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A new series of 8-halogen-4,4a,5,6-tetrahydrothieno[2,3-h]cinnolinone-N2-alkanoic acids was prepared and tested for aldose reductase (ALR2) inhibitory activities. These compounds showed significant inhibitory activity against bovine lens ALR2, with the best compound 2e showing an IC(50) value of 31.4 microM. The presence of the C8-substituents here studied (Cl, Br) on the thienocinnolinone scaffold caused a decrease of the inhibitory potency by a factor of about 4 with respect to the unsubstituted parent compound, while the presence of a C8-methyl group, considered in a previous paper decreased the activity by a factor of about 2. Moreover, the length of the N2 alkanoic chain influences strongly the enzyme inhibitory activity. While most of the carboxylic acids ALR2 inhibitors are acetic acid derivatives, in the case of thienocinnolinone compounds, homologues higher than acetic acids showed to be more active.

The effects of intrastriatal infusion of 3-morpholinosydnonimine (SIN-1) or sodium nitroprusside (SNP) on dopamine (DA), 3-methoxytyramine (3-MT), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), L-dihydroxyphenylalanine (L-DOPA), ascorbic acid and uric acid concentrations in dialysates from the striatum of freely moving rats were evaluated using microdialysis. SIN-1 (1 mM) infusion for 180 min increased microdialysate DA and 3-MT concentrations, while L-DOPA, DOPCA+HVA, ascorbic acid and uric acid levels were unaffected. Co-infusion with ascorbic acid (0.1 mM) inhibited SIN-1-induced increases in DA and 3-MT dialysate concentration. SNP (1 mM) infusion for 180 min increased greatly the dialysate DA concentration to a peak (2950% of baseline) at the end of the infusion, while increases in 3-MT were negligible. In addition, SNP decreased ascorbic acid and L-DOPA but increased uric acid concentration in the dialysate. Co-infusion with deferoxamine (0.2 mM) inhibited the late SNP-induced increase in DA dialysate concentration, but did not affect the decrease in ascorbic acid and increase uric acid dialysate concentrations. SNP (1 mM) infusion for 20 min moderately increased uric acid, DA and 3-MT, but decreased L-DOPA levels in the dialysate. Ascorbic acid concentration increased at the end of SNP infusion. Co-infusion with ascorbic acid (0.1 mM) inhibited the SNP-induced increase in DA and 3-MT, but did not affect the decrease in L-DOPA and increase in uric acid dialysate concentrations. These results suggest that NO released from SIN-1 may account for the increase in the dialysate DA concentration. NO released following decomposition of SNP may account for the early increase in dialysate DA, while late changes in microdialysate composition following SNP may result from an interaction between NO and the ferrocyanide moiety of SNP. Exogenous ascorbic acid inhibits the effect of exogenous NO on DA release probably by scavenging NO, suggesting that endogenous ascorbic acid may modulate the NO control of DA release from 300 striatal dopaminergic terminals.

We have previously shown that manganese enhances L-dihydroxyphenylanine (L-DOPA) toxicity to PC12 cells in vitro. The supposed mechanism of manganese enhancing effect [an increase in L-DOPA and dopamine (DA) auto-oxidation] was studied using microdialysis in the striatum of freely moving rats. Systemic L-DOPA [25 mg kg−1 intraperitoneally (i.p.) twice in a 12 h interval] significantly increased baseline dialysate concentrations of L-DOPA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and uric acid, compared to controls. Conversely, DA and ascorbic acid concentrations were significantly decreased. A L-DOPA oxidation product, presumptively identified as L-DOPA semiquinone, was detected in the dialysate. The L-DOPA semiquinone was detected also following intrastriatal infusion of L-DOPA. In rats given L-DOPA i.p., intrastriatal infusion of N-acetylcysteine (NAC) significantly increased DA and L-DOPA dialysate concentrations and lowered those of L-DOPA semiquinone; in addition, NAC decreased DOPAC+HVA and uric acid dialysate concentrations. In rats given L-DOPA either systemically or intrastriatally, intrastriatal infusion of manganese decreased L-DOPA dialysate concentrations and greatly increased those of L-DOPA semiquinone. These changes were inhibited by NAC infusion. These findings demonstrate that auto-oxidation of exogenous L-DOPA occurs in vivo in the rat striatum. The consequent reactive oxygen species generation may account for the decrease in dialysate DA and ascorbic acid concentrations and increase in enzymatic oxidation of xanthine and DA. L-DOPA auto-oxidation is inhibited by NAC and enhanced by manganese. These results may be of relevance to the L-DOPA long-term therapy of Parkinson's disease. British Journal of Pharmacology (2000) 130, 937–945; doi:10.1038/sj.bjp.0703379

Levels of ascorbic acid (AA), dehydroascorbic acid (DHAA), glutathione (GSH), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), noradrenaline (NA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and 1-methyl-4-phenylpyridinium ion (MPP+) were determined in the striatum, striatal synaptosomes, and/or brain stem of 3- and 6-month-old male Wistar rats given MPTP 35-52 mg/kg IP. In older rats, MPTP 35 mg/kg caused a 38% death rate within 15 min-12 h. Levels of MPTP and MPP+ in the striatum, synaptosomes, and brain stem were directly correlated with the absolute MPTP dose/rat. MPTP decreased striatal DA metabolites and NA levels in the striatum and brain stem, and increased uric acid levels in all regions in all rats. All these changes were significantly correlated with MPP+ levels. GSH levels were increased in younger rats and decreased in older rats. AA oxidation was increased mainly in older rats. We conclude that acute lethality and regional brain MPTP and MPP+ levels depend upon the absolute dose of MPTP/rat rather than the relative dose/kg. In younger rats, the neuronal antioxidant GSH system is more efficient than in older rats, in which the response to MPP(+)-induced oxidative stress also involves AA oxidation. The increase in uric acid levels provides further evidence for a mechanism of MPTP neurotoxicity involving oxidative stress mediated by xanthine oxidase.

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12-35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was significantly correlated to MPP+ concentrations (r = -0.840, P0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = -0.709, P0.05, and r = +0.888, P0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.

A series of bis(benzo[ g ]indoles) bridged by CX-(CH 2 ) n N(Me)(CH 2 ) n -CX (X = O, S, H 2 ; n = 2,3) was synthesized as bifunctional antitumor agents and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. The parent compounds 2a,b exhibited a good level of activity and derivates 2c - g,i,k demonstrated significant inhibitory effects, all with IC 50 values in the low micromolar range. The thioamide analogue 2j showed less potency. It is interesting to note that introduction of substituents on the benzene ring of the benzo[ g ]indole portion of 2a,b did not affect activity, with the only exception of the 7,8-dichloro derivative 2h which became less potent. One member of this series, 2i, was then tested in the hollow fiber cell assay to evaluate, in a preliminary fashion, its in vivo antineoplastic activity. Molecular modelling studies were performed on amide 2a and thioamide 2j to explain the loss of activity of 2j as to 2a. Finally, compound 2a behaved as a typical DNAintercalating agent, as judged from viscosity measurements with Poly(dA-dT) .. poly(dA-dT).

In our search for novel anti-human immunodeficiency virus (HIV)-1 agents, 14 delavirdine analogues were synthesized and evaluated as potential anti-HIV-1 agents in cell-based assays. Compound 1Aa exhibited potent and selective anti-HIV-1 activity in acutely infected MT4 cells, with effective concentration (EC50) values in the submicromolar range.

Designed as a new group of tricyclic molecules containing the thienocycloheptapyridazinone ring system, a number of 2N-substituted-hexahydrothieno-cycloheptapyridazinone derivatives were synthesized and their biological activity evaluated. Among the synthesized compounds, derivatives 7d and 7h were found to possess cytotoxic activity against non-small cell lung cancer and central nervous system cancer cell lines, respectively.

We showed previously that exogenous iron potentiated nitric oxide (NO) donor-induced release of striatal dopamine (DA) in freely moving rats, using microdialysis. In this study, the increase in dialysate DA induced by intrastriatal infusion of the NO-donor 3-morpholinosydnonimine (SIN-1, 1.0 mM for 180 min) was scarcely affected by Ca2+ omission. N-methyl- d -glucamine dithiocarbamate (MGD) is a thiol compound whose NO trapping activity is potentiated by iron(II). Intrastriatal co-infusion of MGD either alone or associated with iron(II), however, potentiated SIN-1-induced increases in dialysate DA. In contrast, co-infusion of the NO trapper 4-(carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO) significantly attenuated the increase in dialysate DA induced by SIN-1 (5.0 mM for 180 min). SIN-1+MGD+iron(II)-induced increases in dialysate DA were inhibited by Ca2+ omission or co-infusion of either deferoxamine or the L-type (Cav 1.1–1.3) Ca2+ channel inhibitor nifedipine; in contrast, the increase was scarcely affected by co-infusion of the N-type (Cav 2.2) Ca2+ channel inhibitor ω-conotoxin GVIA. These results demonstrate that exogenous NO-induced release of striatal DA is independent on extracellular Ca2+; however, in presence of the NO trapper MGD, NO may preferentially react with either endogenous or exogenous iron to form a complex which releases striatal DA with an extracellular Ca2+-dependent and nifedipine-sensitive mechanism.

A series of 4,5-dihydro-1 H -benzo[ g ]indazole-3-carboxamides ( 2a – k ) as analogues of the previously reported CB 2 ligands 6-chloro- and 6-methyl-1-(2′,4′-dichlorophenyl)- N -piperidin-1-yl-1,4-dihydroindeno[1,2- c ]pyrazole-3-carboxamides ( 1a , b ) was synthesized and their affinity and selectivity towards CB 1 and CB 2 receptors were evaluated. Several of the new compounds ( 2a , b , c , d and i ) exhibited CB 1 affinity in the nanomolar range with moderate or negligible affinity towards CB 2 receptors. Compounds 2a and c increased intestinal propulsion in mouse. Their pro-kinetic effects were reversed by the reference CB agonist CP-55,940. Consequently, in vivo CB 1 antagonistic activity was highlighted for these compounds.

Tricyclic pyrazole dimers that comprise two kinds of CONH-(CH(2))(n)-N(CH(3))-(CH(2))(n)-NHCO bridges to which are linked potential DNA-intercalating groups such as 1H-benzo[g]indazole, 2H-benzo[g]indazole and 1,4-dihydroindeno[1,2-c]pyrazole were designed, synthesized and some of them evaluated in vitro by NCI (Bethesda, USA) against nine types of cancer cells. Compounds 2a, 2f-i and 2o-r demonstrated significant antiproliferative activity, all with GI(50) values in the low micromolar range. Preliminary analysis of the structure-activity relationship for dimers 2 indicated that: (i) in the ground terms (2a and 2k) antitumor activities were strongly related to the type of chromophore, (ii) in contrast, either 1H-benzo[g]indazole- or 1,4-dihydroindeno[1,2-c]pyrazole-dimers when bore a N(1)-aryl group (2g, 2h, 2i, 2o, 2p, 2q and 2r) generally showed a good level of antitumor potency and (iii) for the most representative compounds (pairs of compounds: 2g,2h; 2o,2p and 2q,2r) the length of the bridges did not significantly contribute to the variations in cytotoxicity. Two members of this series, 2f and 2q, were selected and tested in the hollow fiber cell assay to evaluate in a preliminary fashion their in vivo antitumor activity. Finally, viscosity measurement of 2f with poly(dA-dT)(2), confirmed that these promising compounds behaved as typical DNA-intercalating agents.

Designed as a new series of so called “bivalent ligand” containing the proposed 2-benzylnaphthimidazole-type structure, a number of 2-benzylnaphth[2,3-d]imidazoles, bearing various substituents, have been prepared by a synthetic approach involving an heterocyclization of 2,3-diaminonaphthalene 4 with appropriate imidates 3 (for 1b–i) followed by alkylation (for 1j–l) with the desired alkylating agent. Compounds 1b–f, h–l were subjected to primary biological evaluation for cancer cell growth inhibition (one-dose, three-cell assay), and the four most active terms, 1c, h, i and j, were then evaluated for their cytotoxic profiles in the National Cancer Institute’s (NCI) human disease-oriented, 60 cell line, in vitro antitumor screening protocol. Among them, two compounds (1h and 1i) are the most representatives demonstrating not only high growth-inhibitory activities against some leukemia cancer cells, but also fairly good activities against the growth of certain cell lines of some solid tumors.

In our search for novel anti-human immunodeficiency virus (HIV)-1 agents, 14 delavirdine analogues were synthesized and evaluated as potential anti-HIV-1 agents in cell-based assays. Compound 1Aa exhibited potent and selective anti-HIV-1 activity in acutely infected MT4 cells, with effective concentration (EC50) values in the submicromolar range.

A series of bis(benzo[ g ]indoles) bridged by CX-(CH 2 ) n N(Me)(CH 2 ) n -CX (X = O, S, H 2 ; n = 2,3) was synthesized as bifunctional antitumor agents and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. The parent compounds 2a,b exhibited a good level of activity and derivates 2c - g,i,k demonstrated significant inhibitory effects, all with IC 50 values in the low micromolar range. The thioamide analogue 2j showed less potency. It is interesting to note that introduction of substituents on the benzene ring of the benzo[ g ]indole portion of 2a,b did not affect activity, with the only exception of the 7,8-dichloro derivative 2h which became less potent. One member of this series, 2i, was then tested in the hollow fiber cell assay to evaluate, in a preliminary fashion, its in vivo antineoplastic activity. Molecular modelling studies were performed on amide 2a and thioamide 2j to explain the loss of activity of 2j as to 2a. Finally, compound 2a behaved as a typical DNAintercalating agent, as judged from viscosity measurements with Poly(dA-dT) .. poly(dA-dT).

The synthesis of the 6-fluoro (I a), 6-chloro (I b) and 6-bromo (I c) derivatives of the known antiinflammatory agent 2-(3-benzoylphenyl)propionic acid (ketoprofen) is reported. The procedure employed involves the direct phase-transfer methylation of the appropriate arylacetonitriles and the subsequent hydrolysis of the alpha-methyl arylacetonitriles (V) thus obtained. It is noteworthy that (V b) and (V c) were not accompanied by alpha, alpha-dimethylated contaminants, owing to the steric hindrance of the chloro and bromine substituent. The pharmacological evaluation of (I a-c) showed that the presence of the halogen unexpectedly abolished the antiinflammatory and antipyretic activities of the model drug. The 6-ethoxy derivative (I d), isolated as by-product of the synthesis of (I a) was also found inactive. A hypothesis has been formulated on the loss of activity of these compounds.