Radiotracer studies of the antitumor metallocene molybdocene dichloride with biomolecules

Neutron irradiation of Cp₂MoCl₂ for 24 h afforded the radiotracer Cp₂⁹⁹MoCl₂ which was characterised by UV–Vis spectroscopy and thin layer chromatography. Binding experiments with the thiol containing protein human serum albumin (HSA) or calf thymus DNA, were monitored for ⁹⁹Mo using a gamma counter. Under the conditions investigated, molar ratios of binding of 0.2:1 (Cp₂MoCl₂:DNA) and 9.4:1 (Cp₂MoCl₂:HSA) were calculated. The results are consistent with in vitro coordination studies that have shown strong preferential interaction of Cp₂MoCl₂ with thiols versus other donor sites in biomolecules including DNA.     

Coordination chemistry of the antitumor metallocene molybdocene dichloride with biological ligands

The relative affinity of molybdocene dichloride (Cp(2)MoCl(2)) for the thiol, amino, carboxylate, phosphate(O) and heterocyclic(N) donor ligands present in amino acids and nucleotides, has been studied in aqueous solutions at pH 2-7, using (1)H, (13)C and (31)P NMR spectroscopy. Molybdocene dichloride forms the highly water soluble, air-stable complexes Cp(2)Mo(Cys)(2) and Cp(2)Mo(GS)(2) with cysteine and glutathione respectively, via coordination of the deprotonated thiol groups. While coordination to the imidazole nitrogen in histidine was observed, no evidence for coordination of the amino or carboxylate groups in the amino acids cysteine, histidine, alanine or lysine to Cp(2)MoCl(2) was detected. Competition experiments with dAMP, ribose monophosphate and histidine showed preferential coordination to the cysteine thiol over the phosphate(O) and heterocyclic(N) groups. Cp(2)Mo(Cys)(2) is stable in the presence of excess dAMP or ribose monophosphate and Cys displaces coordinated histidine, dAMP or ribose monophosphate to give Cp(2)Mo(Cys)(2). These results provide further evidence against interaction with DNA as the key interaction that is related to the antitumor activity of molybdocene dichloride. The implications of these results for the biological activity of the antitumor metallocene and the likely species formed in vivo are discussed.     

Spectroscopic study of the interaction of pazelliptine with nucleic acids

The antitumor drug pazelliptine (PZE) binds to natural and synthetic DNA sequences at 100 mM NaCl, pH 7.0, as deduced from the absorption and fluorescence data. Scatchard plots constructed from the results obtained with poly(dG-dC)-poly(dG-dC) give binding constants of base pairs in the range (2–6) × 10⁵ M⁻¹. The modifications in the absorption and fluorescence spectra observed when PZE binds to various polynucleotides, namely poly(dA-dT)-poly(dA-dT), poly(dA)-poly(dT), poly(dG-dC)-poly(dG-dC) and calf thymus DNA. reveal a change in the protonation state of the drug upon binding, increasing the apparent pK_a of its 9-N nitrogen atom. The PZE excited state properties serve as a sensitive probe to distinguish between homo and hetero A-T sites as well as between AT and GC sites. Fluorescence studies reveal that energy transfer occurs from polynucleotide bases to the bound PZE chromophore, a result consistent with an intercalative mode of binding of the drug to DNA. The emission is enhanced when PZE is bound to A-T base pairs ( 30% increase of φ_F) whereas it is quenched in the vicinity of G-C base pairs ( 90% decrease of φ_F). Furthermore, the fluorescence spectrum obtained with calf thymus DNA is hardly distinguishable from that obtained with poly(dG-dC)-polu(dG-dC), suggesting a binding of PZE to G-C rich regions.     

Synthesis, molecular structure, and polymerization reactivity of ethylenebis(1,3-dimethylcyclopentadienyl)zirconium dichloride

An ethylene-bridged zirconocene complex bearing methyl substituents only on the cyclopentadienyl carbons adjacent to bridge point, ethylenebis(1,3-dimethylcyclopentadienyl)zirconium dichloride (5) was synthesized. Crystal structure of 5 was determined. The complex, 5, when activated with MAO, shows better comonomer incorporation ability than [Ph₂C(Fluo)(Cp)]ZrCl₂ in the ethylene–norbornene copolymerization but it is not better than rac-Et(Ind)₂ZrCl₂ for the ethylene-1-hexene copolymerization in terms of activity and comonomer incorporation.     

The interaction of antitumor active vanadocene dichloride with sulfur-containing amino acids

Vanadocene dichloride (1) reacts with sulfur-containing amino acids, cysteine and methionine, giving new complexes with five- or six-membered chelate ring, but the structure of isolated compounds is affected by the pH value of the reaction mixture. Methionine reacts with aqueous 1 in the pH range of 3-8 affording chelate structure [Cp₂V(N,O-met)]Cl (4). Similar reaction with cysteine gives two different products depending on pH. In the acidic solution, the complex [Cp₂V(O,S-cys)]Cl (2) is present, whereas in neutral media the compound [Cp₂V(N,S-cys)] (3) could be identified. On inspection of spectroscopic measurements, particularly EPR and vibrational spectroscopy, it is evident that sulfur atom of amino acid is bonded directly to the vanadium atom of [Cp₂V]²⁺ moiety. For the purpose of comparison the complexes [Cp₂V(O,S-mpa)] (5) and [Cp₂V(N,S-csam)]⁺ (6a) with related chelating ligands, 3-mercaptopropionic acid (mpa) and cysteamine (csam), respectively, were prepared and spectroscopically characterized. The structure of the complex [Cp₂V(N,S-csam)]BPh₄ (6b) was also determined by X-ray diffraction analysis.     

Heterogenization of racemic ethylenebis(1-indenyl)zirconium dichloride on trimethylaluminum vapor modified silica surface

Heterogeneous metallocene catalysts were prepared by adsorbing rac-Et(Ind)₂ZrCl₂ on a modified silica surface in solution. The modification of silica was conducted in gas phase with atomic layer chemical vapor deposition (ALCVD) technique, where the silica, preheated at either 350 or 600°C, was allowed to react with vaporized trimethylaluminum (TMA) at 250°C. Modified carriers and heterogeneous catalysts were characterized with FTIR, ¹H MAS (magic-angle spinning) NMR, ¹³C, and ²⁹Si CP (cross-polarization) MAS NMR spectroscopies and elemental analyses. In the reaction of TMA with silica, a saturated surface was formed consisting of different (---O)_4−nSi(CH₃)_n (n=1, 2 or 3) and ---AlCH₃ groups. The ratio of ---SiMe to ---AlMe groups was approximately 1.5 in the TMA/SiO₂ carriers. When the metallocene was adsorbed onto the carrier it seemed to react with the surface ---AlCH₃ groups and possibly ---ZrCH₃ groups were formed. Heterogeneous catalysts were tested in the polymerization of ethylene and propylene in the presence of methylalumoxane (MAO). And they produced similar polymer as the homogeneous rac-Et(Ind)₂ZrCl₂ catalyst, but with lower activity. A catalyst with the best activity was achieved from silica that was preheated at 600°C. Moreover, leaching of catalyst was examined whereupon a part of zirconium was observed to desorb from the carrier.     

Liquid chromatographic characterization of the deoxyribonucleoside-5’-phosphates and deoxyribonucleoside-3’,5’-bisphosphates obtained by32P-postlabeling of DNA

Summary The use of high-performance liquid chromatography (HPLC) for the characterization of the adducts formed by the³²P-postlabeling of DNA is described. Adducts formed from the reaction of DNA with small molecules are characterized as deoxyribonucleoside-5′-monophosphates. Adducts formed from the reaction of DNA with larger molecules are characterized as 3′,5′-bisphosphates. In either case, good separations are obtained for adducts, other than methyl, by conventional reversed-phase chromatography using a C₁₈ column. Ion-exchange chromatography can be used in selected circumstances where reversed-phase techniques are not successful. Using sample concentration techniques, sensitivities are achievable which make this technique applicable toin vivo situations.     

[Bis(aminomethyl)dimethylsilane]platinum(II) dichloride: A potential antitumor agent

[Bis(aminomethyl)dimethylsilane]platinum(II) dichloride (1) was synthesized by a three-step procedure. The antitumor activity of 1 was evaluated in the i.p. implanted mouse L1210 leukemia model. A 10 mg kg^?1 dose administered every fourth day for a total of three injections extended the median life span of the dying mice by at least 100% and resulted in 40–50% survivors (day 30) in two experiments corresponding to an approximate 6 log₁₀ reduction in tumor burden at the end of treatment. Compound 1 appeared at least as active as cisplatin under the testing protocols utilized. The closely related bis[aminomethyltrimethylsilane]platinum(II) dichloride complex was inactive in this mouse model.     

Anion coordination chemistry in aqueous solution of polyammonium receptors

The behavior of polyamines as receptors of selected families of anions in water is explored. First metallocyanide interaction with saturated polyammonium hosts is analyzed both in solution and in the solid state. The utility of potentiometry, multinuclear NMR, microcalorimetry and cyclic voltammetry to describe solution features of this chemistry is described for selected systems. Sulfate, phosphate, polyphosphate and nucleotide interactions with large polyammonium receptors are then reviewed. Hydrogen bond formation is discussed from a thermodynamic point of view. The influence of the presence of aromatic fragments within the structure on the binding strength is discussed. Factors affecting ATP hydrolytic cleavage by macrocyclic polyammonium receptors is revisited. Metal complexes are analyzed as anion receptors through formation of mixed complexes. Finally, an example of the influence of anion in crystal growing is provided.     

Synthesis, antitumor and DNA photocleaving activities of novel naphthalene carboxamides: effects of different thio-heterocyclic rings and aminoalkyl side chains

Two kinds of thio-heterocyclic fused naphthalene carboxamides, 3a-b, 4a-b, were designed, synthesized and quantitatively evaluated as efficient antitumor and DNA photocleaving agents. Compound 3a or 3b, having the thiophene ring, intercalated into DNA more strongly than compound 4a or 4b, having the thioxanthene ring. Compound 4a or 4b, photocleaved DNA more efficiently than 3a or 3b via superoxide anion. Compound 4a was the strongest inhibitor for P388 (murine leukemia cell), while 3a was the most cytotoxic one against A549 (human lung cancer cell). Each new compound showed stronger DNA photocleaving activity than corresponding naphthalimide.     

Ruthenium(II) arene complexes with oligocationic triarylphosphine ligands: Synthesis, DNA interactions and in vitro properties

The synthesis, DNA binding properties and cytotoxicity of a series of Ru(II)-arene complexes containing oligocationic ammonium-functionalized triarylphosphines, of the type Ru(p-cymene)Cl₂(L) (L = oligocationic phosphine), are reported. The complexes are highly charged (the overall charge states being +3 and +6) and circular dichroism spectroscopy and gel electrophoresis studies indicate that the compounds interact strongly with DNA via electrostatic interactions. Despite forming strong interactions with DNA, the complexes exhibit only modest cytotoxicities on the human ovarian cancer cell lines A2780 and A2780cisR.     

Adding diversity to ruthenium(II)-arene anticancer (RAPTA) compounds via click chemistry: The influence of hydrophobic chains

The application of click chemistry to develop libraries of organometallic ruthenium-arene complexes with potential anticancer properties has been investigated. A series of ruthenium-imidazole-triazole complexes, with hydrophobic tails, were prepared from a common precursor via click chemistry. The tail could be attached to the ligand prior to coordination to the ruthenium complex or following coordination, the former giving the product in superior yield. The complexes were screened for cytotoxicity in tumourigenic and non-tumourigenic cell lines, and while the compounds were only moderately cytotoxic, good selectivity for tumourigenic cells was observed.     

Synthesis, characterization and structural investigation of the first vanadocene(IV) carboxylic acid complexes prepared from the vanadocene dichloride

Two types of vanadocene complexes with carboxylic acids have been synthesized from the aqueous solution, Cp₂V(OOCR)₂ (R=H, CCl₃ and CF₃) and Cp₂V(OOC-A-COO) (A= - and CH₂), and characterized by EPR, IR, and Raman spectroscopy and X-ray diffraction analysis. Monocarboxylic and dicarboxylic acids form monodentate and chelate complexes, respectively. Both bonding types were evidenced by X-ray diffraction analysis. Structures and EPR HFC tensors were also calculated at the DFT level. Correlation between the complex structure and HFC tensor was established. HFC tensors are characteristic for the type of bond of carboxylic acid on vanadocene fragment. It is shown that the structure of complexes can be determined by the combination of theoretical method with experimental EPR spectra.     

Photoregulation of the Formation and Dissociation of a DNA Duplex by Using the cis–trans Isomerization of Azobenzene

The duplex-forming activity of an oligonucleotide has been photoregulated by making use of the isomerization of an azobenzene moiety in the side chain. When the azobenzene moiety is isomerized from the trans form to the cis form upon photoirradiation, the melting temperature of the duplex between the oligonucleotide and its complementary counterpart is significantly lowered, and the duplex is largely dissociated into two single-stranded oligonucleotides (shown schematically).     

Insights on fluoroquinolones in cancer therapy: chemistry and recent developments

Cancer is a very risky life-threatening disease having most formidable afflictions in the world. Several anticancer agents are commercially accessible, however, the emergence of acquired drug resistance along with extreme adverse effects of these clinically used anticancer medications are major barriers to the effective chemotherapy. Thus, it is recommended to rationally design the newer drugs with few side effects. Fluoroquinolone derivatives are of pivotal interest for researchers due to their admirable pharmacological and pharmacokinetic profiles. They exhibit several favourable characteristics including, higher bioavailability, excellent tissue penetration and relatively low prevalence of adverse and toxic effects. Due to their potential interventions in carcinogenesis and mutagenesis, the focus of the area of research is nowadays shifting towards anticancer aspects of these compounds. This review shows the recent advancements in the development of novel fluoroquinolones as potential anticancer and cytotoxic agents and structure-activity relationships along with the possible modes of action for further development and recent patents filed/granted related to anticancer activity from the last few years have also been tabulated. Also, this review is an attempt to focus on the various upcoming aspects of fluoroquinolones and provides a newer outlook on the possible roles of fluoroquinolones in the treatment of cancer. Scientific information identified in this paper is expected to be useful for aspiring researchers working on the anticancer activity of fluoroquinolones.     

SYNTHESIS AND CHARACTERIZATION OF TITANOCENE POLYMER DERIVATIVES

Titanocene polymer derivatives with potential antitumor properties were synthesized by interfacial condensation. The preformed polymers used are PAA (polyacrylic acid), CPSMA (1:1 alternating copolymer of styrene and maleic anhydride) and DVEMA (1:2 copolymer of divinyl ether and maleic anhydride). The ratio of practical and theoretical titanium content is 73.6%, 92.2% and 86.2% for PAA, CPSMA and DVEMA polymer derivatives respectively. The IR spectra of the polymer derivatives possess the characteristic absorptions of titanocene. XPS (X-ray photoelectron spectroscopy) of O_(1s) and Ti_(2p3/2) supports the existence of Ti-O bonding.     

DNA-associated click chemistry

This review highlights the most recent advances in click chemistry associated with DNA.Cu[I]-catalyzed azides-alkynes Huisgen cycloadditions(CuAAC)and a strain-promoted alkyne-azide cycloaddition(SPAAC)are two popular click reactions that have great impact in DNA science.The simplicity,versatility,orthogonality,and high efficiency of click reaction along with a stable triazole product have been instrumental for the successful application of this reaction in the field of nucleic acid chemistry.CuAAC and SPAAC reactions have been widely used for DNA modification,including DNA labeling,metallization,conjugation,cross-linking,and ligation.Modified oligodeoxynucleotides obtained from click reaction have been extensively applied in the fields of drug discovery,nanotechnology,bio-conjugation,and material sciences,among others.The most recent advances in the synthesis and applications of clickable DNAs are discussed in detail in this article.     

Review: electrochemical studies on some metal complexes having anti-cancer activities

Cancer is a leading cause of death worldwide. Since the discovery of cisplatin, a platinum-based anti-cancer metallodrug, research on metal-based compounds and complexes as potential anti-cancer agents has gained importance in modern medical and chemical sciences. Electrochemical techniques provide useful complements to other analytical methods of analysis such as UV–vis and fluorescence spectroscopy. Since the redox active metal complexes are not amenable to spectroscopic techniques either due to weak absorption bands or overlap of electronic transitions with those of DNA, they can potentially be studied via electrochemical techniques. Due to the resemblance between the electrochemical and biological redox reactions, the application of electrochemical measurements of metal-based anti-cancer drugs is a highly sensitive method. Cyclic voltammetry is a versatile technique to investigate redox activities during drug–DNA interactions. Variations in peak potentials and peak currents of a cyclic voltammogram during a redox reaction resulting from intercalation or electrostatic interactions can be used to determine equilibrium constants (K) and the number of base pair sites. This review is focused on some electrochemical studies of potential metal-based anti-cancer drug candidate?DNA interactions and the correlation between binding studies and anti-cancer activities.     

二茂钛二甘氨酸盐酸盐与DNA作用机理的研究

二氯二茂钛是一种活性很高的抗肿瘤药物,对它的抗肿瘤机理目前尚无定论．我们用核磁共振方法研究二氯二茂钛与单核苷酸的成键特点时发现[1],二氯二茂钛与核苷酸的成键方式既不同于顺铂,又不同于二氯二茂钼、二氯二茂钒等,表明其抗肿瘤机理可能与顺铂有明显不同．由于二氯二茂钛在水中的溶解度不大,故妨碍了对它与DNA作用机理的进一步研究．最近,二氯二茂钛与甘氨酸形成的配合物──二茂钛二甘氨酸盐酸盐,已被成功地合成出来[2]．由于它极易溶于水,且其酸性配体为氨基酸,因此研究该化合物的抗肿瘤活性及其与DNA的作用特点,对了…