (2012) Sorafenib. Drugs 69:223–240. https://doi.org/10.2165/00003495-200969020-00006
Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, Marais R (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140:209–221. https://doi.org/10.1016/j.cell.2009.12.040
Liu L, Cao YC, Chen C, Zhang XM, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66:11851–11858. https://doi.org/10.1158/0008-5472.CAN-06-1377
Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL (2010) Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res 16:5189–5199. https://doi.org/10.1158/1078-0432.CCR-09-3389
Llovet JM, Ricci S, Mazzaferro V (2008) Sorafenib in advanced hepatocellular carcinoma. New Engl J Med 359:378–390. https://doi.org/10.1056/NEJMoa0708857
Xing L, Sheng Z, Wu G, Lu H (2011) Preparation of deuterium-substituted ω-diphenylurea derivatives as antitumor agents. WO2011113203A1
Reig M, Fonseca LGD, Faivre S (2018) New trials and results in systemic treatment of HCC. J Hepatol 69:525–533. https://doi.org/10.1016/j.jhep.2018.03.028
Raevsky OA (2004) Physicochemical descriptors in property-based drug design. Mini-Rev Med Chem 4:1041–1052. https://doi.org/10.2174/1389557043402964
Feng W, Gao X, Dai X (2012) A process for preparing deuterated sorafenib derivatives. CN102675018A
Acknowledgements
This work was supported by “Zhufeng Scholar Program” of Ocean University of China (841412016) and Aoshan Talents Cultivation Program of Qingdao National Laboratory for Marine Science and Technology (No. 2017ASTCP-OS08) to Dr. Wenbao Li.
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Zhong, L., Hou, C., Zhang, L. et al. Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities. Mol Divers 23, 341–350 (2019). https://doi.org/10.1007/s11030-018-9875-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11030-018-9875-7