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Query: UNIPROT:P06889 (Mol)
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The results of experimental studies and quantum chemical simulations of the absorption spectra of 1H-pyrazolo[3,4-b]quinoline and its derivatives are presented. The quantum chemical calculations (semi-empirical AM1 and PM3 methods) show similarity in the absorption spectra of 1H-pyrazolo[3,4-b]quinoline and 1,3-dimethyl-1H-pyrazolo[3,4-b]quinoline which are characterized by five strong absorption bands in the spectral range 200-500 nm. A substitution of the methyl groups by at least one phenyl group causes the drastic changes of the absorption spectra mainly within the spectral range 240-370 nm. We attribute these differences to additional molecular double bonding segments C=C of the substituted phenyl groups, i.e. to pi --> pi* transitions. A comparison of measured and the calculated absorption spectra manifests quite satisfactory agreement for all compounds in the part regarding the spectral position of the first oscillator (absorption threshold). At the same time, the measured spectra demonstrate the considerable broadening practically of all absorption bands and even complete damping some of them in the case of phenyl derivatives. The experiments performed with highly and weakly polar organic solvents shows that the solvent effect on the absorption spectra is small. For this reason the discrepancies between the calculated and the measured spectra are attributed to electron-vibronic coupling as well as to rotational dynamics of phenyl rings.
Spectrochim Acta A Mol Biomol Spectrosc 2004 Nov
PMID:Optical absorption of 1H-pyrazolo[3,4-b]quinoline and its derivatives. 1547 50

In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the nongenotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the noncarcinogen acetaminophen (AAP), were investigated in guanine phosphoribosyltransferase (gpt) delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-wk treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred, although GST-P staining was consistently negative. Positive mutagenicity was detected in IQ- and NPYR-treated rats. Mutant frequencies (MFs) in the liver DNA were 188.0 x 10(-6) and 56.5 x 10(-6), approximately 35-fold and 10-fold higher, respectively, than that of nontreatment control rats (5.5 x 10(-6)). There were no increases in MFs in the DEHP- or AAP-treated rats as compared to the nontreatment control value. IQ induced mainly base substitutions leading to G:C to T:A transversions (56.9%) and deletions of G:C base pairs. In contrast, NPYR primarily caused specific A:T to G:C transitions (49.3%), which are very rare in the other groups. These data provided support for the conclusion that IQ and NPYR hepatocarcinogenesis depends on genotoxic processes and specific DNA adduct formation while DEHP exerts its influence via a nongenotoxic promotional pathway. Our data also indicate that analysis of specific in vivo mutational responses with transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis.
Mol Carcinog 2005 Jan
PMID:In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N-nitrosopyrrolidine, 2-amino-3-methylimidazo[4,5-f]quinoline, and di(2-ethylhexyl)phthalate. 1548 47

New terbium complexes of derivatives of 2-oxo-4-hydroxy-quinoline-3-carboxylic acid are reported, which are highly luminescent, water soluble and do not require luminescence enhancers. The triplet-state energy levels of the ligands, the relative quantum yields (QYs) and the excitation maxima of the respective terbium chelates were determined. The large luminescence enhancement of one of these complexes by nucleic acids was investigated and a mechanism of its interaction with DNA is proposed. The optimal conditions for determination of DNA are equal concentrations of Tb(3+) and ligand R(1) (C = 1 x 10(-6) M), pH 9.0. Under optimal conditions the luminescence intensity (RI) is proportional to the concentration of fish sperm DNA (fsDNA) or calf thymus DNA (ctDNA), respectively, within the range of 0.05-1.5 microg ml(-1). The detection limits were 10 ng ml(-1) for fsDNA and 12 ng ml(-1) for ctDNA.
Spectrochim Acta A Mol Biomol Spectrosc 2005 Jan 01
PMID:New luminescent terbium complex for the determination of DNA. 1555 28

Recent studies have highlighted the importance of a parasite protein referred to as the chloroquine resistance transporter (PfCRT) in the molecular basis of Plasmodium falciparum resistance to the quinoline antimalarials. PfCRT, an integral membrane protein with 10 predicted transmembrane domains, is a member of the drug/metabolite transporter superfamily and is located on the membrane of the intra-erythrocytic parasite's digestive vacuole. Specific polymorphisms in PfCRT are tightly correlated with chloroquine resistance. Transfection studies have now proven that pfcrt mutations confer verapamil-reversible chloroquine resistance in vitro and reveal their important role in resistance to quinine. Available evidence is consistent with the view that PfCRT functions as a transporter directly mediating the efflux of chloroquine from the digestive vacuole.
Mol Microbiol 2005 Apr
PMID:Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. 1581 27

We present here results of experimental studies and quantum-chemical simulations of optical absorption and optical poling effects performed on a new synthesized cyan, ethylcarboxyl and tert-buthyl derivatives of 1H-pyrazolo[3,4-b]quinoline incorporated into polymer matrix or dissolved in organic solutions. The efficiency of second-order optical susceptibility d vs photoinduced power density I(p) clearly saturates to certain magnitude d(eff) at sufficient power densities (I(p) > or = 1.3 GW cm(-2)). Comparing experimental data and results of semiempirical quantum-chemical simulations one can conclude that there exists generally a good correlation between the magnitude of saturated susceptibilities d(eff) and macroscopic hyperpolarizabilities for all compounds except the chromophore 1,3-dimethyl-6-cyano-[PQ] only. The discrepancy for this compound may reflect a specific contribution of surrounding polymer matrix. According to the quantum chemical analysis the methyl-containing cyan and ethylocarcoxyl derivatives reveal four/five strong absorption bands in the spectral range 200-500 nm. A substitution of the methyl groups by the phenyl group causes the substantial changes of the absorption spectra mainly in the spectral range 240-370 nm. Measured and calculated absorption spectra manifest rather good agreement mainly in the part regarding the spectral positions of the first oscillator (absorption threshold). The quantum-chemical PM3 method shows the best agreement with experiment. At the same time a considerable broadening almost of all absorption bands appears as a characteristic feature of all measured spectra. The discrepancies between the calculated and the measured spectra are attributed to electron-vibronic coupling as well as to a specific rotational dynamics of phenyl rings.
Spectrochim Acta A Mol Biomol Spectrosc 2005 Jun
PMID:Optical poling effect and optical absorption of cyan, ethylcarboxyl and tert-buthyl derivatives of 1H-pyrazolo[3,4-b]quinoline: experiment and quantum-chemical simulations. 1586 69

Ferroquine (FQ) is a 4-aminoquinoline antimalarial which contains a quinoline nucleus similar to chloroquine, but a novel ferrocenic group in its side chain. Previous work has demonstrated that this compound has excellent activity against malaria parasites, both in vitro and in vivo, with especially good activity against chloroquine-resistant parasites, but details of its mechanism of action have not previously been reported. In this study, we have investigated the physicochemical properties of FQ for comparison with chloroquine (CQ). Like CQ, FQ forms complexes with hematin in solution (log K = 4.95 +/- 0.05). FQ is an even stronger inhibitor of beta-hematin formation than CQ (IC(50) = 0.78 equiv relative to hematin for FQ vs 1.9 for CQ). These data suggest that the mechanism of action of FQ is likely to be similar to that of CQ and probably involves hematin as the drug target and inhibition of hemozoin formation. However, both the basicity and lipophilicity of FQ are significantly different from those of CQ. The lipophilicity of FQ and CQ are similar when protonated at the putative food vacuole pH of 5.2 (log D = -0.77 and -1.2 respectively), but differ markedly at pH 7.4 (log D = 2.95 and 0.85 respectively). In addition, the pK(a) values of FQ are lower (pK(a1) = 8.19 and pK(a2) = 6.99) than those of CQ (10.03 and 7.94, respectively). This suggests that there will be somewhat less vacuolar accumulation of FQ compared with CQ. Single crystal structure determination of FQ shows the presence of a strong internal hydrogen bond between the 4-amino group and the terminal N atom. This, together with the electron donating properties of the ferrocene moiety, probably explains the decreased pK(a). Interestingly, the decreased accumulation arising from the less basic behavior of this compound is partly compensated for by its stronger beta-hematin inhibition. Increased lipophilicity, differences in geometric and electronic structure, and changes in the N-N distances in FQ compared to CQ probably explain its activity against CQ-resistant parasites.
Mol Pharm
PMID:Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity. 1593 79

In this study, we report the effects of the quinoline derivatives quinine, its optical isomer quinidine, and chloroquine on alpha9alpha10-containing nicotinic acetylcholine receptors (nAChRs). The compounds blocked acetylcholine (ACh)-evoked responses in alpha9alpha10-injected Xenopus laevis oocytes in a concentration-dependent manner, with a rank order of potency of chloroquine (IC50 = 0.39 microM) > quinine (IC50 = 0.97 microM) approximately quinidine (IC50= 1.37 microM). Moreover, chloroquine blocked ACh-evoked responses on rat cochlear inner hair cells with an IC50 value of 0.13 microM, which is within the same range as that observed for recombinant receptors. Block by chloroquine was purely competitive, whereas quinine inhibited ACh currents in a mixed competitive and noncompetitive manner. The competitive nature of the blockage produced by the three compounds was confirmed by equilibrium binding experiments using [3H]methyllycaconitine. Binding affinities (Ki values) were 2.3, 5.5, and 13.0 microM for chloroquine, quinine, and quinidine, respectively. Block by quinine was found to be only slightly voltage-dependent, thus precluding open-channel block as the main mechanism of interaction of quinine with alpha9alpha10 nAChRs. The present results add to the pharmacological characterization of alpha9alpha10-containing nicotinic receptors and indicate that the efferent olivocochlear system that innervates the cochlear hair cells is a target of these ototoxic antimalarial compounds.
Mol Pharmacol 2005 Sep
PMID:Effects of quinine, quinidine, and chloroquine on alpha9alpha10 nicotinic cholinergic receptors. 1595 68

A decline in our ability to successfully treat patients with malaria infections of the parasitic protozoan Plasmodium falciparum with cheap quinoline drugs has led to a huge escalation in morbidity and mortality in recent years. Many approaches have been taken, including classical genetics, reverse genetics and molecular epidemiology, to identify the molecular determinants underlying this resistance. The contribution of the P. falciparum multidrug resistance gene, pfmdr1, to antimalarial resistance has been a source of controversy for over a decade since it was first identified. In the current issue of Molecular Microbiology, Sidhu and colleagues use powerful reverse genetics to demonstrate the importance of commonly occurring alleles of pfmdr1 in conferring resistance to the second-line drugs quinine and sensitivity to the new alternatives mefloquine and artemisinin. They also elegantly highlight the importance of genetic background and epistasis between pfmdr1 and other potential modulators of drug resistance. Such molecular knowledge will facilitate surveillance/monitoring and aid the development of strategies for the reversal of resistance.
Mol Microbiol 2005 Aug
PMID:Multiple drug resistance genes in malaria -- from epistasis to epidemiology. 1609 Oct 34

Intracellular reduction and oxidation pathways regulate protein functionality through both reversible and irreversible mechanisms. The Cdc25 phosphatases, which control cell cycle progression, are potential subjects of oxidative regulation. Many of the more potent Cdc25 phosphatase inhibitors reported to date are quinones, which are capable of redox cycling. Therefore, we used the previously characterized quinolinedione Cdc25 inhibitor DA3003-1 [NSC 663284 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] and a newly synthesized congener JUN1111 [7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] to test the hypothesis that quinone inhibitors of Cdc25 regulate phosphatase activity through redox mechanisms. Like DA3003-1, JUN1111 selectively inhibited Cdc25 phosphatases in vitro in an irreversible, time-dependent manner and arrested cells in the G1 and G2/M phases of the cell cycle. It is noteworthy that both DA3003-1 and JUN1111 directly inhibited Cdc25B activity in cells. Depletion of glutathione increased cellular sensitivity to DA3003-1 and JUN1111, and in vitro Cdc25B inhibition by these compounds was sensitive to pH, catalase, and reductants (dithiothreitol and glutathione), consistent with oxidative inactivation. In addition, both DA3003-1 and JUN1111 rapidly generated intracellular reactive oxygen species. Analysis of Cdc25B by mass spectrometry revealed sulfonic acid formation on the catalytic cysteine of Cdc25B after in vitro treatment with DA3003-1. These results indicate that irreversible oxidation of the catalytic cysteine of Cdc25B is indeed a mechanism by which these quinolinediones inactivate this protein phosphatase.
Mol Pharmacol 2005 Dec
PMID:Redox regulation of Cdc25B by cell-active quinolinediones. 1615 9

GABA(A) receptors composed of alpha(1), beta(2), gamma(1) subunits are expressed in only a few areas of the brain and thus represent interesting drug targets. The pharmacological properties of this receptor subtype, however, are largely unknown. In the present study, we expressed alpha(1)beta(2)gamma(1)-GABA(A) receptors in Xenopus laevis oocytes and analyzed their modulation by 21 ligands from 12 structural classes making use of the two-microelectrode voltage-clamp method and a fast perfusion system. Modulation of GABA-induced chloride currents (I(GABA)) was studied at GABA concentrations eliciting 5 to 10% of the maximal response. Triazolam, clotiazepam, midazolam, 2-(4-methoxyphenyl)-2,3,5,6,7,8,9,10-octahydro-cyclohepta-(b)pyrazolo[4,3-d]pyridin-3-one (CGS 20625), 2-(4-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one (CGS 9896), diazepam, zolpidem, and bretazenil at 1 microM concentrations were able to significantly (>20%) enhance I(GABA) in alpha(1)beta(2)gamma(1) receptors. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, 3-methyl-6-[3-trifluoromethyl-phenyl]-1,2,4-triazolo[4,3-b]pyridazine (Cl 218,872), clobazam, flumazenil, 5-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-3-methyl-[1,2,4]-oxadiazole (Ru 33203), 2-phenyl-4-(3-ethyl-piperidinyl)-quinoline (PK 9084), flurazepam, ethyl-7-methoxy-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylate (l-655,708), 2-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-methyl-thiazole (Ru 33356), and 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)phenylmethanone (Ru 32698) (1 microM each) had no significant effect, and flunitrazepam and 2-phenyl-4-(4-ethyl-piperidinyl)-quinoline (PK 8165) inhibited I(GABA). The most potent compounds triazolam, clotiazepam, midazolam, and CGS 20625 were investigated in more detail on alpha(1)beta(2)gamma(1) and alpha(1)beta(2)gamma(2S) receptors. The potency and efficiency of these compounds for modulating I(GABA) was smaller for alpha(1)beta(2)gamma(1) than for alpha(1)beta(2)gamma(2S) receptors, and their effects on alpha(1)beta(2)gamma(1) could not be blocked by flumazenil. CGS 20625 displayed the highest efficiency by enhancing at 100 microM I(GABA) (alpha(1)beta(2)gamma(2)) by 775 +/- 17% versus 526 +/- 14% I(GABA) (alpha(1)beta(2)gamma(1)) and 157 +/- 17% I(GABA) (alpha(1)beta(2)) (p < 0.05). These data provide new insight into the pharmacological properties of GABA(A) receptors containing gamma(1) subunits and may aid in the design of specific ligands for this receptor subtype.
Mol Pharmacol 2006 Feb
PMID:Pharmacological properties of GABAA receptors containing gamma1 subunits. 1627 24


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