The present paper review the drug-DNA interactions, their types and applications of experimental techniques used to study interactions between DNA and small ligand molecules that are potentially of pharmaceutical interest. DNA has been known to be the cellular target for many cytotoxic anticancer agents for several decades. Understanding how drug molecules interact with DNA has become an active research area at the interface between chemistry, molecular biology and medicine. In this review article, we attempt to bring together topics that cover the breadth of this large area of research. The interaction of drugs with DNA is a significant feature in pharmacology and plays a vital role in the determination of the mechanisms of drug action and designing of more efficient and specifically targeted drugs with lesser side effects. Several instrumental techniques are used to study such interactions. In the present review, we will discuss UV-Visible spectroscopy, fluorescence spectroscopy and cyclic voltammetry. The applications of spectroscopic techniques are reviewed and we have discussed the type of information (qualitative or quantitative) that can be obtained from the use of each technique. Not only have novel techniques been applied to study drug-DNA interactions but such interactions may also be the basis for the development of new assays. The interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases.

Drug-DNA interactions and their study by UV-Visible, fluorescence spectroscopies and cyclic voltametry.

Metal-based antitumor drugs play a relevant role in antiblastic chemotherapy. Cisplatin is regarded as one of the most effective drugs, even if severe toxicities and drug resistance phenomena limit its clinical use. Therefore, in recent years there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity. The variety of metal ion functions in biology has stimulated the development of new metallodrugs other than Pt drugs with the aim to obtain compounds acting via alternative mechanisms of action. Among non-Pt compounds, copper complexes are potentially attractive as anticancer agents. Actually, since many years a lot of researches have actively investigated copper compounds based on the assumption proposal that endogenous metals may be less toxic. It has been established that the properties of copper-coordinated compounds are largely determined by the nature of ligands and donor atoms bound to the metal ion. In this review, the most remarkable achievements in the design and development of copper(I, II) complexes as antitumor agents are discussed. Special emphasis has been focused on the identification of structure-activity relationships for the different classes of copper(I,II) complexes. This work was motivated by the observation that no comprehensive surveys of copper complexes as anticancer agents were available in the literature. Moreover, up to now, despite the enormous efforts in synthesizing different classes of copper complexes, very few data concerning the molecular basis of the mechanisms underlying their antitumor activity are available. This overview, collecting the most significant strategies adopted in the last ten years to design promising anticancer copper(I,II) compounds, would be a help to the researchers working in this field.

Copper complexes as anticancer agents

The copper(II) complex [Cu(tdp)(ClO4)].0.5H2O (1), where H(tdp) is the tetradentate ligand 2-[(2-(2-hydroxyethylamino)ethylimino)methyl]phenol, and the mixed ligand complexes [Cu(tdp)(diimine)]+ (2-5), where diimine is 2,2'-bipyridine (bpy) (2), 1,10-phenanthroline (phen) (3), 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) (4), and dipyrido-[3,2-d:2',3'-f]-quinoxaline (dpq) (5), have been isolated and characterized by analytical and spectral methods. Complexes 1 and [Cu(tdp)(phen)]ClO4 (3) have been structurally characterized, and their coordination geometries around copper(II) are described as distorted octahedral. The equatorially coordinated ethanolic oxygen in 1 is displaced to an axial position upon incorporating the strongly chelating phen, as in 3. The solution structures of all the complexes have been assessed to be square-based using electronic absorption and electron paramagnetic resonance (EPR) spectroscopy. The interaction of the complexes with calf thymus DNA (CT DNA) has been explored by using absorption, emission, and circular dichroic spectral and viscometric studies, and modes of DNA binding for the complexes have been proposed. Absorption spectral (Kb = 0.071 +/- 0.005 (2), 0.90 +/- 0.03 (3), 7.0 +/- 0.2 (4), 9.0 +/- 0.1 x 10(5) M(-1) (5)), emission spectral (Kapp = 4.6 (1), 7.8 (2), 10.0 (3), 12.5 (4), 25.0 x 10(5) M(-1) (5)), and viscosity measurements reveal that 5 interacts with DNA more strongly than the other complexes through partial intercalation of the extended planar ring of the coordinated dpq with the DNA base stack. Interestingly, only complex 4 causes a B to A conformational change upon binding DNA. All the complexes hydrolytically cleave pBR322 supercoiled DNA in 10% DMF/5 mM Tris-HCl/50 mM NaCl buffer at pH 7.1 in the absence of an activating agent, and the cleavage efficiency varies in the order 5 > 3 > 2 > 4 > 1 with 5 displaying the highest Kcat value (5.47 +/- 0.10 h(-1)). The same order of cleavage is observed for the oxidative cleavage of DNA in the presence of ascorbic acid as a reducing agent. Interestingly, of all the complexes, only 5 displays efficient photonuclease activity through double-strand DNA breaks upon irradiation with 365 nm light through a mechanistic pathway involving hydroxyl radicals. The protein binding ability of 1-5 has been also monitored by using the plasma protein bovine serum albumin (BSA), and 4 exhibits a protein binding higher than that of the other complexes. Further, the anticancer activity of the complexes on human cervical epidermoid carcinoma cell line (ME180) has been examined. Interestingly, the observed IC50 values reveal that complex 4, which effects conformational change on DNA and binds to BSA more strongly, exhibits a cytotoxicity higher than the other complexes. It also exhibits approximately 100 and 6 times more potency than cisplatin and mitomycin C for 24 and 48 h incubation times, respectively, suggesting that 4 can be explored further as a potential anticancer drug. Complexes 4 and 5 mediate the arrest of S and G2/M phases in the cell cycle progression at 24 h harvesting time, which progress into apoptosis.

Mixed-Ligand Copper(II)-phenolate Complexes: Effect of Coligand on Enhanced DNA and Protein Binding, DNA Cleavage, and Anticancer Activity

Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that contains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization and DNA repair. In this review, we have summarized our knowledge on quinoline compounds with respect to their anticancer activities, mechanisms of action, structure-activity relationship (SAR), and selective and specific activity against various cancer drug targets. In particular, we focus our review on in vitro and in vivo anticancer activities of quinoline and its analogs in the context of cancer drug development and refinement.

Quinoline as a Privileged Scaffold in Cancer Drug Discovery

Electrochemical sensing of heavy metal ions with inorganic, organic and bio-materials.

A novel cytotoxic ternary copper(II) complex of 1,10-phenanthroline and L-threonine with DNA nuclease activity.

A novel trinuclear copper(II) complex, Cu3-L (L = N,N,N‘,N‘,N‘ ‘,N‘ ‘-hexakis(2-pyridyl)-1,3,5-tris(aminomethyl)benzene), exhibited efficient oxidative strand scission of plasmid DNA. The solution ...

Oxidative DNA strand scission induced by a trinuclear copper(II) complex.

Crystal structure, DNA-binding ability and cytotoxic activity of platinum(II) 2,2′-dipyridylamine complexes

Three novel gold(III) complexes [Au(Quinpy)Cl]Cl (1), [Au(Quingly)Cl]Cl (2) and [Au(Quinala)Cl]Cl (3) [N-(8-quinolyl)pyridine-2-carboxamide = HQuinpy; N-(8-quinolyl)glycine-carboxamide = HQuingly; N-(8-quinolyl)-L-alanine-carboxamide = HQuinala] have been synthesized and characterized. The crystal structures of complexes 2 and 3 reveal that Au(III) is coordinated by three N atoms from the ligand and one Cl− anion. Complex 2 crystallized in the monoclinic system while complex 3 crystallized in the orthorhombic system. The complexes were tested against a series of tumour cell lines including B16-BL6, P388, HL-60, A-549 and BEL-7402. The data show that complex 1 is highly cytotoxic against the A-549 cells with an inhibition rate of 94.4% at a concentration of 10−6 mol L−1. Complex 3 is active against B16-BL6 with an inhibition rate of 67.52% at a concentration of 10−7 mol L−1. The interactions of complexes 1–3 with calf thymus (CT) DNA and 5′-GMP were investigated by UV-vis, fluorescence and ESMS spectroscopies. The data show that the interaction between Au(III) complexes and CT-DNA may be the intercalation effect, and complex 3 forms a 5′-GMP adduct as detected by ESMS.

Novel Au(III) complexes of aminoquinoline derivatives: crystal structure, DNA binding and cytotoxicity against melanoma and lung tumour cells

A novel hexadentate ligand, N,N,N',N',N",N"-hexa(2-pyridyl)-1,3,5-tris(aminomethyl)benzene (L), was designed and synthesized. The X-ray structure analysis reveals that the three dipyridylamine (DPA) groups of L are almost perpendicular to the central trimethylenebenzene, and two of them are spacially close to each other while the third one is further apart. The trinuclear Pt(II) complexes [Pt(3)LCl(6)] (1) and [Pt(3)L(CBDCA)(3)] (2) (where CBDCA represents cyclobutane dicarboxylic acid) were prepared and fully characterized by IR, NMR, and ESMS spectroscopy. A mononuclear complex, [PtL(CBDCA)] (3), was also prepared and structurally characterized, which suggests that controlled formation of mono-, di-, and trinuclear complexes with L is possible. Spectroscopic data showed that complexes 2 and 3 are able to bind to calf thymus DNA and their CBDCA group can be readily replaced by thiourea.

Toward the design of novel polynuclear platinum antitumor complexes: a polydentate ligand system based on dipyridylamine and 1,3,5-trimethylenebenzene.

Chao Tu

Papers

A novel cytotoxic ternary copper(II) complex of 1,10-phenanthroline and L-threonine with DNA nuclease activity.

Oxidative DNA strand scission induced by a trinuclear copper(II) complex.

Crystal structure, DNA-binding ability and cytotoxic activity of platinum(II) 2,2′-dipyridylamine complexes

Novel Au(III) complexes of aminoquinoline derivatives: crystal structure, DNA binding and cytotoxicity against melanoma and lung tumour cells

Toward the design of novel polynuclear platinum antitumor complexes: a polydentate ligand system based on dipyridylamine and 1,3,5-trimethylenebenzene.