Gold(I)-Triphenylphosphine Complexes with Hypoxanthine-Derived Ligands: In Vitro Evaluations of Anticancer and Anti-Inflammatory Activities

Abstract

A series of gold(I) complexes involving triphenylphosphine (PPh3) and one N-donor ligand derived from deprotonated mono- or disubstituted hypoxanthine (HLn) of the general composition [Au(Ln)(PPh3)] (1–9) is reported. The complexes were thoroughly characterized, including multinuclear high resolution NMR spectroscopy as well as single crystal X-ray analysis (for complexes 1 and 3). The complexes were screened for their in vitro cytotoxicity against human cancer cell lines MCF7 (breast carcinoma), HOS (osteosarcoma) and THP-1 (monocytic leukaemia), which identified the complexes 4–6 as the most promising representatives, who antiproliferative activity was further tested against A549 (lung adenocarcinoma), G-361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) cell lines. Complexes 4–6 showed a significantly higher in vitro anticancer effect against the employed cancer cells, except for G-361, as compared with the commercially used anticancer drug cisplatin, with IC50 ≈ 1–30 µM. Anti-inflammatory activity was evaluated in vitro by the assessment of the ability of the complexes to modulate secretion of the pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in the lipopolysaccharide-activated macrophage-like THP-1 cell model. The results of this study identified the complexes as auspicious anti-inflammatory agents with similar or better activity as compared with the clinically applied gold-based antiarthritic drug Auranofin. In an effort to explore the possible mechanisms responsible for the biological effect, the products of interactions of selected complexes with sulfur-containing biomolecules (L-cysteine and reduced glutathione) were studied by means of the mass-spectrometry study.

In Vitro Antitumor Active Gold(I) Triphenylphosphane Complexes Containing 7-Azaindoles

“…The Au1–N1 and Au1–P1 bond lengths, as well as the P1–Au1–N1 bond angle values (see Table 2) fall within the ranges of 1.97–2.12 Å (average of 2.06(3) Å) and 2.21–2.28 Å (average of 2.235(8) Å), and 168.4–179.6° (average of 175(2)°), respectively, in agreement with similar triphenylphosphanegold(I) complexes containing heterocyclic N -donor ligands, e.g., [21,22,28], deposited in the Cambridge Crystallographic Data Centre (CCDC; version 5.37 updated to May 2016 [33]). For the previously reported X-ray structure of [Au(aza)(PPh 3 )] ( 1 in this work) [28], its P1–Au1–N1 bond angle value of 176.6° is consistent with the value of 7 , but differs markedly from that of 8 ′.…”

“…The complexes 1 – 8 were prepared in acetone from [AuCl(PPh 3 )] using a general procedure, as previously described in the literature for similar triphenylphosphanegold(I) complexes containing heterocyclic N -donor ligands different from 7-azaindole (Figure 1) [19,20,21,22,30]. The used 7-azaindoles (H n aza) were deprotonated in situ by an equimolar amount of NaOH.…”

“…Interestingly, although the A2780 cells are naturally sensitive to the biological action of various types of gold(I) complexes including the substituted-phosphane ones (low micromolar or even nanomolar range of the IC 50 values), the potency of the previously reported substituted-phosphanegold(I) complexes is usually comparable or only slightly higher than cisplatin [18,21,22,42,43,44,45]. In other words, the seven-fold higher in vitro anticancer activity of 8 against the A2780 cells seems to be, to the best of our knowledge, exceptional in the field of gold(I) complexes.…”

“…Recently, our research group reported the triphenylphosphanegold(I) complexes containing N 6-benzyladenine-, hypoxanthine- and 9-deazahypoxanthine-derived N -donor ligands (HL), [Au(L)(PPh 3 )], which exhibited high cytotoxicity, ability to overcome acquired resistance to cisplatin , selectivity towards cancer cells over the normal ones and/or high anti-inflammatory activity [19,20,21,22]. In this work, we report on new complexes of the general composition [Au( n aza)(PPh 3 )] ( 1 – 8 ) containing the N 1-deprotonated, C2-, C3-, C4-, and/or C5-substituted 7-azaindole-based ligands ( n aza; Figure 1).…”

Pleiotropic effects of gold(I) mixed-ligand complexes of 9-deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines

“…Among the above-mentioned metals, a due attention is focused on Au-complexes owing to their use in the treatment of rheumatoid arthritis, such as sodium aurothiomalate (Myochrysin ® , sodium ((2-carboxy-1-carboxylatoethyl)thiolato)gold(I)), aurothioglucose (Solganol ® , {(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-oxane-2-thiolato}gold(I) and Auranofin (Ridaura ® , triethylphosphine-(2,3,4,6-tetra-O-acetyl-b-D-thiopyranosato)gold [5e7]. Recently, we published a series of four works dealing with the study of antiinflammatory and anti-cancer properties of gold(I) complexes having the composition of [Au(L)(PPh) 3 ], where L stands for a deprotonated form of 6-benzylaminopurine [8,9], 9-deazahypoxanthine [10] and hypoxanthine derivatives [11]. Some of the presented compounds overcame the activity of Auranofin (in the case of anti-inflammatory activity) and cisplatin (in the case of anti-cancer activity) as reference compounds.…”