Synthesis and antitumor activities of novel rhein α-aminophosphonates conjugates

Gui-yang Yao; Man-yi Ye; Ri-zhen Huang; Ya-jun Li; Ying-ming Pan; Qing Xu; Zhi-xin Liao; Heng-shan Wang

doi:10.1016/j.bmcl.2013.12.030

Synthesis and antitumor activities of novel rhein α-aminophosphonates conjugates

Bioorg Med Chem Lett. 2014 Jan 15;24(2):501-7. doi: 10.1016/j.bmcl.2013.12.030. Epub 2013 Dec 16.

Authors

Gui-yang Yao¹, Man-yi Ye², Ri-zhen Huang², Ya-jun Li², Ying-ming Pan², Qing Xu³, Zhi-xin Liao⁴, Heng-shan Wang⁵

Affiliations

¹ State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Science of Guangxi Normal University, Guilin 541004, PR China; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
² State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Science of Guangxi Normal University, Guilin 541004, PR China.
³ College of Pharmacy, Guilin Medical University, Guilin 541004, PR China.
⁴ Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China. Electronic address: zxliao@seu.edu.cn.
⁵ State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Science of Guangxi Normal University, Guilin 541004, PR China. Electronic address: whengshan@163.com.

PMID: 24378217
DOI: 10.1016/j.bmcl.2013.12.030

Abstract

Several rhein α-aminophosphonates conjugates (5a-5q) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially, compound 5i exhibited the strongest cytotoxicity against Hct-116 cells (IC50 was 5.32 μM). All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. The mechanism of compound 5i was preliminarily investigated by Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound 5i induced apoptosis in Hct-116 cancer cells. Cell cycle analysis showed that these compound 5i mainly arrested Hct-116 cells in G1 stage. The effects of 5i on the activation of caspases expression indicated that 5i might induce apoptosis via the membrane death receptor pathways. In addition, the binding properties of a model analog 5i to DNA were investigated by methods (UV-vis, fluorescence, CD spectroscopy and FRET-melting) in compare with that of rhein. Results indicated that 5i showed moderate ability to interact ct-DNA.

Keywords: Apoptosis; Cytotoxicity; DNA binding; Rhein; Synthesis; α-Aminophosphonates.

Publication types

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

MeSH terms

Anthraquinones / chemical synthesis*
Anthraquinones / pharmacology
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Cycle Checkpoints / drug effects
Cell Cycle Checkpoints / physiology
HCT116 Cells
HeLa Cells
Hep G2 Cells
Humans
Organophosphonates / chemical synthesis*
Organophosphonates / pharmacology

Substances

Anthraquinones
Antineoplastic Agents
Organophosphonates
rhein