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Some new substituted pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones were prepared and their cytotoxic activity was evaluated using acronycine as the reference compound. The conformation of the molecules was also investigated in an effort to correlate this parameter with the biological activity.
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We have previously shown that phenothiazines sensitize multidrug resistant (MDR) cells to chemotherapeutic drugs in a manner related to specific structural features, and have identified structurally related thioxanthenes with increased anti-MDR activity. We have now studied the structure-activity relationships of 16 thioxanthenes in the human breast cancer line MCF-7 AdrR. trans-Thioxanthene stereoisomers were 2- to 7-fold more potent than cis-thioxanthenes for antagonizing MDR. The most potent thioxanthenes possessed a halogenated tricyclic ring connected by a 3-carbon alkyl bridge to a piperazinyl or piperadinyl side group. The chemosensitizing effects of the lead compound, trans-flupenthixol, its stereoisomer cis-flupenthixol, its phenothiazine homologue fluphenazine, and the calcium channel blocker verapamil, were further studied in a series of sensitive and MDR cell lines. trans-Flupenthixol caused a greater reversal of cellular resistance to doxorubicin, vinblastine, vincristine, and colchicine in MCF-7 AdrR, KB-V1, and P388/DOX MDR cells than the other chemosensitizers. In particular, trans-flupenthixol was 2- to 3-fold more potent for reversing MDR than equimolar concentrations of verapamil. Furthermore, trans-flupenthixol fully reversed resistance to doxorubicin, vincristine, and colchicine in MDR MCF-7 and NIH 3T3 cells transfected with the mdr1 gene. None of these agents altered MDR in a non-P-glycoprotein expressing MCF-7 cell line selected with mitoxantrone, nor in any of the parental cell lines. The stereoselective antagonism of the flupenthixol isomers on several putative cellular targets was studied to explore the mechanism of their chemosensitizing activity. cis- and trans-flupenthixol were equally active inhibitors of protein kinase C and calmodulin. Both cis- and trans-flupenthixol were also potent inhibitors of [3H]azidopine binding to P-glycoprotein. The apparent lack of clinical toxicity of trans-flupenthixol makes it an attractive drug for possible use in the modulation of tumor resistance in vivo if appropriate tissue concentrations can be achieved.
Five acidic calix[4]arenes with carboxylic or sulfonic groups at either the upper or lower rim of the cavity and one resorc[4]arene were investigated to separate three thioxanthenes (flupentixol, clopenthixol, chlorprothixene) and a dibenz[b,e]oxepin derivative (doxepin) with cis-/trans-isomerism by nonaqueous capillary electrophoresis (NACE). Partial filling of the capillary with the UV-absorbing selectors led to a low detection limit and an advantageous signal-to-noise ratio (S/N). A sufficient electrophoretic mobility of the calixarenes towards the anode was necessary to outweigh the oppositely directed electroosmotic flow (EOF). This depended from the functional groups, the dissociation and the hydrodynamic radius of the cyclophanes. In contrast, the resorcinarene was useable only by addition of sodium dodecyl sulfate (SDS) because only the complex of the two selectors had an anodic apparent electrophoretic mobility. p-Sulfonyl-calix[4]arene (ss-a1) was the most capable selector for all E/Z-isomers with maximal alpha-values ranging from 1.056 for doxepin to 1.224 for chlorprothixene. This was due to the sufficient migration in reversed direction to the EOF even at low pH* values of 3.0. Otherwise, electrostatic as well as hydrophobic interactions with the positively charged isomers seem to contribute to a superior recognition. Increasing the concentration up to 15 mM ss-a1 and using acidic media (pH* 5.0) led to high separation efficiency. Changing the organic solvent provides a powerful tool to improve selectivity with N,N-dimethylformamide-methanol (DMF-MeOH)-mixtures for thioxanthenes. Further electrophoretic parameters were optimized, such as the concentration of the electrolytes, the addition of SDS, the kind of electrolytes and the voltage. Distinct differences in selectivities were found between the derivatives with thioxanthene and dibenzo[b,e]oxepin ring system, respectively. Further, the different basic side chain was responsible for the different selectivity at higher pH* values. In contrast, the substitution at position 2 of the thioxanthenes played a secondary role. Based on the studies of single parameters a method for a simultaneous separation of the four pairs of isomers within 13 min was developed.
The aim of the present investigation was to illustrate the antibacterial effect of various phenothiazine and thioxanthene derivatives on mycobacteria in vitro. It was demonstrated that clopenthixol is about twice as potent as chlorpromazine (CPZ) and levomepromazine-maleate is about half as potent as CPZ, measured by the inhibitory effect on the growth of the mycobacterial strains. Measured in the same way the stereoisomeric compounds of flupenthixol are shown to be more potent than the stereo-isomeric compounds of clopenthixol and chlorprothixen. The two last-named compounds are equal in potency. The stereo-isomeric analogs of the thioxanthene derivatives are equal in antibacterial potency against the slow-growing mycobacteria. The mycobacterial strains investigated show no difference in sensitivity between the cis (Z)--and and trans (E)--compounds of the thioxanthenes. It seems particularly promising that also the more resistant mycobacteria other than Mycobacterium tuberculosis, e.g. M. avium and M. intracellulare, are sensitive in the concentration range investigated. Considered as a whole, these results might be a stimulus to investigate the antimicrobial effect of the thioxanthenes in vivo.
Derivatives of 9-(1,3-dithiol-2-ylidene)fluorene (9) and 9-(1,3-dithiol-2-ylidene)thioxanthene (10) have been synthesised using Horner-Wadsworth-Emmons reactions of (1,3-dithiol-2-yl)phosphonate reagents with fluorenone and thioxanthen-9-one. X-ray crystallography, solution electrochemistry, optical spectroscopy, spectroelectrochemistry and simultaneous electrochemistry and electron paramagnetic resonance (SEEPR), combined with theoretical calculations performed at the B3P86/6-31G** level, elucidate the interplay of the electronic and structural properties in these molecules. These compounds are strong two-electron donors, and the oxidation potentials depend on the electronic structure of the oxidised state. Two, single-electron oxidations (E(1)ox < E(1)ox) were observed for 9-(1,3-dithiol-2-ylidene)fluorene systems (9). In contrast, derivatives of 9-(1,3-dithiol-2-ylidene)thioxanthene (10) display the unusual phenomenon of inverted potentials (E(1)ox > E(1)ox) resulting in a single, two-electron oxidation process. The latter is due to the aromatic structure of the thioxanthenium cation (formed on the loss of a second electron), which stabilises the dication state (10(2+)) compared with the radical cation. This contrasts with the nonaromatic structure of the fluorenium cation of system 9. The two-electron oxidation wave in the thioxanthene derivatives is split into two separate one-electron waves in the corresponding sulfoxide and sulfone derivatives 27-29 owing to destabilisation of the dication state.
Some neuroleptic drugs of the phenothiazine and thioxanthene groups have an antimicrobial effect in vitro. This is also true for neuroleptically inactive stereo-isomeric analogs of the thioxanthenes e.g. trans(E)-clopenthixol (t-CPT). In a murine pneumococcus peritonitis model t-CPT demonstrated a slight, but non-significant antibacterial effect in doses of 0.3-0.9 mg per mouse, while higher doses seemed to enhance the bacterial virulence. If combined with subtherapeutic doses of penicillin, a significantly higher survival rate was obtained compared with either drug given alone. In vitro studies demonstrated a similar synergistic effect. These results indicate that at least one non-neuroleptic thioxanthene stereo-isomer has an antibiotic potential also in vivo. The mechanism of action is not known.
A series of thioxanthenes was tested for cytotoxicity to isolated rat hepatocytes, as measured by the loss of an intracellular enzyme (GOT) to the surrounding medium. The relative order of potency was found to be: SKF 10812 greater than cis- = trans-chlorprothixene = N-756A greater than cis- = trans-flupenthixol greater than xanthiol greater than methixene = cis- = trans-clopenthixol = N-716 greater than N-710. The presence of an unsaturated exocyclic bond increased the apparent toxicity as did the presence of a substituent (trifluoromethyl, chlorine, bromine) at the two position of the tricyclic nucleus. The trifluoromethyl substituted thioxanthenes were three to four times more potent than their halogenated analogs, but there were no differences in potency among the halogenated (chlorine or bromine) thioxanthenes. Compounds which had a dimethylaminopropylidene side chain were five to six times stronger in causing enzyme leakage than were their analog which had a hydroxyethylpiperazinylpropylidene side chain. Although only the cis-isomers of each compound are highly active neuroleptics, both isomers were equipotent at causing the efflux of GOT from rat hepatocytes.
Benzamides or thioxanthenes were tested as potential antagonists of the cyclic AMP accumulation induced by 10(-4) M dopamine in intact rabbit retinae in vitro in the presence of 5 to 7 mM theophylline. The neuroleptic sulpiride (10(-4) M) was found to be totally inactive whereas a substituted benzamide (clebopride) had small but significant antagonist effect at the same concentration. Among thioxanthenes, isomers of cisconfiguration, which are potent neuroleptics, completely inhibit the cyclic AMP accumulation induced by dopamine, in contrast to trans-isomers which had no inhibitory effects. These data would confirm that retina in vitro is another suitable model for screening antipsychotic activity of classical neuroleptics and that the mechanism of action of sulpiride still needs further investigation.
An investigation of the structure-affinity relationships for the binding of thioxanthene-related structures indicates that an intact thioxanthene ring is not required for binding at sigma(1) receptors, and that with the appropriate structural modifications, affinity can be enhanced to the subnanomolar level. Certain of the analogs displayed sigma(1)-fold selectivity for sigma(1) versus sigma(2) receptors.
The chromatographic behavior of six calix[n]arene phases (n=4, 6, 8) and one calix[4]resorcinarene phase is described for the separation of cis- and trans-isomers of three thioxanthene (flupentixol, clopenthixol, chlorprothixene) and one benz[b,e]oxepin derivative (doxepin). The influences of two different organic modifiers (MeOH, MeCN) for the separation of the isomers on every column are described. Different selectivities of the stationary phases exist as a function of the ring size of the calixarenes and their substitution at the "upper rim" with p-tert.-butyl groups. Furthermore, the influence of free phenol groups on the resorcinarene phase is discussed. Relations between structural elements of the analytes and the retention behavior on the stationary phases are found. The selectivity of the calixarene and resorcinarene stationary phases is compared with a RP-C18 phase containing the same base silica. Advantages of the resorcinarene as well as of the calixarene columns exist for the separation of cis- and trans-isomers of three compounds dependent from the substitution in position 2 of the thioxanthenes, respectively the kind of the basic side chain of all substances.
The present study establishes correlations of in vivo growth inhibition of a solid tumor, pancreatic ductal adenocarcinoma (Panc03), of mice with the steric and electrostatic fields and the hydrophobic parameter log P of a series (32) of 1-[[2-(dialkylamino)alkyl]amino]- 9H-thioxanthen-9-ones by the 3D-QSAR method comparative molecular field analysis (CoMFA). The template molecular model was hycanthone methanesulfonate (19), the structure of which had been established previously by X-ray crystallography. The hycanthone base is protonated at the terminal nitrogen N(2), and an intramolecular hydrogen bond is present between the proximal nitrogen N(1) and carbonyl oxygen O(1) atoms. Crystallographic data also indicate a planar arrangement of bonds around N(1). However, the molecular geometry of 19, optimized by semiempirical molecular orbital methods (PM3, MNDO, AM1), showed the expected trigonal-pyramidal configuration for N(1). A comparison of MO and ab initio methods applied to a model compound, 1-amino-9H-thioxanthen-9-one, led to the selection of PM3 as the method for full geometry optimization of first the cationic and then the neutral forms of 1-32, whereas AM1 provided atomic charges for these same structures save those incorporating a sulfonamide moiety (5, 7, 20, 25, 26, 29, 31, and 32). Acceptable values for the latter were obtained from ab initio calculations. Structures were aligned by minimizing root-mean-square (rms) differences in the fitting of structures to 19 using the FIT option of SYBYL. An alternative strategy of alignment, steric and electrostatic alignment (SEAL), was invoked to provide a comparison of statistical data generated with the rms alignment. The rms-fit alignment of structures produced slightly better cross-validated and conventional r2 values than those generated with the SEAL method. In addition, the rms-fit data indicate that a shift in the lattice of one-half of its spacing has a much smaller effect on the CoMFA data for a lattice of 1 A than one of 2 A. Inclusion of log P in a CoMFA of the neutral structures effected a small (ca. 8-10%) but significant improvement in cross-validated r2 values. The relative contributions of the hydrophobic effects and the steric and electrostatic fields to the conventional r2 values were 16%, 42%, and 42%, respectively. By contrast, incorporation of frontier molecular orbital (HOMO and LUMO) energies or their gaps in the PLS analyses failed to enhance correlation coefficients derived for either the charged or uncharged compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
Conformational analyses have been performed on several phenothiazine and thioxanthene dopamine antagonists using the MM2-87 program and parameter set. The compounds that were examined are thioridazine (2), methotrimeprazine (3), cis- and trans-chlorprothixene, and a piperidylidene derivative of chlorprothixene. In addition, (+)-2 and (-)-3 were determined by X-ray crystallography to have the R absolute configuration. The above compounds were superimposed onto loxapine, which was used as a template for the previously proposed dopamine D2 receptor ligand model. The conformational properties and receptor affinities of these compounds were found to be entirely consistent with the ligand model. For example, a conformer of (+)-R-2 that is consistent with the ligand model is lower in energy than a consistent conformer for (-)-S-2, which agrees with the higher D2 receptor affinity of the former. Similarly, in agreement with the much higher affinity of (-)-R-3 relative to (+)-S-3, only the former contains a low energy conformer consistent with the ligand model. The ligand model is also consistent with the greater potency of cis-thioxanthenes over the trans isomers. These results emphasize the importance of the correct orientation of the ammonium hydrogen for high affinity at the D2 receptor. The pharmacophore for D2 receptor ligands is compared with a recently proposed pharmacophore for D1 ligands.
Efflux-related multidrug resistance (MDR) is a significant means by which bacteria can evade the effects of selected antimicrobial agents. Genome sequencing data suggest that Staphylococcus aureus may possess numerous chromosomally encoded MDR efflux pumps, most of which have not been characterized. Inhibition of these pumps, which may restore clinically relevant activity of antimicrobial agents that are substrates for them, may be an effective alternative to the search for new antimicrobial agents that are not substrates. The inhibitory effects of selected phenothiazines and two geometric stereoisomers of the thioxanthene flupentixol were studied using strains of S. aureus possessing unique efflux-related MDR phenotypes. These compounds had some intrinsic antimicrobial activity and, when combined with common MDR efflux pump substrates, resulted in additive or synergistic interactions. For S. aureus SA-1199B, which overexpresses the NorA MDR efflux pump, and for two additional strains of S. aureus having non-NorA-mediated MDR phenotypes, the 50% inhibitory concentration (IC(50)) for ethidium efflux for all tested compounds was between 4 and 15% of their respective MICs. Transport of other substrates was less susceptible to inhibition; the prochlorperazine IC(50) for acriflavine and pyronin Y efflux by SA-1199B was more than 60% of its MIC. Prochlorperazine and trans(E)-flupentixol were found to reduce the proton motive force (PMF) of S. aureus by way of a reduction in the transmembrane potential. We conclude that the mechanism by which phenothiazines and thioxanthenes inhibit efflux by PMF-dependent pumps is multifactorial and, because of the unbalanced effect of these compounds on the MICs and the efflux of different substrates, may involve an interaction with the pump itself and, to a lesser extent, a reduction in the transmembrane potential.
The hitherto existing investigations on the placental transfer of psycholeptic drugs mostly do not answer the question whether the active compounds themselves or their metabolites or both get into the fetus. As published informations on this problem partly are contradictory the placental transfer of psycholeptic drugs was investigated with the thioxanthenes flupentixol and chlorprothixen for examples. After oral application to rats on the 15th and 20th days of gestation the intact thioxenthenes themselves as well as their sulfoxides and desalkylated metabolites were detectable in placenta, uterus and fetus. The last mentioned substances and the intact thioxanthenes were determined quantitatively. The concentration (mug/g tissue) in the fetus is lower than in uterus and placenta. The results are discussed.
Total fatty acids were analysed in thrombocytes of schizophrenic patients treated with a "high dose" or "low dose" monotherapy of neuroleptic drugs phenothiazine or thioxanthene. The ratio of the very long chain fatty acid hexacosanoic acid to the long chain fatty acid docosanoic acid (C26:0/C22:0) increased in the "high dose" and "low dose" groups as compared to healthy untreated controls (P less than 0.05). The polyunsaturated fatty acid arachidonic acid decreased in the "high" and "low dose" groups (P less than 0.01 and P less than 0.05). The polyunsaturated fatty acids alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid were not detectable in most of the "high dose" schizophrenic patients, however, they were found in the "low dose" group and in the controls. There was a negative correlation between the daily dosage of phenothiazine and the percentages of the polyunsaturated fatty acids arachidonic acid and alpha-linolenic acid+eicosapentaenoic acid+docosahexaenoic acid in thrombocytes (r = -0.87, P less than 0.01 and r = -0.81, P less than 0.01). Two patients of the "high dose" group with an especially high and long lasting monotherapy of neuroleptics were nearly devoid of polyunsaturated fatty acids in their thrombocytes. Untreated schizophrenic patients exhibited a fatty acid pattern in their thrombocytes not markedly different from that of the healthy untreated control group. We conclude that neuroleptic drugs phenothiazine or thioxanthene can alter the fatty acid pattern of thrombocytes.
A flow-injection (FI) methodology using tris(2,2'-dipyridyl)ruthenium(II), [Ru(dipy)3(2+)], chemiluminescence (CL) was developed for the rapid and sensitive determination of three thioxanthene derivatives, namely zuclopenthixol hydrochloride, flupentixol hydrochloride and thiothixene. The method is based on the CL reaction of the studied thioxanthenes with [Ru(dipy)3(2+)] and Ce(IV) in a sulfuric acid medium. Under the optimum conditions, calibration graphs were obtained over the concentration ranges 0.002-6 migrograms/ml for zuclopenthixol hydrochloride, 0.5-15 micrograms/ml for flupentixol hydrochloride and 0.05-7.5 micrograms/ml for thiothixene. The limits of detection (s/n = 3) were 4.2 x 10(-9) mol/l zuclopenthixol hydrochloride, 2 x 10(-8) mol/l flupentixol hydrochloride and 4.5 x 10(-8) mol/l thiothixene. The method was successfully applied to the determination of these compounds in dosage forms and biological fluids.
A series of new N-(9H-xanthen-9-yl)aminoalkanamide and N-(9H-thioxanthen-9-yl)aminoalkanamide derivatives was synthesized and evaluated as potential intercalators by measuring their DNA binding affinity. They were also tested for cytotoxic activity against L1210. The results suggest that the cytotoxicity of these molecules was not due to an intercalating mechanism.