Evaluation of copper-dependent proteasome-inhibitory and apoptosis-inducing activities of novel pyrrolidine dithiocarbamate analogues

  • Authors:
    • Zhiyong Yu
    • Fei Wang
    • Vesna Milacic
    • Xiaofeng Li
    • Qiuzhi Cindy Cui
    • Bin Zhang
    • Bing Yan
    • Q. Ping Dou
  • View Affiliations

  • Published online on: December 1, 2007     https://doi.org/10.3892/ijmm.20.6.919
  • Pages: 919-925
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Abstract

Apoptosis has a central role in the pathogenesis of many human diseases, one of which is cancer. One of the most important strategies to regulate apoptosis is via the ubiquitin-proteasome pathway. It has been shown that inhibition of proteasomal chymotrypsin-like activity is a strong apoptosis-inducing stimulus and that actively proliferating cancer cells are more sensitive to proteasome inhibitors than normal or untransformed cells. Dithioscarbamates are a class of metal-chelating compounds with various applications in medicine. We reported previously that certain members of dithiocarbamates, such as pyrrolidine dithiocarbamate (PDTC), diethyldithiocarbamate and disulfiram, are able to bind with tumor cellular copper, forming an active complex with proteasome-inhibitory, apoptosis-inducing and anti-cancer activities. In the current study, we synthesized eight PDTC analogues with substitutions made to the pyrrolidine ring and studied their structure-activity relationships. We found that substitution of the pyrrolidine ring with piperidine had almost no effect on their proteasome-inhibitory and anti-proliferative potencies in human breast cancer cells. However, after the pyrrolidine ring was substituted with morpholine, the activity of the mixtures slightly decreased but was completely lost when piperazine with the attached ethyl group was used for the substitution. This structure-activity relationship was confirmed by the results generated with the corresponding copper complexes. Our data further support the novel concept of using accumulated copper in human cancer cells as a selective approach for chemotherapy.

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December 2007
Volume 20 Issue 6

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Yu Z, Wang F, Milacic V, Li X, Cui QC, Zhang B, Yan B and Dou QP: Evaluation of copper-dependent proteasome-inhibitory and apoptosis-inducing activities of novel pyrrolidine dithiocarbamate analogues. Int J Mol Med 20: 919-925, 2007
APA
Yu, Z., Wang, F., Milacic, V., Li, X., Cui, Q.C., Zhang, B. ... Dou, Q.P. (2007). Evaluation of copper-dependent proteasome-inhibitory and apoptosis-inducing activities of novel pyrrolidine dithiocarbamate analogues. International Journal of Molecular Medicine, 20, 919-925. https://doi.org/10.3892/ijmm.20.6.919
MLA
Yu, Z., Wang, F., Milacic, V., Li, X., Cui, Q. C., Zhang, B., Yan, B., Dou, Q. P."Evaluation of copper-dependent proteasome-inhibitory and apoptosis-inducing activities of novel pyrrolidine dithiocarbamate analogues". International Journal of Molecular Medicine 20.6 (2007): 919-925.
Chicago
Yu, Z., Wang, F., Milacic, V., Li, X., Cui, Q. C., Zhang, B., Yan, B., Dou, Q. P."Evaluation of copper-dependent proteasome-inhibitory and apoptosis-inducing activities of novel pyrrolidine dithiocarbamate analogues". International Journal of Molecular Medicine 20, no. 6 (2007): 919-925. https://doi.org/10.3892/ijmm.20.6.919