Synthesis, Biological and Pharmacokinetic Characterization of a Novel Leucine Ureido Derivative As a Multi-target Anticancer Agent

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2025 Feb 11

PMID 39931415

Authors

Fangyuan Shi

Qifu Xu

Yingjie Zhang

Jiangying Cao

Chunxi Liu

Anchang Liu

Affiliations

Soon will be listed here.

Abstract

Previously, a novel series of leucine ureido derivatives containing the 1,2,3-triazole moiety were identified and validated as potent aminopeptidase N inhibitors with marked and antitumor potencies. Moreover, synergistic anti-proliferation effects against tumor cells were found when used in combination with 5-Fluorouracil (5-FU). Herein, a novel leucine ureido derivative (compound 3) was synthesized by coupling cytotoxic agent 5-FU with leucine ureido derivatives containing the 1,2,3-triazole moiety esterification. The biological activity evaluation showed that compound 3 exhibited more potent anti-proliferative, anti-metastatic, anti-angiogenic activities than the positive control bestatin. Furthermore, it was observed that compound 3 was very stable in simulated gastric fluid, while slowly cleaved in simulated intestinal fluid. pharmacokinetic study displayed that compound 3 was absorbed quickly after oral administration in rats and maintained for a long time, but exhibited poor oral bioavailability. Generally speaking, compound 3 is a promising lead for further development of more potent analogs as anticancer agents.

References

Tian Z, DU G, Xie S, Zhao J, Gao W, Wang C . Synthesis and bioevaluation of 5-fluorouracil derivatives. Molecules. 2007; 12(11):2450-7. PMC: 6149112. DOI: 10.3390/12112450. View

Chen Z, Han L, Xu M, Xu Y, Qian X . Rationally designed multitarget anticancer agents. Curr Med Chem. 2013; 20(13):1694-714. DOI: 10.2174/0929867311320130009. View

Pan X, Wang C, Wang F, Li P, Hu Z, Shan Y . Development of 5-Fluorouracil derivatives as anticancer agents. Curr Med Chem. 2011; 18(29):4538-56. DOI: 10.2174/092986711797287584. View

Mina-Osorio P . The moonlighting enzyme CD13: old and new functions to target. Trends Mol Med. 2008; 14(8):361-71. PMC: 7106361. DOI: 10.1016/j.molmed.2008.06.003. View

Espinoza-Fonseca L . The benefits of the multi-target approach in drug design and discovery. Bioorg Med Chem. 2005; 14(4):896-7. DOI: 10.1016/j.bmc.2005.09.011. View

Luan Y, Xu W . The structure and main functions of aminopeptidase N. Curr Med Chem. 2007; 14(6):639-47. DOI: 10.2174/092986707780059571. View

Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim H . CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010; 120(9):3326-39. PMC: 2929722. DOI: 10.1172/JCI42550. View

Amin S, Adhikari N, Jha T . Design of Aminopeptidase N Inhibitors as Anti-cancer Agents. J Med Chem. 2018; 61(15):6468-6490. DOI: 10.1021/acs.jmedchem.7b00782. View

Mucha A, Drag M, Dalton J, Kafarski P . Metallo-aminopeptidase inhibitors. Biochimie. 2010; 92(11):1509-29. PMC: 7117057. DOI: 10.1016/j.biochi.2010.04.026. View

10.

Rawlings N, Barrett A . MEROPS: the peptidase database. Nucleic Acids Res. 1998; 27(1):325-31. PMC: 148173. DOI: 10.1093/nar/27.1.325. View

11.

Lis M, Szczypka M, Suszko A, Obminska-Mrukowicz B . Influence of bestatin, an inhibitor of aminopeptidases, on T and B lymphocyte subsets in mice. Pol J Vet Sci. 2011; 14(3):393-403. DOI: 10.2478/v10181-011-0059-y. View

12.

Antczak C, De Meester I, Bauvois B . Ectopeptidases in pathophysiology. Bioessays. 2001; 23(3):251-60. PMC: 7161874. DOI: 10.1002/1521-1878(200103)23:3<251::AID-BIES1035>3.0.CO;2-O. View

13.

Guzman-Rojas L, Rangel R, Salameh A, Edwards J, Dondossola E, Kim Y . Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment. Proc Natl Acad Sci U S A. 2012; 109(5):1637-42. PMC: 3277167. DOI: 10.1073/pnas.1120790109. View

14.

Shimma N, Umeda I, Arasaki M, Murasaki C, Masubuchi K, Kohchi Y . The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine. Bioorg Med Chem. 2000; 8(7):1697-706. DOI: 10.1016/s0968-0896(00)00087-0. View

15.

Tokuhara T, Hattori N, Ishida H, Hirai T, Higashiyama M, Kodama K . Clinical significance of aminopeptidase N in non-small cell lung cancer. Clin Cancer Res. 2006; 12(13):3971-8. DOI: 10.1158/1078-0432.CCR-06-0338. View

16.

Cao J, Ma C, Zang J, Gao S, Gao Q, Kong X . Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry. Bioorg Med Chem. 2018; 26(12):3145-3157. DOI: 10.1016/j.bmc.2018.04.041. View

17.

Mishima Y, Terui Y, Sugimura N, Matsumoto-Mishima Y, Rokudai A, Kuniyoshi R . Continuous treatment of bestatin induces anti-angiogenic property in endothelial cells. Cancer Sci. 2007; 98(3):364-72. PMC: 11158285. DOI: 10.1111/j.1349-7006.2007.00393.x. View

18.

Aozuka Y, Koizumi K, Saitoh Y, Ueda Y, Sakurai H, Saiki I . Anti-tumor angiogenesis effect of aminopeptidase inhibitor bestatin against B16-BL6 melanoma cells orthotopically implanted into syngeneic mice. Cancer Lett. 2004; 216(1):35-42. DOI: 10.1016/j.canlet.2004.06.050. View

19.

Cao J, Zang J, Kong X, Zhao C, Chen T, Ran Y . Leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry. Part II. Bioorg Med Chem. 2019; 27(6):978-990. DOI: 10.1016/j.bmc.2019.01.041. View