Abstract
A class of phosphane gold(I) compounds, made of azoles and phosphane ligands, was evaluated for a screening on the regards of Breast Cancer cell panels (BC). The compounds possess N-Au-P or Cl-Au-P bonds around the central metal, and they differ for the presence of aprotic or protic polar groups in the azoles and/or the phosphane moieties to tune their hydrophilicity. Among the six candidates, only the compounds having the P-Au-N environment and not displaying neither the hydroxyl nor carboxyl groups in the ligands were found active. The compounds were screened by MTT tests in SKBR3, A17, and MDA-MB231 cancer cells, and two compounds (namely the 4,5-dicyano-imidazolate-1yl-gold(I)-(triphenylphosphane, 5, and 4,5-dichloro-imidazolate-1yl-gold(I)-triphenylphosphane, 6) were found very cytotoxic, with the most active with an IC50 value of 3.46 μM in MDA-MB231 cells. By performing enzymatic assays in the treated cells lysates, the residual enzymatic activity of dihydrofolate reductase (DHFR) has been measured after cell treatment for 4 or 12 h in comparison with control cells. Upon 12 h of treatment, the activity of DHFR was significantly reduced in both SKBR3 and A17 cells by compounds 5 and 6, but not in human MDA-MB231 cells; interestingly, it was found remarkably high after 4 h of treatment, revealing a time dependence for the DHFR enzymatic assays. The DHFR inhibition data have been compared to those for the thioredoxin reductase (TrxR), the most recognized molecular target for gold compounds. For this latter, similar residual activities (i.e., 37 and 49% for the match of SKBR3 cells and compound 5 or 6, respectively) were found. Binding studies on the regards of ct-DNA (calf-thymus-DNA) and of plasma transporters proteins, such as BSA (bovine serum albumin) and ATF (apo transferrin), were performed. As expected for gold compounds, the data support strong binding to proteins (Ksv values range: 1.51 ÷ 2.46 × 104 M−1) and a weaker interaction with ct-DNA's minor groove (Ksv values range: 1.55 ÷ 6.12 × 103 M−1).
Highlights
Breast Cancer (BC) is the second most frequent cancer worldwide and, by far, the most recurrent cancer among the female gender with the esteem of 2.1 million new cases detected in 2018 (25% of all cancers) (Bray et al, 2018)
The IR spectrum displays a large band attributable to the OH group centered at 3226 cm−1 and a band at 1631 cm−1 which appears 52 cm−1 redshifted from the 1683 cm−1 carbonyl band of the starting 2-COOH-Ph2PAuCl; the overall 1H NMR patterns and the ESI(–) and ESI(+) MS peaks at 599 and 600 m/z, attributed to [M]− and [M + H]+ ions, respectively, are diagnostic for the molecular structure of compound 3 reported in Scheme 1
A class of azolate/phosphane gold(I) compounds has been evaluated for a screening on the regards of BC cell panels
Summary
Breast Cancer (BC) is the second most frequent cancer worldwide and, by far, the most recurrent cancer among the female gender with the esteem of 2.1 million new cases detected in 2018 (25% of all cancers) (Bray et al, 2018). HER2 overexpression is associated with poor prognosis, but HER2+ BC patients can be treated with HER2-targeted therapies, such as the monoclonal antibodies trastuzumab and pertuzumab, the antibody-drug conjugate trastuzumab emtansine (T-DM1), and the tyrosine kinase inhibitor lapatinib, alone or in combination with chemotherapy (see Table 1). These targeted treatments improve patient overall survival but drug resistance mechanisms often compromise their long-term effectiveness and most patients eventually relapse. BLBC is treated with a combination of surgery, radiotherapy and chemotherapy (Schwentner et al, 2012; Nakai et al, 2016; Zheng et al, 2018), that is often not successful against metastatic
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