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The leaving group in Au(i)-phosphine compounds dictates cytotoxic pathways in CEM leukemia cells and reactivity towards a Cys2His2 model zinc finger.
Dalton Trans. 2020 May 20 [Online ahead of print]DT

Abstract

Gold(i)-phosphine "auranofin-like" compounds have been extensively explored as anticancer agents in the past decade. Although potent cytotoxic agents, the lack of selectivity towards tumorigenic vs. non-tumorigenic cell lines often hinders further application. Here we explore the cytotoxic effects of a series of (R3P)AuL compounds, evaluating both the effect of the basicity and bulkiness of the carrier phosphine (R = Et or Cy), and the leaving group L (Cl- vs. dmap). [Au(dmap)(Et3P)]+ had an IC50 of 0.32 μM against the CEM cell line, with good selectivity in relation to HUVEC. Flow cytometry indicates reduced G1 population and slight accumulation in G2, as opposed to auranofin, which induces a high population of cells with fragmented DNA. Protein expression profile sets [Au(dmap)(Et3P)]+ further apart from auranofin, with proteolytic degradation of caspase-3 and poly(ADP-ribose)-polymerase (PARP), DNA strand-break induced phosphorylation of Chk2 Thr68 and increased p53 ser15 phosphorylation. The cytoxicity and observable biological effects correlate directly with the reactivity trend observed when using the series of gold(i)-phosphine compounds for targeting a model zinc finger, Sp1 ZnF3.

Authors+Show Affiliations

Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo (USP), Sao Paulo, SP 05508-000, Brazil. raphael.enoque@gmail.com and Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA. npfarrell@vcu.edu.Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA. npfarrell@vcu.edu and The Massey Cancer Center, Virginia Commonwealth University, Richmond 23294, Virginia, USA.Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA. npfarrell@vcu.edu and Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284-2006, USA. npfarrell@vcu.edu and The Massey Cancer Center, Virginia Commonwealth University, Richmond 23294, Virginia, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32432260

Citation

de Paiva, Raphael E F., et al. "The Leaving Group in Au(i)-phosphine Compounds Dictates Cytotoxic Pathways in CEM Leukemia Cells and Reactivity Towards a Cys2His2 Model Zinc Finger." Dalton Transactions (Cambridge, England : 2003), 2020.
de Paiva REF, Peterson EJ, Du Z, et al. The leaving group in Au(i)-phosphine compounds dictates cytotoxic pathways in CEM leukemia cells and reactivity towards a Cys2His2 model zinc finger. Dalton Trans. 2020.
de Paiva, R. E. F., Peterson, E. J., Du, Z., & Farrell, N. P. (2020). The leaving group in Au(i)-phosphine compounds dictates cytotoxic pathways in CEM leukemia cells and reactivity towards a Cys2His2 model zinc finger. Dalton Transactions (Cambridge, England : 2003). https://doi.org/10.1039/d0dt01136c
de Paiva REF, et al. The Leaving Group in Au(i)-phosphine Compounds Dictates Cytotoxic Pathways in CEM Leukemia Cells and Reactivity Towards a Cys2His2 Model Zinc Finger. Dalton Trans. 2020 May 20; PubMed PMID: 32432260.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The leaving group in Au(i)-phosphine compounds dictates cytotoxic pathways in CEM leukemia cells and reactivity towards a Cys2His2 model zinc finger. AU - de Paiva,Raphael E F, AU - Peterson,Erica J, AU - Du,Zhifeng, AU - Farrell,Nicholas P, Y1 - 2020/05/20/ PY - 2020/5/21/entrez JF - Dalton transactions (Cambridge, England : 2003) JO - Dalton Trans N2 - Gold(i)-phosphine "auranofin-like" compounds have been extensively explored as anticancer agents in the past decade. Although potent cytotoxic agents, the lack of selectivity towards tumorigenic vs. non-tumorigenic cell lines often hinders further application. Here we explore the cytotoxic effects of a series of (R3P)AuL compounds, evaluating both the effect of the basicity and bulkiness of the carrier phosphine (R = Et or Cy), and the leaving group L (Cl- vs. dmap). [Au(dmap)(Et3P)]+ had an IC50 of 0.32 μM against the CEM cell line, with good selectivity in relation to HUVEC. Flow cytometry indicates reduced G1 population and slight accumulation in G2, as opposed to auranofin, which induces a high population of cells with fragmented DNA. Protein expression profile sets [Au(dmap)(Et3P)]+ further apart from auranofin, with proteolytic degradation of caspase-3 and poly(ADP-ribose)-polymerase (PARP), DNA strand-break induced phosphorylation of Chk2 Thr68 and increased p53 ser15 phosphorylation. The cytoxicity and observable biological effects correlate directly with the reactivity trend observed when using the series of gold(i)-phosphine compounds for targeting a model zinc finger, Sp1 ZnF3. SN - 1477-9234 UR - https://www.unboundmedicine.com/medline/citation/32432260/The_leaving_group_in_Au(i)-phosphine_compounds_dictates_cytotoxic_pathways_in_CEM_leukemia_cells_and_reactivity_towards_a_Cys2His2_model_zinc_finger L2 - https://doi.org/10.1039/d0dt01136c DB - PRIME DP - Unbound Medicine ER -
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