Synthesis and evaluation of a class of 1,4,7-triazacyclononane derivatives as iron depletion antitumor agents

Sheng Wang; Yongkang Gai; Shasha Zhang; Lei Ke; Xiang Ma; Guangya Xiang

doi:10.1016/j.bmcl.2017.11.048

Synthesis and evaluation of a class of 1,4,7-triazacyclononane derivatives as iron depletion antitumor agents

Bioorg Med Chem Lett. 2018 Jan 15;28(2):117-121. doi: 10.1016/j.bmcl.2017.11.048. Epub 2017 Nov 28.

Authors

Sheng Wang¹, Yongkang Gai², Shasha Zhang¹, Lei Ke¹, Xiang Ma³, Guangya Xiang⁴

Affiliations

¹ School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
² Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
³ School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address: [email protected].
⁴ School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address: [email protected].

PMID: 29233652
DOI: 10.1016/j.bmcl.2017.11.048

Abstract

Iron depletion has been confirmed as an efficient strategy for cancer treatment. In the current study, a series of 1,4,7-triazacyclononane derivatives HE-NO2A, HP-NO2A and NE2P2A, as well as the bifunctional chelators p-NO₂-PhPr-NE3TA and p-NH₂-PhPr-NE3TA were synthesized and evaluated as iron-depleting agents for the potential anti-cancer therapy against human hepatocellular carcinoma. The cytotoxicity of these chelators was measured using hepatocellular cancer cells and compared with the clinically available iron depletion agent DFO and the universal metal chelator DTPA. All these 1,4,7-triazacyclononane-based chelators exhibited much stronger antiproliferative activity than DFO and DTPA. Among them, chelators with phenylpropyl side chains, represented by p-NO₂-PhPr-NE3TA and p-NH₂-PhPr-NE3TA, displayed the highest antiproliferative activity against HepG2 cells. Hence, these compounds are attractive candidates for the advanced study as iron depletion agents for the potential anti-cancer therapy, and could be further in conjugation with a targeting moiety for the future development in targeted iron depletion therapy.

Keywords: 1,4,7-Triazacyclononane derivatives; Antitumor agents; Iron deprivation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Chelating Agents / chemical synthesis
Chelating Agents / chemistry
Chelating Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Hep G2 Cells
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Humans
Iron / metabolism*
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Chelating Agents
Heterocyclic Compounds
1,4,7-triazacyclononane
Iron