Comparative QSAR studies on substituted bis-(acridines) and bis-(phenazines)-carboxamides: a new class of anticancer agents

Quantitative structure-activity relationships have been formulated for two sets of DNA binding topoisomerase agents (bis-acridines and bis-phenazines) acting on murine P388 leukemia cells, murine Lewis lung carcinoma (LL(C)) cells and human Jurkat leukemia wild-type (JL(C)) cells. For the acridines, all three QSARs (1-3) show only a (small negative) hydrophobic effect. In sharp contrast, the phenazines in all three studies (4-6) show a strong hydrophobic effect, with the optimum ClogP being near 7.3 for all examples. This suggests that, despite the structural similarity of the compounds, different modes of enzyme and/or DNA binding may be involved.     

Synthesis, characterization and biological activity of complexes of lanthanum(III) with 2-(1'-phenyl- 2'-carboxyl-3'-aza-n-butyl)-1,10-phenanthroline and 2-(1'-p-phenol-2'-carboxyl-3'-aza-n-butyl)-1,10-phenanthroline

Two novel ligands 2-(1'-phenyl-2'-carboxyl-3'-aza-n-butyl)-1,10-phenanthroline (L1) and 2-(1'-p-phenol-2'-carboxyl-3'-aza-butyl)-1,10-phenanthroline (L2), and their La(III) complexes of La(III)L1, La(III)(L1)(2), La(III)L2, and La(III)(L2)(2), were synthesized and characterized by (1)H NMR, elemental analysis, IR, thermal analysis and conductance measurement. All complexes have been assayed for anticancer activity in vitro against HL-60 (human leukocytoma) cells, PC-3MIE8 (human prostate carcinoma) cells, BGC-823 (human stomach carcinoma) cells, MDA-MB-435 (human galactophore carcinoma) cells, Bel-7402 (human liver carcinoma) cells, and HeLa (human cervix carcinoma) cells. Results showed that the two complexes La(III)L1 and La(III)(L1)(2) exhibited good cytotoxic activity against different cell lines in general; and La(III)(L1)(2) is more effective than cisplatin against all six cell lines. DNA-binding studies indicated that, besides the intercalation, the complexes bind to DNA by the other interaction(s).     

Characterisation of a new chimeric ligand for galanin receptors: galanin(1-13)-[D-Trp(32)]-neuropeptide Y(25-36)amide

In this work, we studied a novel chimeric peptide, M242, galanin(1-13)-[D-Trp(32)]-neuropeptide Y(25-36)amide, and examined its properties in comparison with its parent peptide, M32, galanin(1-13)-neuropeptide Y(25-36)amide, a previously known high-affinity ligand for galanin receptors, and galanin itself. Binding assays performed in Bowes cells known to express human galanin receptor type 1 (hGalR1) and in Chinese hamster ovary cells overexpressing human galanin receptor type 2 (hGalR2) revealed that all three ligands had comparable affinities: at hGalR1<1 nM and at hGalR2<10 nM. However, in rat hippocampal membranes M242 had a 24-fold lower affinity than galanin (9.4 vs. 0.4 nM) and 134-fold lower affinity than M32 (9.4 vs. 0.07 nM). In the same tissue, we also examined the effects of these peptides on adenylate cyclase activity. M32 showed a weak antagonistic behaviour but M242 acted as a potent biphasic regulator of adenylate cyclase. In conclusion, we present and characterise a new peptide M242, which could be a useful tool in studies of galaninergic signalling.     

A new polymorph of dichlorido(1,10-phenanthroline)platinum(II)

A yet unreported polymorph of [PtCl₂(1,10-phenanthroline)] was obtained by slow decomposition, in CH₂Cl₂ solution, of [Pt{CH₂CH₂N(CH₂CH₃)₂-κC,κN}(1,10-phenanthroline)](ClO₄). The structure of the new orthorhombic form, III, (space group Pna2₁), is described and compared to those of the two already reported forms, I and II, which are monoclinic (space group P2₁/c) and orthorhombic (space group Pca2₁), respectively [21]. Polymorph III appears to be the least stable of the three.     

Stereoselectivity in the metabolism of drobuline (d1-1-(isopropylamino) -4,4-diphenyl-2-butanol) a new anti-arrhythmic agent

The metabolism of drobuline has been examined in the dog, rabbit, rat, guinea pig and hamster. In the dog, unlike the other species, glucuronide conjugation is the major route of metabolism. The structure of the conjugate has been established as an O-glucuronide by isolation using HPLC following by field desorption mass spectral analysis. When the separate $\text{d}$- and $\text{l}$-isomers of drobuline were administered to a series of dogs the $\text{l}$-isomer reached plasma levels approximately three time higher than those of the $\text{d}$-isomer. Deuterium labeled drobuline was synthesized and resolved by multiple crystallizations of the malate salts. Racemic mixtures containing $\text{d}$₆-$\text{d}$ and $\text{h}$₆-$\text{l}$ drobuline and $\text{d}$₆-$\text{l}$ and $\text{h}$₆-$\text{d}$ drobuline were prepared and analyzed by GC-MS as the pentafluoropropionate derivatives. When either racemic mixture was administered to dogs (10 mg/kg, p.o.) the plasma levels of the $\text{l}$-isomer were found to be approximately three times those of the $\text{d}$-isomer. Using these deuterium labeled mixtures the disposition of the two isomers has been examined in the isolated perfused dog liver, in hepatocytes and isolated microsomes. The results indicate that the difference in plasma levels of the $\text{d}$- and $\text{l}$-isomers is not dependent upon stereospecific absorption or excretion but rather it is caused by metabolism of the $\text{d}$-isomer at a faster rate than that of the $\text{l}$-isomer.     

Crystal structures of α- and β-(1,10-phenanthroline)tetrahydroborato(triphenylphosphine)copper(I) and (2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline)tetrahydroboratocopper(I)

Copper(I) is five coordinate in (1,10-phenanthroline)tetrahydroborato(triphenylphosphine)copper(I). This compound crystallizes from either toluene as the yellow, α-form, a = 16.247(8), b = 9.750(7), c = 9.322(5) Å, α = 62.92(4), β = 84.77(4), γ = 84.34(5)°, triclinic P$\text{1}$, Z = 2, or from a xylene/methylene chloride mixture as the red β-form, X-ray cell, a = 13.675(11), b = 10.115(8), c = 9.700(7) Å, α = 95.22(6), β = 96.22(6), γ = 101.02(6)°; neutron cell, as the tetradeuteroborate, a = 13.703(1), b = 10.096(8), c = 9.74(1) Å, α = 95.23(9), β = 96.51(8), γ = 101.04(2)°, triclinic, P$\text{1}$, Z = 2. For both forms, unidentate triphenylphosphine, bidentate 1,10-phenanthroline and unsymmetrical bidentate BH₄^? completes the copper(I) coordination but there are subtle differences between the two. When the ligand 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, dmdp, replaces 1,10-phenanthroline, the compound obtained is four coordinate with no tpp in the crystal. [C(dmdp)BH₄] is monoclinic, Cc, a = 14.522(4), b = 20.07(2), c = 7.718(2) Å, β = 106.17(2)°, Z = 4.     

Cetamolol: a new cardioselective beta-adrenoceptor blocking agent without membrane-stabilizing activity

Cetamolol, a new beta-adrenoceptor blocker with partial agonist activity and cardioselectivity, was studied in vivo to determine its membrane-stabilizing effects. Comparisons were carried out with atenolol, pindolol, practolol, propranolol, timolol, dexpropranolol, lidocaine, and procaine. The following results indicated that cetamolol lacked membrane-stabilizing activity: (i) failure to cause local anesthesia on the rabbit cornea and motor nerve of the rat tail; (ii) ineffectiveness in reversing ventricular arrhythmias induced by coronary artery litigation in dogs; (iii) failure to reduce cardiac automaticity in catecholamine-depleted dogs as determined by the rate of a subatrial rhythm during ventricular (vagal) escape; and (iv) lack of a significant increase in atrioventricular conduction time in vagotomized or atropinized dogs in contrast to the effect in normal dogs indicating a reflex effect of cetamolol. Other results include a restoration of sinus rhythm in dogs with ventricular tachycardia induced by ouabain, and a dose-related decline in the force of cardiac contraction in anesthetized dogs at doses from 3 to 15 mg/kg, which occurred after an initial increase in force owing to intrinsic sympathomimetic activity. Although the mechanisms for the latter two effects are not clear at this time, explanations other than membrane-stabilizing activity have been considered in view of the other findings. It is concluded that cetamolol lacks membrane-stabilizing activity even at inordinately high doses.     

Hydrolysis of PET and bis-(benzoyloxyethyl) terephthalate with a new polyesterase from Penicillium citrinum

A polyethylene terephthalate (PET) model substrate, bis-(benzoyloxyethyl)terephthalate (3PET), was used to screen for micro-organisms producing enzymes hydrolyzing PET. From this screen, a strain growing on 3PET was isolated and identified as Penicillium citrinum. The polyesterase responsible for 3PET and PET hydrolysis was purified to electrophoretic homogeneity. The polyesterase had a molecular weight of 14.1 kDa, and the K_m and K_cat values on 4-nitrophenyl butyrate were 0.57?mM and 0.21?s^?1, respectively. Highest enzyme activities were obtained when P. citrinum was grown on a medium containing cutin, which was hydrolyzed by the polyesterase. Surface hydrolysis of PET with the enzyme lead to an increase in hydrophilicity based on rising height (+5.1?cm) and drop dissipation measurements (55?s). Both from PET and 3PET bis-(2-hydroxyethyl)terephthalate and mono-(2-hydroxyethyl)terephthalate were released, while only low amounts of terephthalic acid were liberated.     

Hydrolysis of PET and bis-(benzoyloxyethyl) terephthalate with a new polyesterase from Penicillium citrinum

A polyethylene terephthalate (PET) model substrate, bis-(benzoyloxyethyl)terephthalate (3PET), was used to screen for micro-organisms producing enzymes hydrolyzing PET. From this screen, a strain growing on 3PET was isolated and identified as Penicillium citrinum. The polyesterase responsible for 3PET and PET hydrolysis was purified to electrophoretic homogeneity. The polyesterase had a molecular weight of 14.1 kDa, and the K_m and K_cat values on 4-nitrophenyl butyrate were 0.57 mM and 0.21 s^-1, respectively. Highest enzyme activities were obtained when P. citrinum was grown on a medium containing cutin, which was hydrolyzed by the polyesterase. Surface hydrolysis of PET with the enzyme lead to an increase in hydrophilicity based on rising height (+5.1 cm) and drop dissipation measurements (55 s). Both from PET and 3PET bis-(2-hydroxyethyl)terephthalate and mono-(2-hydroxyethyl)terephthalate were released, while only low amounts of terephthalic acid were liberated.     

EDTA bis-(methyl tyrosinate): a chelating peptoid peroxynitrite scavenger

Conjugation of ethylenediaminetetra-acetic acid (EDTA) to methyl tyrosinate generates a chelating peptoid EDTA bis-(methyl tyrosinate), (EBMT). Peroxynitrite-mediated nitration was studied for the free peptoid and its ferric and cupric complexes. The nitration products were monitored by electronic absorption spectroscopy at lambda(max) of 420 nm (mono-nitrated) and 440 nm (di-nitrated). Peak deconvolution was effected by pH manipulation as the mono-nitrated analogue of tyrosine exhibited a bathochromic shift from 365 nm (below its pK(a) of 6.8) to 420 nm. Rates of nitration were: free peptoid 相似文献   

Discovery of 6-[4-(6-nitroxyhexanoyl)piperazin-1-yl)]-9H-purine,as pharmacological post-conditioning agent

Novel purine analogues bearing nitrate esters were designed and synthesized in an effort to develop compounds triggering endogenous cardioprotective mechanisms such as ischemic preconditioning (IPC) or postconditioning (PostC). The majority of the compounds reduced infarct size compared to the control group in anesthetized rabbits, whereas administration of the most active analogue 16 at a dose of 3.8 μmol/kg resulted on a significant reduction of infarct size, compared to PostC group (13.4 ± 1.9% vs 26.4 ± 2.3%). These findings introduce a novel class of promising pharmacological compounds that could be used as mimics or enhancers of PostC.     

1-(2-((Z)-6-(2-(Trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one as a new potent apoptosis agent

Compounds 4a–f, 5a–f and 6–9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.     

Spectral and structural studies of a new oxalato-bridged dinuclear copper(II) complex having two 3-(thiophen-2-yl)-1,10-phenanthroline ligands in a trans configuration

In this paper, spectral and structural characterizations of a new dinuclear copper(II) complex (1), formulated as [Cu₂(3-(thiophen-2-yl)-1,10-phenanthroline)₂(μ-oxalate)(DMF)₂](ClO₄)₂ (DMF = N,N′-dimethylformamide), have been described. Two five-coordinate copper(II) centers are bridged by a four-dentate oxalate dianion forming a planar molecular geometry with the Cu-Cu separation of 5.117(4) Å. The two ligands in 1 adopt a trans configuration to each other and two monodentate DMF molecules are positioned at each side of the molecular plane. In addition, typical π-π stacking interactions are found between adjacent phenanthroline and thiophene rings forming a layered packing structure. A compressed pyramidal configurational alteration is observed for each copper(II) center when the temperature is decreased from 291(2) to 100(2) K.