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Carotenoid production was determined in illuminated anaerobically maintained cultures of Rhodospirillum rubrum in media with and without 4-[beta-(diethylamino)-ethoxy]-benzophenone. In treated cultures, lycopene--which normally is not produced by R. rubrum--accumulated as the predominant pigment, and total carotenoids increased five- to sixfold.
Eight analogs of cholesterol (1) containing a benzophenone group have been synthesized as prospective photoaffinity labels for studies in cellular sterol efflux and HDL formation. Six of these compounds (4-9) have the photophore replacing different portions of the cholesterol alkyl side chain, and two (10 and 11) have it attached via nitrogen at carbon 3. The suitability of these analogs as cholesterol surrogates was determined by examining their ability to replace [3H]1 in fibroblasts preequilibrated with [3H]1. All eight analogs were effective in replacing natural 1 in competition with [3H]1 for apolipoprotein A-I-induced efflux. These are the first compounds shown to replace cholesterol successfully in a complex pathway of multiple intracellular steps. The results suggest an unexpected tolerance of biological membranes regarding the incorporation of sterols of differing chemical structure.
Benzophenone derivatives, garcinol (1) and isogarcinol (2) isolated from the pericarps of Garcinia purpurea (Guttiferae), and xanthochymol (3) and a mixture of isoxanthochymol (4) cycloxanthochymol (5) from the pericarps of G. subelliptica were evaluated for their antibacterial activity against methicillin-resistant Staphylococcus aureus. Among them, 3 showed the lowest minimum inhibitory concentration at 3.1-12.5 micrograms/ml. This concentration is nearly equal to that of the antibiotic, vancomycin.
From aerial parts of Tripterospermum japonicum, 6'-O-beta-D-glucopyranosylmorroniside, benzophenone glucoside, named triptephenoside and 2'''- and 4'''-O-acetyl-2''-O-alpha-L-rhamnopyranosylisovitexins were isolated, along with known iridoid and secoiridoid glucosides, and C-glycosyl flavones.
The reproductive toxicity of benzophenone (BZP) was evaluated in a two generation test in which male and female Sprague-Dawley (SD) rats, parental (F0) and first generation (F1), were exposed to BZP by feeding diet containing BZP at concentrations of 0 (control), 100, 450 or 2000 ppm. With regard to the effects of BZP on the F0 and F1 parental animals, inhibition of body weight gain and food consumption, significantly elevated renal weights, dilatation of the renal proximal tubules, and regeneration of the proximal tubular epithelium were recognized at doses of 450 ppm and 2000 ppm, along with an increase in hepatic weight and centrilobular hepatocytic hypertrophy, considered as vital adaptive changes, at the doses of 100 ppm or more. Obvious effects on the endocrine system and reproductive toxicological effects were not found even at the dose of 2000 ppm in the F0 or F1 parent. There were no test substance related changes in the estrous cycle, reproductive capability, delivery and lactation, sperm parameters, serum hormone levels, or necropsy findings. As for effects on the offspring, inhibition of body weight gain was observed in both the F1 and F2 males and females of the 2000 ppm group. No effects of BZP treatment were recognized in the number of male and female F1 or F2 pups delivered, viability, anogenital distance (AGD), physical development, the results of reflex and response tests, or on the observation results of external abnormalities. From the present study of BZP administered to rats over two successive generations, the no observed effect level (NOEL) on the parental animals is concluded to be less than 100 ppm. Concerning the effects on the endocrine system and the reproductive toxicity in the parental animals, the NOEL is 2000 ppm. In terms of the effects on the offspring, the NOEL is considered to be 450 ppm.
Farnesyltransferase catalyzes the transfer of a farnesyl residue from farnesylpyrophosphate to the thiol of a cysteine side chain of proteins which carry at the C-terminus the so called CAAX-sequence. Although the exact cellular events affected by farnesyltransferase inhibiton remain to be determined, farnesyltransferase has become a major target in the development of potential anti-cancer drugs. Numerous farnesyltransferase inhibitors have been described from which the majority are CAAX-peptidomimetics possessing a free thiol group which coordinates the enzyme-bound zinc ion. The development of farnesyltransferase inhibitors is clearly directed towards the so-called non-thiol farnesyltransferase inhibitors because of adverse drug effects connected to free thiols. This review mainly deals with the efforts of the authers group towards the design of non-thiol-farnesyltransferase inhibitors. Our first step on the way to non-thiol farnesyltransferase inhibitors was the development of an CAAX-peptidomimetic based on a pharmacophore model. On the basis of this benzophenone core, bisubstrate analogues were developed as one class of non-thiol farnesyltransferase inhibitors. In most non-thiol farnesyltransferase inhibitors known in literature nitrogene containing heterocycles are used as cysteine replacements supposedly coordinating the enzyme bound zinc. However, we and others have shown that nitrogen heterocycles can be replaced by aryl residues lacking the ability to coordinate metal atoms, an observation which let to the postulation of two hitherto unknown aryl binding sites. Using flexible docking of model compounds and GRID analysis we were able to locate these postulated aryl binding sites. Subsequently, we used one of this aryl binding sites for the structure based design of highly active non-thiol farnesyltransferase inhibitors.
Eight synthetic benzophenones were tested for their inhibitory effects on xanthine oxidase (XO). The enzyme, XO catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid, which has a lambda max of 295 nm, forming the basis for a spectrophotometric assay for the activity of XO. The results showed that 2,2',4,4'-tetrahydroxybenzophenone (6), 3,4,5,2',3',4'-hexahydroxybenzophenone (8) and 4,4'-dihydroxybenzophenone (3) displayed the inhibitory effects on XO with an order of activity of IC50 = 47.59, 69.40 and 82.94 microM, respectively. The apparent inhibition constants (Ki) of (8) and (3) were 15.61 and 64.86 microM respectively, and both of them induced mixed type (non-competitive-uncompetitive) inhibitions of the substrate xanthine.
A series of fluorenone and benzophenone 1,4-dihydropyridine derivatives were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties.
Structural variation of the 2-acylamino moiety of some benzophenone farnesyltransferase inhibitors led to the para-trifluoromethylphenylpropionyl derivative with relatively low farnesyltransferase inhibition but considerable antimalarial activity and no cytotoxicity.
The use of amino acids as acyl substitutents at the 2-amino group of our benzophenone core structure yielded compounds with mainly good to moderate farnesyltransferase inhibitory and moderate antimalarial activity. However, these farnesyltransferase inhibitors display some degree of selectivity towards malarial parasites since there was no cytotoxic activity observed at 70-80 microM.
Incorrect diagnosis of photoallergy to sunscreen products represents a unique clinical dilemma. Increasing sunscreen usage for suspected idiopathic photosensitivity or a change to a sunscreen containing the same photoallergen only worsens the problem. While photoallergy to p-aminobenzoic acid and its esters is well known by dermatologists and the lay public, benzophenone photoallergy is not well appreciated. We report herein the cases of four individuals with photoallergy to oxybenzone in sunscreens. It is likely that such reactions will become more commonplace since oxybenzone is by far the most frequently used agent in modern, high sun protection factor sunscreens (greater than 8 sun protection factor) being marketed today.
The authors confirm the validity of a method of detection for 18 benzodiazepines. Its original feature consists of the extraction in an acid medium. Between 70 and 100 per cent of the drug is recovered, except for the benzophenones which are strongly basic. The yield of hydrolysis is between 70 and 95 per cent, except for diazepam and lormetazepam, for which the yield is about 50 per cent. Depending on the nature of the benzodiazepines, the limit of detection of the process described is between 5 and 20 micrograms/l of urine. Following a single therapeutic dose in non-dependent volunteers, the benzodiazepines were detectable for at least 36 to 48 hours.
Reaction ability of partially reduced human methemoglobin was estimated by the rate of protein addition of carbon monoxide immediately after reduction. Impulse of photoexcitation allowed two variants of these experiments to be carried out: immediately after partial reduction of methemoglobin with photoradicals of benzophenone 3,3',4,4'-tetracarbon acid and after photodissociation of the carboxy-complex obtained in the first case. It has been shown that at protein reduction "p" less than or equal to 0.03 under these conditions the initially obtained R-form of protein is partially transformed into the less reactive T-form.
A novel benzophenone derivative, 2-(2-benzoyl-4-chlorophenoxy)-N-methylpropionamide (Ch-13), induced phenotypic differentiation linked to the inhibition of cell proliferation in human thymic acute lymphoblastic leukemia cell line HPB-ALL cells. The Ch-13-induced morphological changes consist of a decrease in cell size, nucleolar disappearance, and an alteration in the chromatin distribution, resembling large or atypical lymphocytes. Treatment with Ch-13 brought about a remarkable reduction in OKT6-, OKT4/Leu3a-, and OKT9-positive cells. At the optimal differentiation-inducing dose (5 X 10(-5)M), Ch-13 inhibited the cell proliferation, de novo DNA synthesis, and specific antibody-induced cell surface antigen capping.
Some acyl- and aroyl derivatives of benzophenone oximes variously benzene substituted were prepared and tested in vitro and in vivo against fungal plant pathogens of different taxonomic classes. The tested compounds showed remarkable activity, especially some O-acetyl derivatives.
The reduction of benzophenone with the magnesium complex [(2,6-iPr(2)C(6)H(3)-bian)Mg(thf)(3)] (1), containing the 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene dianion, affords the pinacolato complex [(2,6-iPr(2)C(6)H(3)-bian)Mg(thf)](2)[micro-O(2)C(2)Ph(4)].(C(6)H(6))(4) (2). The reaction of 1 with 9(10H)-anthracenone yields the 9-anthracenolato complex [(2,6-iPr(2)C(6)H(3)-bian)Mg(OC(14)H(9))(thf)(2)] (3). Complexes 2 and 3 were characterized by elemental analyses, UV/Vis, IR, and ESR spectroscopy, as well as by single crystal X-ray diffraction. Complex 2 dissociates in solution with splitting of the bridging pinacolato unit, forming the biradical diimino/ketyl complex [(2,6-iPr(2)C(6)H(3)-bian)Mg(thf)(OCPh(2))].
The compound 4-amino-3-(3'-methoxycarbonyl-2'-thioureido) benzophenone has shown promise as a prodrug of the anthelmintic mebendazole. The compound is stable in acid and neutral media and is rapidly hydrolysed in base. An HPLC assay procedure for mebendazole, the prodrug and their known or expected metabolites and degradation products in aqueous media and rat blood has been developed. The prodrug administrated orally to rats is rapidly converted to mebendazole. The area under the blood level versus time curve of mebendazole, in rats dosed with the prodrug, is more than twice that obtained after dosing rats with an equimolar amount of mebendazole. Only the prodrug, mebendazole and known metabolites of mebendazole are detected in rats dosed with the prodrug.
The benzophenone derivative of 1,3-bis(D-mannos-4-yloxy)-2-propylamine (BB-BMPA) has been tested as an exofacial photoaffinity label for the sugar transport systems of human erythrocytes and rat adipocytes. The half-maximal inhibition constants for the reagent are 971 microM in erythrocytes and 536 microM in basal and 254 microM in insulin-treated adipocytes. The photolabelling of erythrocyte membranes is very specific for the 50 kDa transporter peptide and is completely displaced by D-glucose. The exofacial photoaffinity labelling of adipocytes also shows labelling of a 50 kDa transporter peptide, which is displaced by cytochalasin B, but extensive nonspecific labelling of a 75 kDa plasma membrane peptide occurs. The transporter is labelled in insulin-treated cells but not in basal cells which indicates that this in situ labelling technique selectively reveals only those transporters that visit and are active in the plasma membrane during the labelling period. This also indicates that in basal cells transporters do not turn over rapidly. Subcellular redistribution of transporters after the labelling period has been studied. Following incubation and washing at 37 degrees C in the presence of insulin, 30% of the transporters photolabelled at the plasma membrane are internalised and are found in the light microsome fraction of the cell. The proportion of transporter that is observed to be internalised is much greater than can be accounted for by a contamination of the light microsome fraction by plasma membrane. The labelled 50 kDa transporter peptide in the light microsomes is enriched when compared with the carry-over of the 75 kDa nonspecifically labelled plasma membrane peptide. Thus we have obtained direct evidence for transporter translocation.