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PubMed1997

A fluoroquinolone antibiotic with a methoxy group at the 8 position yields reduced generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine after ultraviolet-A irradiation.

We have previously reported that two fluoroquinolone antibiotics gave rise to 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) in DNA of cells concurrently exposed to UV-A and that this correlated with clinical phototoxicity. To determine the structural basis for generation of oxidative damage, the ability of two synthetic fluoroquinolone candidate antibiotics, Bayer 12-8039 (12-8039) and Bayer Y3118 (Y3118), to give rise to 8-oxo-dG in cultured liver epithelial cells was compared. 12-8039 contains a methoxy group at the 8 position of the quinolone nucleus, whereas Y3118 contains a chlorine group at the same position. Y3118 produced dose-dependent increases in 8-oxo-dG formation in cultured cells after UVA irradiation, whereas the 8-OCH3-substituted 12-8039 produced no increase. Also, after exposure to 20 J/cm2 UVA, UV spectral scans of both compounds revealed that Y3118 underwent photodegradation whereas 12-8039 was stable. These results demonstrate that the presence of an 8-OCH3 group on the quinolone nucleus is important for the reduction of photogeneration of oxidative DNA damage and photodegradation in the presence of UVA irradiation. From this, we suggest that 12-8039 has little phototoxic potential.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1995

Synthesis of new N(6)-substituted 2-phenyl-8-azaadenosines. Their affinity for adenosine A1 and A2 receptors. A comparison with the corresponding 2-phenyl-9-benzyl-8-azaadenines. VI.

Comparison of the affinity towards adenosine receptors of 2-phenyl-8-azaadenosines, bearing a lipophilic substituent on N(6), with the corresponding 2-phenyl-8-azaadenines was carried out. The compounds have good A1 affinity and high A1 selectivity. The obtained Ki(rib)/Ki(benz) ratios for A1 receptors, which showed variable values depending on the structure of the N(6) substituent, confirmed that 2-phenyl-8-azaadenines are characterized by greater freedom inside A1 receptors. This situation may be a favourable test of the hypothesized double disposition of these exogenous molecules within A1 receptors.

Adenine↗
PubMed2002

Electronic structure of reduced symmetry peripheral fused-ring-substituted phthalocyanines.

Reduced symmetry phthalocyanines are finding use in an increasing number of industrial applications. A detailed understanding of the electronic structure of the pi-system will greatly facilitate the design of new complexes, which fit the specifications required in many of these emerging high technology fields. NMR, electronic absorption, magnetic circular dichroism (MCD), and fluorescence emission and excitation spectra have been recorded for five generic metal phthalocyanine (MPc) derivatives in which additional benzene rings are fused either radially or obliquely onto at least one of the four peripheral benzo groups. The spectroscopy of four radially substituted compounds, zinc mononaphthotribenzotetraazaporphyrine (Zn3B1N), zinc monobenzotrinaphthotetraazaporphyrine (Zn1B3N), and two cis and trans zinc dibenzodinaphthotetraazaporphyrine (Zn2B2N) isomers, is compared to that of the obliquely fused structural isomer of Zn3B1N (Zn3BoN) and the D(4)(h)() symmetry parent compounds, ZnPc and zinc naphthalocyanine (ZnNc). The selection of Zn(II) as the central metal eliminates the possibility of charge transfer between the metal and ring. None of the complexes studied contain any sigma-bonded peripheral substituents. (1)H NMR signals of the seven compounds are assigned on the basis of the coupling patterns, integrated proton numbers, and decoupling experiments. The SIMPFIT program was used to perform spectral band deconvolution analyses of absorption and MCD spectra. ZINDO molecular orbital calculations are described, and the optical spectra are assigned on the basis of the MO models that have been developed previously to account for the spectral properties of metal porphyrin (MP(-2)) and metal phthalocyanine (MPc(-2)) complexes.

Algorithms↗
PubMed2004

Synthesis and structure-activity relationships of 1,5-diazaanthraquinones as antitumour compounds.

1,5-Diazaanthraquinone derivatives were synthesized employing single and double hetero Diels-Alder strategies. Their in vitro antitumour activity was assayed using three cell lines. Some of these compounds, specially those bearing methyl or ethyl groups at the C-3,7 positions or chloro at C-4 and methyl at C-7, showed IC(50) values in the 10(-8)M range for human lung carcinoma and human melanoma, which makes them attractive candidates for further development as anticancer agents.

Anthraquinones↗
PubMed2006

Design and synthesis of 3,5-disubstituted benzamide analogues of DNK333 as dual NK1/NK2 receptor probes.

N-[(R,R)-(E)-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (DNK333, 1b) has been reported to be a potent and balanced dual neurokinin (tachykinin) receptor antagonist. A recent clinical trial using DNK333 has shown that it blocks the NKA-induced bronchoconstriction in patients with asthma. A series of six analogues 3-8 derived from modification of 3,5-bis(trifluoromethyl)benzamide moiety of DNK333 has been synthesized to serve as the dual NK(1)/NK(2) receptor probes. The 3,5-dinitro substituted benzamide compound 3 was found to possess potent and balanced dual NK(1)/NK(2) receptor antagonist activities (pK(b)=8.4 for the NK(1) receptors, pK(b)=7.87 for the NK(2) receptors) in the functional assay using guinea pig trachea. Furthermore, SAR analysis suggests that steric, electronic, and lipophilic characteristics of substituents in the benzamide region of DNK333 have a crucial effect on both the NK(1) and NK(2) receptor antagonist activities.

Animals↗
PubMedDate not supplied

Nuclear magnetic spin-lattice relaxation of water protons caused by metal cage compounds.

The nuclear magnetic spin-lattice relaxation rates of water protons are reported for solutions of manganese(II), copper(II), and chromium(III) cage complexes of the sarcophagine type. As simple aqueous solutions, the complexes are only modest magnetic relaxation agents, presumably because they lack protons on atoms in the first-coordination-sphere protons that are sufficiently labile to mix the large relaxation rate at the metal complex with that of the bulk solvent. The relaxation is approximately modeled using spectral density functions derived for translational diffusion of the interacting dipole moments with the modification that the electron spin relaxation rate is directly included as a contribution to the correlation time. In all cases studied, the electron spin relaxation rate is sufficiently large that it contributes directly to the water-proton spin relaxation process. The poor relaxation efficiency of the cage compound may, however, be improved dramatically by binding the complex to a protein. The efficiency is improved even further if the rotational motion of the protein is reduced drastically by an intermolecular cross-linking reaction. The relaxation efficiency of the cross-linked protein-cage complexes rivals that of the best first-coordination-sphere relaxation agents like [Gd(DTPA)(H2O)]2- and [Gd(DOTA)(H2O)]-.

Aza Compounds↗
PubMed1999

Activity of moxifloxacin against mycobacteria.

Moxifloxacin is an 8-methoxyquinolone compound with activity against a wide range of bacteria. We tested its activity in comparison with four other quinolones and isoniazid against clinical isolates of mycobacteria. It proved to be the most active of the quinolones tested against Mycobacterium tuberculosis (MIC90 0.25 mg/L), Mycobacterium avium-intracellulare (MIC90 1.0 mg/L), Mycobacterium kansasii (MIC90 0.06 mg/L) and Mycobacterium fortuitum (MIC90 1 mg/L). These data indicate that moxifloxacin merits further study as an antimycobacterial agent.

4-Quinolones↗
PubMed2005

Synthesis of novel DNA cross-linking antitumour agents based on polyazamacrocycles.

We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC(50) values 6-100microM) comparable with chlorambucil (45microM) and melphalan (8.5microM). In particular the cyclen derivative 2a was more than 10(4) times more effective at cross-linking DNA (2a XL(50)<<10nM) than chlorambucil (XL(50) 100microM), and showed significant cytotoxicity in human tumour cells in vitro.

Antineoplastic Agents↗
PubMedDate not supplied

Sulfomethylation of Di-, Tri-, and polyazamacrocycles: a new route to entry of mixed-side-chain macrocyclic chelates.

The sulfomethylation of piperazine and the polyazamacrocycles, [9]aneN3, [12]aneN3, [12]aneN4, and [18]aneN6 with formaldehyde bisulfite in aqueous medium at various pH values is described. The number of methanesulfonate groups introduced into these structures was found to be largely determined by pH. At neutral pH, disubstituted products of [9]aneN3, [12]aneN3, [12]aneN4 are formed and, in the latter case, the trans-1,7-bis(methanesulfonate) isomer was predominant. Similarly, a single, symmetrical trisubstituted product was formed with [18]aneN6 at neutral pH. Monomethanesulfonated products of these same polyaza compounds were formed at more acidic pH's. These sulfomethylated products were used as an entry into a series of mono- and diacetate, phosphonate, and phosphinate derivatives of [9]aneN3, [12]aneN3, and [12]aneN4. The sulfonate groups may be converted to acetates without isolation of intermediates by using cyanide to displace the sulfonate(s) followed by acidic hydrolysis. The aminomethanesulfonates may also be oxidatively hydrolyzed by using aqueous triiodide as a prelude to the preparation of aminomethanephosphonates or aminomethanephosphinates.

Aza Compounds↗
PubMed2003

"Broad spectrum" antidepressants: is more better for the treatment of depression?

The majority of antidepressants in current use selectively inhibit the reuptake of serotonin and/or norepinephrine. "Broad spectrum" antidepressants are compounds that inhibit the reuptake of norepinephrine, serotonin and dopamine, the three biogenic amines most closely linked to depression. The pharmacological profile of one such compound has recently been described (European Journal of Pharmacology, 461 (2003) 99). DOV 21,947, an azabicyclo[3.1.0]hexane, potently inhibits norepinephrine, serotonin and dopamine reuptake by the corresponding human transporter proteins. DOV 21,947 is orally active in the forced swim and tail suspension tests, preclinical procedures that are highly predictive of antidepressant action in patients. A closely related compound, DOV 216,303 is safe and well-tolerated in Phase I studies. The plasma concentrations of DOV 216,303 following both single and multiple doses appear sufficient to inhibit norepinephrine, serotonin, and dopamine reuptake. Based on the pivotal role proposed for dopamine in depression, it has been hypothesized that a broad spectrum antidepressant will produce a more rapid onset and/or higher efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine.

Animals↗
PubMed2004

Sorption and oxic degradation of the explosive CL-20 during transport in subsurface sediments.

The abiotic sorption and oxic degradation processes that control the fate of the explosive CL-20, Hexanitrohexaazaisowurtzitane, in the subsurface environment were investigated to determine the potential for vadose and groundwater contamination. Sorption of aqueous CL-20 is relatively small (K(d) = 0.02-3.83 cm3 g(-1) for 7 sediments and 12 minerals), which results in only slight retardation relative to water movement. Thus, CL-20 could move quickly through unsaturated and saturated sediments of comparable composition to groundwater, similar to the subsurface behavior of RDX. CL-20 sorption was mainly to mineral surfaces of the sediments, and the resulting isotherm was nonlinear. CL-20 abiotically degrades in oxic environments at slow rates (i.e., 10s to 100s of hours) with a wide variety of minerals, but at fast rates (i.e., minutes) in the presence of 2:1 phyllosilicate clays (hectorite, montmorillonite, nontronite), micas (biotite, illite), and specific oxides (MnO2 and the ferrous-ferric iron oxide magnetite). High concentrations of surface ferrous iron in a dithionite reduced sediment degraded CL-20 the fastest (half-life < 0.05 h), but 2:1 clays containing no structural or adsorbed ferrous iron (hectorite) could also quickly degrade CL-20 (half-life < 0.2 h). CL-20 degradation rates were slower in natural sediments (half-life 3-800 h) compared to minerals. Sediments with slow degradation rates and small sorption would exhibit the highest potential for deep subsurface migration. Products of CL-20 oxic degradation included three high molecular weight compounds and anions (nitrite and formate). The 2-3.5 moles of nitrite produced suggest CL-20 nitro-groups are degraded, and the amount of formate produced (0.2-1.2 moles) suggests the CL-20 cage structure is broken in some sediments. Identification of further degradation products and CL-20 mineralization rates is needed to fully assess the impact of these CL-20 transformation rates on the risk of CL-20 (and degradation product) subsurface movement.

Adsorption↗
PubMed2004

Development of cobalt(3,4-diarylsalen) complexes as tumor therapeutics.

[1,6-Bis(2-hydroxyphenyl)-3,4-diaryl-2,5-diazahexa-1,5-diene]cobalt(II) complexes (cobalt(3,4-diarylsalen)) with 2-, 3-, or 4-OCH(3)/OH substituents in the 3,4-standing aryl rings were synthesized and tested for antitumor activity in vitro on the MCF-7, MDA-MB 231, and LNCaP/FGC cell lines. The cytotoxicity depended on both the configuration of the diene ligand and the kind of substituents in the 3,4-standing aromatic rings. d,l-7 (2-OCH(3)), d,l-8 (3-OCH(3)), and d,l-9 (4-OCH(3)) were equipotent to cisplatin, while the respective hydroxy-substituted complexes (d,l-10 (2-OH), d,l-11 (3-OH), and d,l-12 (2-OH)) as well as all of the meso-configured compounds (m-7 to m-12) did not influence the cell growth. Interestingly, a high catalytic potency and a rapid and high accumulation in MCF-7 cells (15- to 25-fold compared to the cell culture medium (5 microM)) were demonstrated for m-7 (2-OCH(3)), m-8 (3-OCH(3)), and m-9 (4-OCH(3)). Therefore, a mode of action based on a cobalt-catalyzed oxidative damage of the DNA is not very likely.

Antineoplastic Agents↗
PubMed2005

Efficient approaches toward the solid-phase synthesis of new heterocyclic azoniaspiro ring systems: synthesis of tri- and tetrasubstituted 10-oxo- 3,9-diaza-6-azoniaspiro[5.5]undecanes.

[Reaction: see text]. An efficient approach for the parallel solid-phase synthesis of novel heterocyclic azoniaspiro ring systems is described. The target compounds, the 1,8,9-trisubstituted 10-oxo-3,9-diaza-6-azoniaspiro[5.5]undecanes, were obtained starting from resin-bound reduced dipeptides. The azoniaspiro cation was formed by intramolecular attack of a tertiary nitrogen on pendent alpha-bromocarbonyl. N-3 acylated and N-3 alkylamino carbonyl derivatives of the 1,8,9-trisubstituted 10-oxo-3,9-diaza-6-azoniaspiro[5.5]undecanes were obtained following in solution treatment of the N-3 azoniaspiro derivatives with different carboxylic acids and isocyanates.

Alkanes↗
PubMed2003

Thiosemicarbazole (thiacetazone-like) compound with activity against Mycobacterium avium in mice.

In vitro screening of thiacetazone derivatives indicated that two derivatives, SRI-286 and SRI-224, inhibited a panel of 25 Mycobacterium avium complex (MAC) isolates at concentrations of 2 micro g/ml or lower. In mice, SRI-224 and thiacetazone had no significant activity against the MAC in livers and spleens, but treatment with SRI-286 resulted in significant reduction of bacterial loads in livers and spleens. A combination of SRI-286 and moxifloxacin was significantly more active than single drug regimens in liver and spleen.

Animals↗
PubMed2002

[In vitro activity of moxifloxacin against respiratory pathogens in Latin America].

We compared the in vitro activity of moxifloxacin, levofloxacin and six other antibiotics frequently used in respiratory tract infections, against 1563 Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis clinical isolates from 21 centers in 10 Latin American countries from March 2000 to April 2001. Moxifloxacin was the most active compound against all the species included. Moxifloxacin was 2- to 4-fold more active than levofloxacin against Gram-positive bacteria. This difference was much higher against levofloxacin-resistant S. pneumoniae isolates (MIC: 0.5 mg/l vs 8 mg/l). The activity of moxifloxacin against H. influenzae and M. catarrhalis was similar to levofloxacin; all the isolates were inhibited at < or = 1 mg/l concentrations of moxifloxacin and levofloxacin.

Anti-Infective Agents↗
PubMed2001

trans-2,4,4,6,8,8-Hexamorpholino-2,6-bis(n-propylamino)cyclo-2lambda5,4lambda5,6lambda5,8lambda5-tetraphosphazatetraene.

The title compound, C(30)H(64)N(12)O(6)P(4), consists of a centrosymmetric chair-shaped cyclic tetrameric phosphazene ring with six bulky morpholino and two n-propylamino side groups. The two n-propylamino side groups are in trans positions. The bulky substituents mainly determine the eight-membered-ring conformation. The endocyclic N-P-N angles around the P atoms having different substituents are not the same as the P-N-P angles of the macrocyclic ring.

Aza Compounds↗
PubMed1998

In vitro activity of BAY 12-8039, a new fluoroquinolone, against species representative of respiratory tract pathogens.

The in vitro antibacterial activity of BAY 12-8039, a novel 8-methoxy-quinolone, was compared with those of other quinolones, amoxicillin/clavulanate, cefuroxime and erythromycin against species commonly implicated in respiratory tract infections as well as viridans group streptococci. The new compound was highly active against methicillin-susceptible staphylococci (MIC90 0.125 microgram/ml), penicillin-susceptible and penicillin-resistant pneumococci (MIC90 0.5 and MIC50 0.25 microgram/ml, respectively), penicillin-susceptible and penicillin-resistant viridans group streptococci (MIC90 0.5 and 0.25 microgram/ml, respectively), group A streptococci (MIC90 0.25 microgram/ml), M. catarrhalis (MIC90 0.125 microgram/ml) and H. influenzae (MIC90 0.063 microgram/ml), irrespective of beta-lactamase production. It was, however, less active against methicillin-resistant staphylococci (MIC50 and MIC90, 2 and 4 micrograms/ml, respectively). The new compound demonstrated bactericidal activity at concentrations 2, 4, 8 times the MIC against representative isolates of the above collection. At a concentration of eight times the MIC, the frequency of spontaneous resistance ranged from 2.5 x 10(-7) to < 4 x 10(-8). These results suggested that BAY 12-8039 would be a promising agent for the eradication of respiratory tract pathogens and that clinical trials assessing its efficacy for the management of infections caused by these organisms are warranted.

Amoxicillin↗
PubMed2006

Hydrogen bonding in meso-4,5-diphenyl-3,6-diazaoctane-1,8-diol: the formation of one-dimensional linear chains of edge-fused rings.

The molecule of the title compound, C18H24N2O2, resides on a crystallographic inversion centre. The molecule adopts a transoid conformation with respect to the central C-C single bond and is in the meso form. A polarimetric study of the compound did not show any optical activity, indicating that the compound is a racemic mixture entirely consistent with the centrosymmetric C2/c space group. In the molecule, there is one intramolecular N-H...O interaction, resulting in the formation of a five-membered ring. In the crystal structure, intermolecular O-H...N and C-H...O interactions are also observed. These interactions form an R2(2)(9) ring and one-dimensional linear chains of edge-fused rings running parallel to the [010] direction, which stabilize the crystal packing.

Aza Compounds↗