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Biscarbene gold(i) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability.

ABSTRACT: A series of gold(i) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepared and evaluated for their effects against cancer cells and pathogenic bacteria. Proliferation inhibition was observed in cancer cells and in Gram-positive bacteria, whereas Gram-negative bacteria were less sensitive towards the compounds. The protein binding and cellular uptake were quantified and the combined results indicated a strong correlation between cellular bioavailability and antiproliferative effects. The biscarbene gold complexes inhibited bacterial and mammalian TrxRs with low to moderate potency. However, based on the obtained structure-activity-relationships and the high cellular accumulation levels, TrxR inhibition can be considered as a relevant contributor to the cellular pharmacology of biscarbene gold(i) complexes.

SUBMITTER: Schmidt C

PROVIDER: S-EPMC6072206 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Biscarbene gold(i) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability.

Schmidt Claudia C Karge Bianka B Misgeld Rainer R Prokop Aram A Brönstrup Mark M Ott Ingo I

MedChemComm 20170627 8

A series of gold(i) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepared and evaluated for their effects against cancer cells and pathogenic bacteria. Proliferation inhibition was observed in cancer cells and in Gram-positive bacteria, whereas Gram-negative bacteria were less sensitive towards the compounds. The protein binding and cellular uptake were quantified and the combined results indicated a strong correlation between cellular bioavailability and an ...[more]

PMID: 30108879

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Project description: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).

Project description:IntroductionMulti-drug resistance (MDR) is one of the leading reasons that cause the failures of cancer treatment. Novel agents that may reverse MDR and neutralize drug-resistant cancer cells are highly desirable for clinical practice. The targeting of cellular redox homeostasis and/or mitochondria-mediated energy metabolism are promising strategies for the suppression of drug-resistant cancer cells. Based on the structure of mono-gold(I) complex auranofin (AF), a drug candidate under clinical trials for cancer, we synthesized a new dual-gold(I) complex QB1561 and tested if it can inhibit drug-resistant cancer cells overexpressing ATP-binding cassette (ABC) transporters. We also investigated if QB1561 could inhibit thioredoxin reductase (TrxR), a well-known target of AF and other gold complexes, and assessed its impact on mitochondrial respiration.MethodologyCell viability of drug-resistant cells upon QB1561 alone or combined with topotecan and mitoxantrone was determined by MTS assay. The expression of ABC sub-family G member 2 (ABCG2) in the lung cancer cell line NCI-H460/MX20 after treatment with QB1561 was assessed by Western blot. The Vi-sensitive ABCG2 ATPase activity in the membrane vesicles of High Five insect cells, TrxR activity, and ROS production were measured following QB1561 treatment. Colony formation was used to assess QB1561's anticancer potential. SeaHorce Seahorse XF Analyzers were used to measure the oxygen consumption rate (OCR).ResultsQB1561 suppressed the proliferation of drug-resistant cancer cells overexpressing ABC transporters, with IC50 values ranging from 0.57 to 1.80 μM, which was more effective than AF. QB1561 was able to partially reverse the resistance of mitoxantrone and topotecan in lung cancer NCI-H460/MX20 cells which overexpressed ABCG2, without altering the expression levels of ABCG2. QB1561 suppressed the colony formation of NCI-H460/MX20 cells, probably via ROS induction due to TrxR inhibition. QB1561 also efficiently suppressed OCR, suggesting its inhibition on mitochondrial respiration.ConclusionQB1561 was effective for the treatment of MDR in drug-resistant cancer cells. Its further evaluation could be useful for the design and development of more gold-based anticancer drugs.

Dataset Information

Biscarbene gold(i) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability.

Publications

Biscarbene gold(i) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability.

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