guanosine-monophosphate and Ovarian-Neoplasms

Platinum-based antineoplastic agents play a major role in the treatment of numerous types of cancer. A new bulky, lipophilic, and chiral ligand based on 1,2-diaminodiamantane in both of its enantiomeric forms was employed for the preparation of new platinum(ii) complexes with chloride and oxalate ligands. The dichloride complexes have a higher solubility and were evaluated as anti-proliferation agents for human ovarian cancer cell lines A2780 and cisplatin-resistant A2780cis. Its R,R-enantiomer showed increased efficacy compared to cisplatin for both cancer cell lines. A chromatographic approach was used to estimate the solvent partition coefficient of the dichloride complex. The binding of diamondoid-based platinum complexes to nucleotides was tested for both enantiomers with guanosine monophosphate (GMP) and deoxyguanosine monophosphate (dGMP) and occurs at a similar or faster rate for both isomers compared to cisplatin despite greatly increased steric demand. These findings highlight the potential in 1,2-diaminodiamantane as a viable pharmacophore.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Coordination Complexes; Drug Design; Drug Resistance, Neoplasm; Female; Guanosine Monophosphate; Humans; Isomerism; Ligands; Molecular Conformation; Organoplatinum Compounds; Ovarian Neoplasms; Platinum; Structure-Activity Relationship

Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion (1)H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH(3))(2)} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'-GMP at temperatures of 60°C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cisplatin; Dendrimers; Dose-Response Relationship, Drug; Drug Carriers; Drug Dosage Calculations; Female; Guanosine Monophosphate; Humans; Kinetics; Magnetic Resonance Spectroscopy; Mice; Mice, Nude; Ovarian Neoplasms; Particle Size; Polyamines; Spectrophotometry, Atomic; Xenograft Model Antitumor Assays

Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [(eta6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Design; Female; Guanosine Monophosphate; Humans; Hydrolysis; Inhibitory Concentration 50; Kinetics; Ligands; Molecular Structure; Organometallic Compounds; Ovarian Neoplasms; Ruthenium