The cytotoxic complex, [PtCl(Am) 2 (ACRAMTU)](NO 3 ) 2 (1) ((Am) 2 = ethane-1,2-diamine, en; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea), is a dual platinating/ intercalating DNA binder that, unlike clinical platinum agents, does not induce DNA cross-links. Here, we demonstrate that substitution of the thiourea with an amidine group leads to greatly enhanced cytotoxicity in H460 non-small cell lung cancer (NSCLC) in vitro and in vivo. Two complexes were synthesized: 4a (Am 2 = en) and 4b (Am = NH 3 ), in which N- [2-(acridin-9-ylamino) ethyl]-N-methylpropionamidine replaces ACRAMTU. Complex 4a proves to be a more efficient DNA binder than complex 1 and induces adducts in sequences not targeted by the prototype. Complexes 4a and 4b induce H460 cell kill with IC 50 values of 28 and 26 nM, respectively, and 4b slows tumor growth in a H460 mouse xenograft study by 40% when administered at a dose of 0.5 mg/kg. Compound 4b is the first non-cross-linking platinum agent endowed with promising activity in NSCLC.

No abstract

Platinum-acridine conjugates were prepared from [PtCl2(ethane-1,2-diamine)] and the novel acridinylthioureas MeHNC(S)NMeAcr (6) and MeHNC(S)NMe(CH2CH2)NHAcr (15) by replacing one chloro leaving group in the cisplatin analogue with thiourea sulfur. In HL-60 leukemia cells, IC(50) values for 7 (Pt-tethered 6) and 16 (Pt-tethered 15) were 75 and 0.13 microM, respectively. In the ovarian cell lines 2008 and C13, 16 was active at micromolar concentrations and showed only partial cross-resistance with clinical cisplatin. Possible structure-activity relationships are discussed.

89Zr–Tetraazamacrocycle complexes display extraordinary stability.

In this work we have revisited the charge-transfer crystal system perylene− TCNQ and found that this complex can crystallize with a 2:1 stoichiometric ratio in addition to the 1:1 and 3:1 stoichiometries previously observed. The vibrational and electronic properties of these perylene−TCNQ charge-transfer crystals have been investigated by means of Raman scattering measurements and density functional theory calculations. Electrical measurements were also performed by preparing organic field-effect transistors (OFETs) from the crystals. The Raman spectra in the low-frequency range (below 200 cm −1 ) are found to be unique to the specific crystal structure and can therefore be used to determine the stoichiometry. The Raman data and the X-ray diffraction measurements indicate that at room temperature the amount of charge transferred to the TCNQ molecule is less than 0.2e for all three compounds, and is nearly the same in P1T1 and P2T1 but is slightly larger in P3T1. The electronic structure calculations suggest good intrinsic charge transport properties for both holes and electrons in P1T1 and P2T1 and only for holes in P3T1. Ambipolar charge transport characteristics were found for P2T1 and hole and electron charge transport characteristics were found in P3T1 and P1T1, respectively.

No abstract

Nitroxyl (HNO/NO(-)), the reduced form of nitric oxide, has gained attention based on its separate chemistry and biology from nitric oxide. The inherent reactivity of HNO requires new and mechanistically unique donors for the detailed study of HNO chemistry and biology. Oxidation of cyclohexanone oxime with lead tetraacetate yields 1-nitrosocyclohexyl acetate, whereas oxidation of oximes in the presence of excess carboxylic acid gives various acyloxy nitroso compounds. These bright blue compounds exist as monomers as indicated by their infrared, proton, and carbon NMR spectra, and X-ray crystallographic analysis reveals the nitroso groups possess a "nitroxyl-like" bent configuration. Hydrolysis of these compounds produces nitrous oxide, the dimerization and dehydration product of HNO, and provides evidence for the intermediacy of HNO. Both thiols and oxidative metal complexes inhibit nitrous oxide formation. Hydrolysis of these compounds in the presence of ferric heme complexes forms ferrous nitrosyl complexes providing further evidence for the intermediacy of HNO. Kinetic analysis shows that the rate of hydrolysis depends on pH and the structure of the acyl group of the acyloxy nitroso compound. These compounds relax pre-constricted rat aortic rings similar to known HNO donors. Together, these results identify acyloxy nitroso compounds as a new class of HNO donors.

No abstract