Monofunctional and Interstrand DNA Adducts of Platinum(II) Complexes

The effects produced in DNA by monofunctional or interstrand adducts of platinum(II) complexes have been summarized. The monofunctional adducts destabilize DNA in a sequence-dependent manner via conformational distortions, which may have a denaturational character. It has been suggested that this conformational alteration facilitates in DNA the formation of the bidentate DNA adducts, whose formation is associated with a permanent or transient local denaturation. In addition, DNA interstrand cross-linking by cis-diamminedichloroplatinum(II) and its trans isomer produce in DNA lesions that have quite different characteristics. It has been suggested that these differences may have relevance to the distinct antitumor efficacy of the two platinum isomers

Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates

We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs

Chiral discrimination in platinum anticancer drugs.

In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated

Conformation, protein recognition and repair of DNA interstrand and intrastrand cross-links of Antitumor trans-[PtCl(2)(NH(3))(thiazole)]

Replacement of one ammine in clinically ineffective trans-[PtCl(2)(NH(3))(2)] (transplatin) by a planar N-heterocycle, thiazole, results in significantly enhanced cytotoxicity. Unlike ‘classical’ cisplatin {cis-[PtCl(2)(NH(3))(2)]} or transplatin, modification of DNA by this prototypical cytotoxic transplatinum complex trans-[PtCl(2)(NH(3))(thiazole)] (trans-PtTz) leads to monofunctional and bifunctional intra or interstrand adducts in roughly equal proportions. DNA fragments containing site-specific bifunctional DNA adducts of trans-PtTz were prepared. The structural distortions induced in DNA by these adducts and their consequences for high-mobility group protein recognition, DNA polymerization and nucleotide excision repair were assessed in cell-free media by biochemical methods. Whereas monofunctional adducts of trans-PtTz behave similar to the major intrastrand adduct of cisplatin [J. Kasparkova, O. Novakova, N. Farrell and V. Brabec (2003) Biochemistry, 42, 792–800], bifunctional cross-links behave distinctly differently. The results suggest that the multiple DNA lesions available to trans-planaramine complexes may all contribute substantially to their cytotoxicity so that the overall drug cytotoxicity could be the sum of the contributions of each of these adducts. However, acquisition of drug resistance could be a relatively rare event, since it would have to entail resistance to or tolerance of multiple, structurally dissimilar DNA lesions

Somatostatin receptor-targeted organometallic iridium(III) complexes as novel theranostic agents

A novel somatostatin receptor-targeted anticancer agent based on the conjugation of a highly cytotoxic and luminiscent cyclometalated iridium(III) complex to tumor-targeting vectors based on octreotide peptide has been described, and its potential for targeted theranostic applications has been demonstrated

Photoactivatable organometallic pyridyl ruthenium(II) arene complexes

The synthesis and characterization of a family of piano-stool RuII arene complexes of the type [(η6-arene)Ru(N,N′)(L)][PF6]2, where arene is p-cymene (p-cym), hexamethylbenzene (hmb), or indane (ind), N,N′ is 2,2′-bipyrimidine (bpm), 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione (phendio), or 4,7-diphenyl-1,10-phenanthroline (bathophen), and L is pyridine (Py), 4-methylpyridine (4-MePy), 4-methoxypyridine (4-MeOPy), 4,4′-bipyridine (4,4′-bpy), 4-phenylpyridine (4-PhPy), 4-benzylpyridine (4-BzPy), 1,2,4-triazole (trz), 3-acetylpyridine (3-AcPy), nicotinamide (NA), or methyl nicotinate (MN), are reported, including the X-ray crystal structures of [(η6-p-cym)Ru(bpm)(4-MePy)]2+ (2), [(η6-p-cym)Ru(bpm)(4-BzPy)]2+ (6), [(η6-p-cym)Ru(bpm)(trz)]2+ (7), [(η6-p-cym)Ru(phen)(Py)]2+ (10), and [(η6-ind)Ru(bpy)(Py)]2+ (13). These complexes can selectively photodissociate the monodentate ligand (L) when excited with UVA or white light, allowing strict control of the formation of the reactive aqua species [(η6-arene)Ru(N,N′)(OH2)]2+ that otherwise would not form in the dark. The photoproducts were characterized by UV–vis absorption and 1H NMR spectroscopy. DFT and TD-DFT calculations were employed to characterize the excited states and to obtain information on the photochemistry of the complexes. All the RuII pyridine complexes follow a relatively similar photochemical L-ligand dissociation mechanism, likely to occur from a series of 3MC triplet states with dissociative character. The photochemical process proved to be much more efficient when UVA-range irradiation was used. More strikingly, light activation was used to phototrigger binding of these potential anticancer agents with discriminating preference toward 9-ethylguanine (9-EtG) over 9-ethyladenine (9-EtA). Calf thymus (CT)-DNA binding studies showed that the irradiated complexes bind to CT-DNA, whereas the nonirradiated forms bind negligibly. Studies of CT-DNA interactions in cell-free media suggest combined weak monofunctional coordinative and intercalative binding modes. The RuII arene complexes [(η6-p-cym)Ru(bpm)(Py)]2+ (1), [(η6-p-cym)Ru(bpm)(4-MeOPy)]2+ (3), [(η6-p-cym)Ru(4,4′-bpy)]2+ (4), [(η6-hmb)Ru(bpm)(Py)]2+ (8), [(η6-ind)Ru(bpm)(Py)]2+ (9), [(η6-p-cym)Ru(phen)(Py)]2+ (10), [(η6-p-cym)Ru(bathophen)(Py)]2+ (12), [(η6-p-cym)Ru(bpm)(NA)]2+ (15), and [(η6-p-cym)Ru(bpm)(MN)]2+ (16) were cytotoxic toward A2780 human ovarian cancer cell line in the absence of photoirradiation (IC50 values in the range of 9.0–60 μM)

Bipyrimidine ruthenium(II) arene complexes : structure, reactivity and cytotoxicity

The synthesis and characterization of complexes [(η6-arene)Ru(N,N′)X][PF6], where arene is para-cymene (p-cym), biphenyl (bip), ethyl benzoate (etb), hexamethylbenzene (hmb), indane (ind) or 1,2,3,4-tetrahydronaphthalene (thn), N,N′ is 2,2′-bipyrimidine (bpm) and X is Cl, Br or I, are reported, including the X-ray crystal structures of [(η6-p-cym)Ru(bpm)I][PF6], [(η6-bip)Ru(bpm)Cl][PF6], [(η6-bip)Ru(bpm)I][PF6] and [(η6-etb)Ru(bpm)Cl][PF6]. Complexes in which N,N′ is 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione or 4,7-diphenyl-1,10-phenanthroline (bathophen) were studied for comparison. The RuII arene complexes undergo ligand-exchange reactions in aqueous solution at 310 K; their half-lives for hydrolysis range from 14 to 715 min. Density functional theory calculations on [(η6-p-cym)Ru(bpm)Cl][PF6], [(η6-p-cym)Ru(bpm)Br][PF6], [(η6-p-cym)Ru(bpm)I][PF6], [(η6-bip)Ru(bpm)Cl][PF6], [(η6-bip)Ru(bpm)Br][PF6] and [(η6-bip)Ru(bpm)I][PF6] suggest that aquation occurs via an associative pathway and that the reaction is thermodynamically favourable when the leaving ligand is I > Br ≈ Cl. pK a* values for the aqua adducts of the complexes range from 6.9 to 7.32. A binding preference for 9-ethylguanine (9-EtG) compared with 9-ethyladenine (9-EtA) was observed for [(η6-p-cym)Ru(bpm)Cl][PF6], [(η6-hmb)Ru(bpm)Cl]+, [(η6-ind)Ru(bpm)Cl]+, [(η6-thn)Ru(bpm)Cl]+, [(η6-p-cym)Ru(phen)Cl]+ and [(η6-p-cym)Ru(bathophen)Cl]+ in aqueous solution at 310 K. The X-ray crystal structure of the guanine complex [(η6-p-cym)Ru(bpm)(9-EtG-N7)][PF6]2 shows multiple hydrogen bonding. Density functional theory calculations show that the 9-EtG adducts of all complexes are thermodynamically preferred compared with those of 9-EtA. However, the bmp complexes are inactive towards A2780 human ovarian cancer cells. Calf thymus DNA interactions for [(η6-p-cym)Ru(bpm)Cl][PF6] and [(η6-p-cym)Ru(phen)Cl][PF6] consist of weak coordinative, intercalative and monofunctional coordination. Binding to biomolecules such as glutathione may play a role in deactivating the bpm complexes

Fe II metallohelices stabilize DNA G‐quadruplexes and downregulate the expression of G‐quadruplex‐regulated oncogenes

DNA G-quadruplexes (G4s) have been identified within the promoter regions of many proto-oncogenes. Thus, G4s represent attractive targets for cancer therapy, and the design and development of new drugs as G4 binders is a very active field of medicinal chemistry. Here, molecular biophysics and biology methods were employed to investigate the interaction of chiral metallohelices with a series of four DNA G4s (hTelo, c-myc, c-kit1, c-kit2) that are formed by the human telomeric sequence (hTelo) and in the promoter regions of c-MYC and c-KIT proto-oncogenes. We show that the investigated water-compatible, optically pure metallohelices, which are made by self-assembly of simple nonpeptidic organic components around FeII ions and exhibit bioactivity emulating the natural systems, bind with high affinity to G4 DNA and much lower affinity to duplex DNA. Notably, both enantiomers of a metallohelix containing a m-xylenyl bridge (5 b) were found to effectively inhibit primer elongation catalyzed by Taq DNA polymerase by stabilizing G4 structures formed in the template strands containing c-myc and c-kit2 G4-forming sequences. Moreover, both enantiomers of 5 b downregulated the expression of c-MYC and c-KIT oncogenes in human embryonic kidney cells at mRNA and protein levels. As metallohelices also bind alternative nucleic acid structures, they hold promise as potential multitargeted drugs

A cyclometallated IrIII complex conjugated to a coumarin derivative is a potent photodynamic agent against prostate differentiated and tumorigenic cancer stem cells

A cyclometalated IrIII complex conjugated to a far-red-emitting coumarin, IrIII-COUPY (3), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis. Herein, we show, using DU145 tumor cells, taken as the model of hormone-refractory and aggressive prostate cancer cells resistant to conventional antineoplastic drugs, that the photoactivated conjugate 3 very efficiently eliminates both prostate bulk, differentiated and prostate, hardly treatable CSCs simultaneously and with a similar efficiency. Notably, the very low toxicity of IrIII-COUPY conjugate in the prostate DU145 cells in the dark and its pronounced selectivity for tumor cells compared with noncancerous cells could result in low side effects and reduced damage of healthy cells during the photoactivated therapy by this agent. Moreover, the experiments performed with the 3D spheroids formed from DU145 CSCs showed that conjugate 3 can penetrate the inner layers of tumorspheres, which might markedly increase its therapeutic effect. Also interestingly, this conjugate induces apoptotic cell death in prostate cancer DU145 cells associated with calcium signaling flux in these cells and autophagy. To the best of our knowledge, this is the first study demonstrating that a photoactivatable metal-based compound is an efficient agent capable of killing even hardly treatable CSC

Walking of antitumor bifunctional trinuclear PtII complex on double-helical DNA

The trinuclear BBR3464 ([{trans-PtCl(NH3)2}2µ-(trans-Pt(NH3)2(H2N(CH2)6NH2)2)]4+) belongs to the polynuclear class of platinum-based anticancer agents. DNA adducts of this complex differ significantly in structure and type from those of clinically used mononuclear platinum complexes, especially, long-range (Pt, Pt) intrastrand and interstrand cross-links are formed in both 5′–5′ and 3′–3′ orientations. We show employing short oligonucleotide duplexes containing single, site-specific cross-links of BBR3464 and gel electrophoresis that in contrast to major DNA adducts of clinically used platinum complexes, under physiological conditions the coordination bonds between platinum and N7 of G residues involved in the cross-links of BBR3464 can be cleaved. This cleavage may lead to the linkage isomerization reactions between this metallodrug and double-helical DNA. Differential scanning calorimetry of duplexes containing single, site-specific cross-links of BBR3464 reveals that one of the driving forces that leads to the lability of DNA cross-links of this metallodrug is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule