Joseph Molnár

3,5-dibenzoyl-1,4-dihydropyridines: synthesis and MDR reversal in tumor cells.

Fifteen 4-phenyl-3,5-dibenzoyl-1,4-dihydropyridines (BzDHPs) (1-15) substituted at the 4-phenyl ring were synthesized and compared to their cytotoxic activity and multidrug resistance (MDR)-reversing activity in in vitro assay systems. Among them, 2-CF3 (5) (IC50=8.7 microM), 2-Cl (11) (IC50=7.0 microM) and 3-Cl (12) (IC50=7.0 microM) derivatives showed the highest cytotoxic activity against human oral squamous carcinoma (HSC-2) cells. The activity of P-glycoprotein (Pgp) response for MDR in tumor cells was reduced by some of derivatives (3, 4, 8, 12), verapamil (VP) and nifedipine (NP). These data suggest that 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (12) can be recommended as a new drug candidate for MDR cancer treatment.

Cancer prevention and therapy with kiwifruit in Chinese folklore medicine: A study of kiwifruit extracts

Kiwi gold fruits were extracted successively with hexane, acetone, methanol and 70% methanol, and further fractionated by silica gel and ODS column chromatographies for the assays of various biological activities. Five fractions H1, H2 (hexane extract), Al, A2 (acetone extract) and M2 (methanol extract) showed selective cytotoxic activity against human oral tumor cell lines, which was more sensitive than human gingival fibroblasts. More hydrophilic fractions [70M3, 70M4, 70M5] of 70% methanol extract displayed higher anti-HIV activity, radical generation and O2- scavenging activity. The antibacterial activity of 70% methanol extracts [70M0, 70M1, 70M2, 70M3, 70M4] was generally lower than that of more lipophilic fractions (hexane, acetone, methanol extracts), although each fraction did not show any specific antimicrobial action. All fractions were inactive against Helicobacter pylori. These results demonstrate that gold kiwifruit extracts contain valuable, various bioactive materials, which can be separated with each other.

Antimicrobial activity of trifluoromethyl ketones and their synergism with promethazine

The antimicrobial effects of 30 trifluoromethyl ketones [1-30] were studied on various representative bacteria. Of the ketones, 4,4,4-trifluoro-1-phenyl-1,3-butanedione [10], 1,1,1-trifluoro-3-(4,5-dimethyloxazol-2-yl)-2-propanone [11] and 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone [18] were found to exhibit potent antibacterial activity against the Gram-positive Bacillus megaterium and Corynebacterium michiganese, but not against Gram-negative bacteria such as Pseudomonas aeruginosa and Serratia marcescens. Compounds 11 and 18 inhibited the Escherichia coli. Compound 18 was also effective against yeasts. The combination of promethazine with 18 was significantly synergistic against E. coli strains, especially the proton pump deficient mutant. The results suggest that membrane transporters are the target of trifluoromethyl ketones. The inhibition was more marked in the proton pump deficient E. coli mutant than in the wild type, which suggested that the antibacterial effect of trifluoromethyl ketones is partly prevented by the proton pump system.

3,5‐Dibenzoyl‐4‐(3‐phenoxyphenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP7) as a new multidrug resistance reverting agent devoid of effects on vascular smooth muscle contractility

The aim of this study was to investigate the effects of 3,5‐diacetyl‐ (DP1–DP5) and 3,5‐dibenzoyl‐1,4‐dihydropyridines (DP6–DP11) on vascular functions in vitro, by comparing their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, and to quantify their multidrug resistance (MDR)‐reversing activity in L5178 Y mouse T‐lymphoma cells transfected with MDR1 gene. In rat aorta, the 11 compounds tested, but 3,5‐dibenzoyl‐4‐(3‐phenoxyphenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP7), 3,5‐dibenzoyl‐4‐(3‐chlorophenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP9), 3,5‐dibenzoyl‐4‐(4‐chlorophenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP10) and 3,5‐dibenzoyl‐4‐phenyl‐1,4‐dihydro‐2,6‐dimethylpyridine (DP11), antagonized 60 mM K+ (K60)‐induced contraction in a concentration‐dependent manner, with IC50 (M) values ranging between 5.65 × 10−7 and 2.23 × 10−5. The 11 dihydropyridines tested, but DP7, inhibited L‐type Ca2+ current recorded in artery myocytes in a concentration‐dependent manner, with IC50 (M) values ranging between 1.12 × 10−6 and 6.90 × 10−5. The K+‐channel opener cromakalim inhibited the Ca2+‐induced contraction in K30 but not that evoked in K60. On the contrary, DP7 was ineffective in both experimental conditions. When the rings were preincubated with 1 mM Ni2+ plus 1 μM nifedipine, the response to phenylephrine was significantly reduced by 2,5‐di‐t‐butyl‐1,4‐benzohydroquinone (BHQ), a well‐known endoplasmic reticulum Ca2+‐ATPase inhibitor. DP7 had no effects on this model system. In L5178 MDR cell line, the 11 dihydropyridines tested, but 3,5‐diacetyl‐4‐(2‐nitrophenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP1), 3,5‐diacetyl‐4‐(3‐phenoxyphenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP2) and 3,5‐diacetyl‐4‐(3‐chlorophenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP4), exhibited an MDR‐reversing activity, with IC50 values ranging between 3.02 × 10−7 and 4.27 × 10−5, DP7 being the most potent. In conclusion, DP7 may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of vascular effects.

New phenothiazine-type multidrug resistance modifiers: anti-MDR activity versus membrane perturbing potency ☆

The phenothiazine multidrug resistance (MDR) modulators are chemically diversified but share the common feature to be hydrophobic cationic molecules. Molecular mechanisms of their action may involve interactions with either P-glycoprotein or membrane lipid matrix. In the present work we study the anti-MDR and biophysical membrane effects of new phenothiazine derivatives differing in the type of group substituting phenothiazine ring at position 2 (H-, Cl-, CF(3)-) and in the side chain group (NHCO(2)CH(3) or NHSO(2)CH(3)). Within each phenothiazine subset we found that anti-MDR activity (determined by P-glycoprotein inhibition assessed by flow cytometry) correlates with the theoretically calculated hydrophobicity value (logP) and experimental parameters (determined by calorimetry and fluorescence spectroscopy) of lipid bilayers. It is concluded that the biological and biophysical activity of phenothiazine derivatives depends more on the type of ring substitution than on the nature of the side chain group.

Synthesis and biological activity of N-acylphenothiazines

Previous studies have demonstrated the relationship between radical intensity and cytotoxic activity in water-soluble compounds. This relationship was investigated in lipophilic compounds. Several N-acylphenothiazines showed higher cytotoxic activity against human leukemic and squamous carcinoma cell lines than phenothiazine, the parent compound. Electron spin resonance (ESR) spectroscopy showed that these active compounds produced much lower amounts of radicals than phenothiazine. Several compounds failed to inhibit the cytopathic effects of human immunodeficiency virus (HIV) infection in MT-4 cells. It suggested that the radical-mediated-mechanisms has not involved in the induction of cytotoxic activity by lipophilic compounds, such as N-acylphenothiazines.

Neither lipophilicity nor membrane-perturbing potency of phenothiazine maleates correlate with the ability to inhibit P-glycoprotein transport activity

Although phenothiazines are known as multidrug resistance modifiers, the molecular mechanism of their activity remains unclear. Since phenothiazine molecules are amphiphilic, the interactions with membrane lipids may be related, at least partially, to their biological effects. Using the set of phenothiazine maleates differing in the type of phenothiazine ring substitution at position 2 and/or in the length of the alkyl bridge-connecting ring system and side chain group, we investigated if their ability to modulate the multidrug resistance of cancer cells correlated with model membrane perturbing potency. The influence exerted on lipid bilayers was determined by liposome/buffer partition coefficient measurements (using the absorption spectra second-derivative method), fluorescence spectroscopy and calorimetry. Biological effects were assessed by a flow cytometric functional test based on differential accumulation of fluorescent probe DiOC2(3) by parental and drug-resistant cells. We found that all phenothiazine maleates were incorporated into lipid bilayers and altered their biophysical properties. With only few exceptions, the extent of membrane perturbation induced by phenothiazine maleates correlated with their lipophilicity. Within the group of studied derivatives, the compounds substituted with CF3- at position 2 of phenothiazine ring were the most active membrane perturbants. No clear relation was found between effects exerted by phenothiazine maleates on model membranes and their ability to modulate P-glycoprotein transport activity.

Immunomodulating effect of 2,3,4,5-tetrahydro-1H-3-benzazepines (a new class of non-nucleoside inhibitors of reverse transcriptase)

The effects of newly synthesized, reverse transcriptase inhibitors, 3-benzazepines, for their effects on natural killer (NK) cell and blast transformation in human peripheral blood mononuclear cells were investigated. The most effective reverse transcriptase inhibitors were KF1, KF2 and KF3, which primarily suppressed immunological functions. Besides the inhibition of T cell proliferation, the benzazepines also show inhibitory effect on NK cell functions, in particularly, against large granular lymphocytes and monocytes. The B lymphocytes and Fc mediated killer functions were less inhibited.

Toxic interactions between clozapine and ampicillin

Abstract Severe adverse side effects have recently been reported after co-administration of the drugs, ampicillin and clozapine, to a schizophrenic patient. In the present work, conductimetric results indicate that ampicillin and clozapine form a 1:2 charge transfer complex which tends to associate together in water. In contrast, a charge transfer complex with a stoichiometric ratio of 2 moles ampicillin to 1 mole clozapine is obtained when the conductimetric experiment is carried out using acetonitrile as a solvent. Also, the complex appears to dissociate easily in the non-aqueous solution. Nevertheless, in both systems, unexpectedly high capacitance readings were obtained, indicating an adsorption phenomenon of the drugs on electrode surfaces. Further, conductimetric results obtained in water and with Sonification yields a 1:1 ampicillin to clozapine mole ratio. Such results were used to infer the formation of micelles in aqueous solutions. The observed change in stoichiometric ratio of the ampicillin-clozapine complex in aqueous and non-aqueous systems was then used to suggest the action of the drugs on the surface of biomembranes.