The leaving group in Au(I)-phosphine compounds dictates cytotoxic pathways in CEM leukemia cells and reactivity towards a Cys(2)His(2) model zinc finger

Autor(es)

de Paiva, Raphael E. F. ^{[1, 2]} ; Peterson, Erica J. ^{[2, 3]} ; Du, Zhifeng ^{[2, 4]} ; Farrell, Nicholas P. ^{[2, 3]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Fundamental Chem, Inst Chem, BR-05508000 Sao Paulo, SP - Brazil

^[2] Virginia Commonwealth Univ, Dept Chem, Box 2006, Richmond, VA 23284 - USA

^[3] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23294 - USA

^[4] Huazhong Univ Sci & Technol, Tongji Sch Pharm, Wuhan 430030, Hubei - Peoples R China

• Tipo de documento: Artigo Científico
• Fonte: DALTON TRANSACTIONS; v. 49, n. 45, p. 16319-16328, DEC 7 2020.
• Citações Web of Science: 0

Resumo

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 mu M 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, Sp1ZnF3. (AU)

• Processo FAPESP: 18/21537-6 - Aplicações de ligantes imínicos polidentados na modulação da reatividade de íons cobre em doenças relacionadas a inflamação e em reações de acoplamento bio-ortogonais
• Beneficiário: Raphael Enoque Ferraz de Paiva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado