benzophenones

Summary

Summary: Derivatives of benzophenone (with the structural formula phenyl-(C=O)-phenyl).

Top Publications

  1. Zucchi S, Blüthgen N, Ieronimo A, Fent K. The UV-absorber benzophenone-4 alters transcripts of genes involved in hormonal pathways in zebrafish (Danio rerio) eleuthero-embryos and adult males. Toxicol Appl Pharmacol. 2011;250:137-46 pubmed publisher
    ..The results indicate that BP-4 interferes with the sex hormone system of fish, which is important for the risk assessment of this UV-absorber. ..
  2. Gago Ferrero P, Díaz Cruz M, Barcelo D. Occurrence of multiclass UV filters in treated sewage sludge from wastewater treatment plants. Chemosphere. 2011;84:1158-65 pubmed publisher
    ..Results revealed the presence of UV filters in 15 wastewater treatment plants in Catalonia (Spain) at concentrations ranging from 0.04 to 9.17 ?g g(-1) dw. ..
  3. Pardo Andreu G, Nuñez Figueredo Y, Tudella V, Cuesta Rubio O, Rodrigues F, Pestana C, et al. The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications. Toxicol Appl Pharmacol. 2011;253:282-9 pubmed publisher
    ..These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. ..
  4. Zheleva Dimitrova D, Nedialkov P, Girreser U, Kitanov G. Benzophenones and flavonoids from Hypericum maculatum and their antioxidant activities. Nat Prod Res. 2012;26:1576-83 pubmed publisher
    The occurrence of three known benzophenones, namely annulatophenonoside, acetylannulatophenonoside and annulatophenone as well as a flavonol O-glycoside guajaverin in the aerial parts of Hypericum maculatum Crantz was established...
  5. Maciel Rezende C, de Almeida L, Costa E, Pires F, Alves K, Viegas C, et al. Synthesis and biological evaluation against Leishmania amazonensis of a series of alkyl-substituted benzophenones. Bioorg Med Chem. 2013;21:3114-9 pubmed publisher
    ..All derivatives exhibited better biological activity than their hydroxylated benzophenones precursors, and new compound LFQM-123 (3c) was 250-fold more active than its precursor 4,4'-..
  6. Thiel A, Guth S, Böhm S, Eisenbrand G. Dicofol degradation to p,p'-dichlorobenzophenone - a potential antiandrogen. Toxicology. 2011;282:88-93 pubmed publisher
    ..e. TRMP-2 (testosterone-repressed prostate message-2) mRNA and PSA (prostate-specific antigen) protein. ..
  7. Zhang Z, Ren N, Li Y, Kunisue T, Gao D, Kannan K. Determination of benzotriazole and benzophenone UV filters in sediment and sewage sludge. Environ Sci Technol. 2011;45:3909-16 pubmed publisher
    b>Benzophenones and benzotriazoles are widely used as ultraviolet (UV) light filters and stabilizers in cosmetics, skin creams, and body lotions and as corrosion inhibitors in building materials, automobile components, and automotive ..
  8. Bitsios P, Roussos P. Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. Pharmacogenomics. 2011;12:559-66 pubmed publisher
    ..It will soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotype-specific, targeted treatments of cognitive and negative symptoms of schizophrenia. ..
  9. Chen J, Song J, Yuan P, Tian Q, Ji Y, Ren Patterson R, et al. Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development. J Biol Chem. 2011;286:34752-60 pubmed publisher
    ..These results suggest that MB-COMT specific inhibitors can be developed and that tolcapone may be less hazardous at low doses and in specific genetic backgrounds. ..

More Information

Publications62

  1. Woydziak Z, Fu L, Peterson B. Synthesis of fluorinated benzophenones, xanthones, acridones, and thioxanthones by iterative nucleophilic aromatic substitution. J Org Chem. 2012;77:473-81 pubmed publisher
    ..This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones and provides scalable access to known and novel precursors to ..
  2. Farrell S, Tunbridge E, Braeutigam S, Harrison P. COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition. Biol Psychiatry. 2012;71:538-44 pubmed publisher
    ..The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders. ..
  3. Kunisue T, Chen Z, Buck Louis G, Sundaram R, Hediger M, Sun L, et al. Urinary concentrations of benzophenone-type UV filters in U.S. women and their association with endometriosis. Environ Sci Technol. 2012;46:4624-32 pubmed publisher
    ..65; 95% CI = 1.07, 2.53). Given that 2,4OH-BP possesses an estrogenic activity higher than that of 2OH-4MeO-BP, our results invite the speculation that exposure to elevated 2,4OH-BP levels may be associated with endometriosis. ..
  4. Simpkins N, Holtrup F, Rodeschini V, Taylor J, Wolf R. Comparison of the cytotoxic effects of enantiopure PPAPs, including nemorosone and clusianone. Bioorg Med Chem Lett. 2012;22:6144-7 pubmed publisher
    ..All of the isomers examined gave surprisingly similar results in the screens. ..
  5. Díaz Carballo D, Gustmann S, Acikelli A, Bardenheuer W, Buehler H, Jastrow H, et al. 7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells. Phytomedicine. 2012;19:1298-306 pubmed publisher
    ..Here, we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer...
  6. Kuete V, Tchakam P, Wiench B, Ngameni B, Wabo H, Tala M, et al. Cytotoxicity and modes of action of four naturally occuring benzophenones: 2,2',5,6'-tetrahydroxybenzophenone, guttiferone E, isogarcinol and isoxanthochymol. Phytomedicine. 2013;20:528-36 pubmed publisher
    ..b>Benzophenones are known to display many pharmacological properties including cytotoxic activities...
  7. Almanza G, Quispe R, Mollinedo P, Rodrigo G, Fukushima O, Villagomez R, et al. Antioxidant and antimutagenic polyisoprenylated benzophenones and xanthones from Rheedia acuminata. Nat Prod Commun. 2011;6:1269-74 pubmed
    Dichloromethane extract of the stem bark of Rheedia acuminata yielded three benzophenones with antioxidant activity, the new one named acuminophenone A (1), guttiferone K (2) and isoxanthochymol (3), along with the known xanthones ..
  8. Popolo A, Piccinelli A, Morello S, Sorrentino R, Osmany C, Rastrelli L, et al. Cytotoxic activity of nemorosone in human MCF-7 breast cancer cells. Can J Physiol Pharmacol. 2011;89:50-7 pubmed publisher
    ..However, nemorosone was not able to interfere with E2-induced Ca²(+) release. These findings suggest that nemorosone may have therapeutic application in the treatment of breast cancer because of its activity on ER?...
  9. Holtrup F, Bauer A, Fellenberg K, Hilger R, Wink M, Hoheisel J. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br J Pharmacol. 2011;162:1045-59 pubmed publisher
    ..This study forms the basis for further investigations identifying nemorosone's direct molecular target(s). ..
  10. Leegwater Kim J, Waters C. Tolcapone in the management of Parkinson's disease. Expert Opin Pharmacother. 2006;7:2263-70 pubmed
    ..A recent review of the data on tolcapone-treated patients suggests that, with proper monitoring of liver function, the potential for hepatotoxicity with tolcapone use is negligibly small. ..
  11. Jorga K, Kroodsma J, Fotteler B, Heizmann P, Meyer J, Rasch M, et al. Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites. Clin Pharmacol Ther. 1998;63:646-54 pubmed
    ..Our data did not indicate a requirement for dosage adjustment in the presence of moderate chronic hepatitis. ..
  12. Wilkens C, Aldrich R. State-independent block of BK channels by an intracellular quaternary ammonium. J Gen Physiol. 2006;128:347-64 pubmed
    ..Our results suggest that access of intracellular bbTBA to the BK channel cavity is not strictly gated by channel opening and closing, and imply that the permeation gate for BK channels may not be intracellular. ..
  13. Xu S, Ye M, Xu D, Li X, Pan C, Zou H. Matrix with high salt tolerance for the analysis of peptide and protein samples by desorption/ionization time-of-flight mass spectrometry. Anal Chem. 2006;78:2593-9 pubmed
    ..Furthermore, it has been found that this matrix can also effectively suppress the cation ion adduction of the peptides in the presence of high concentrations of metal ions in sample solution...
  14. Ye X, Kuklenyik Z, Needham L, Calafat A. Quantification of urinary conjugates of bisphenol A, 2,5-dichlorophenol, and 2-hydroxy-4-methoxybenzophenone in humans by online solid phase extraction-high performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2005;383:638-44 pubmed
    ..To our knowledge, this is the first study describing the distribution of urinary conjugates of BP-3 and 2,5-DCP in humans. ..
  15. Schlumpf M, Cotton B, Conscience M, Haller V, Steinmann B, Lichtensteiger W. In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001;109:239-44 pubmed
    ..5% in olive oil. Our findings indicate that UV screens should be tested for endocrine activity, in view of possible long-term effects in humans and wildlife. ..
  16. Balmer M, Buser H, Müller M, Poiger T. Occurrence of some organic UV filters in wastewater, in surface waters, and in fish from Swiss Lakes. Environ Sci Technol. 2005;39:953-62 pubmed
    ..The lipid-based bioconcentration factor (BCF(L)) estimated from the fish (roach) data and SPMD-derived water concentrations was about 1-2.3 x 10(4) and thus approximately 1 order of magnitude lower than expected from its Kow value. ..
  17. Wang S, Lee W. Determination of benzophenones in a cosmetic matrix by supercritical fluid extraction and capillary electrophoresis. J Chromatogr A. 2003;987:269-75 pubmed
    b>Benzophenones are common additives in commercial sunscreen products...
  18. Ceravolo R, Piccini P, Bailey D, Jorga K, Bryson H, Brooks D. 18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease. Synapse. 2002;43:201-7 pubmed
    ..0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD. ..
  19. Morohoshi K, Yamamoto H, Kamata R, Shiraishi F, Koda T, Morita M. Estrogenic activity of 37 components of commercial sunscreen lotions evaluated by in vitro assays. Toxicol In Vitro. 2005;19:457-69 pubmed
    ..Two benzophenones showed agonistic activity in the yeast two-hybrid assay without S9 mix...
  20. Castro M, do Nascimento A, Ikegaki M, Costa Neto C, Alencar S, Rosalen P. Identification of a bioactive compound isolated from Brazilian propolis type 6. Bioorg Med Chem. 2009;17:5332-5 pubmed publisher
    ..92-106microg/mL) against Streptococcus mutans, Streptococcus sobrinus, Streptococcus oralis, Staphylococcus aureus, and Actinomyces naeslundii, and the results of its cytotoxic and antimicrobial activities were considered good. ..
  21. Acuña U, Jancovski N, Kennelly E. Polyisoprenylated benzophenones from Clusiaceae: potential drugs and lead compounds. Curr Top Med Chem. 2009;9:1560-80 pubmed
    Many new polyisoprenylated benzophenones with a bicyclo[3.3.1]-nonane-2,4,9-trione core structure have been isolated from plants in the Clusiaceae family, and their potent biological properties have been the subject of several studies...
  22. Ito C, Itoigawa M, Miyamoto Y, Onoda S, Rao K, Mukainaka T, et al. Polyprenylated benzophenones from Garcinia assigu and their potential cancer chemopreventive activities. J Nat Prod. 2003;66:206-9 pubmed
    In a further study on the chemical constituents of Garcinia assigu, two new benzophenones corresponding to the 13-O-methyl ethers (1 and 2) of the known isogarcinol and garcinol, respectively, were isolated and characterized, along with ..
  23. Janjua N, Kongshoj B, Andersson A, Wulf H. Sunscreens in human plasma and urine after repeated whole-body topical application. J Eur Acad Dermatol Venereol. 2008;22:456-61 pubmed publisher
    ..In plasma, the 96-h median concentrations were higher compared with the 24-h concentrations for 4-MBC and OMC in men and for BP-3 and 4-MBC in females. ..
  24. Factor S, Molho E, Feustel P, Brown D, Evans S. Long-term comparative experience with tolcapone and entacapone in advanced Parkinson's disease. Clin Neuropharmacol. 2001;24:295-9 pubmed
    ..However, the risks associated with this drug, particularly hepatic injury, and the requirement for rigorous blood monitoring, need to be considered when choosing an appropriate treatment for patients with advanced PD. ..
  25. Nugent C, Prins J, Whitehead J, Savage D, Wentworth J, Chatterjee V, et al. Potentiation of glucose uptake in 3T3-L1 adipocytes by PPAR gamma agonists is maintained in cells expressing a PPAR gamma dominant-negative mutant: evidence for selectivity in the downstream responses to PPAR gamma activation. Mol Endocrinol. 2001;15:1729-38 pubmed
    ..The growing evidence that the effects of PPAR gamma on adipogenesis and glucose uptake can be dissociated may have important implications for the development of improved antidiabetic drug treatments. ..
  26. Way J, Görgün C, Tong Q, Uysal K, Brown K, Harrington W, et al. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem. 2001;276:25651-3 pubmed
  27. Jeon H, Chung Y, Ryu J. Simultaneous determination of benzophenone-type UV filters in water and soil by gas chromatography-mass spectrometry. J Chromatogr A. 2006;1131:192-202 pubmed
    ..The established method was successfully applied to monitor the residue measurement of the BP-type UV filters in environmental water and soil samples...
  28. Mitcheva M, Kondeva M, Vitcheva V, Nedialkov P, Kitanov G. Effect of benzophenones from Hypericum annulatum on carbon tetrachloride-induced toxicity in freshly isolated rat hepatocytes. Redox Rep. 2006;11:3-8 pubmed
    Five benzophenones and a xanthone, isolated from Hypericum annulatum Moris, were investigated for their protective effect against carbon tetrachloride toxicity in isolated rat hepatocytes...
  29. Brown K, Henke B, Blanchard S, Cobb J, Mook R, Kaldor I, et al. A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes. 1999;48:1415-24 pubmed
    ..In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients. ..
  30. Cuesta Rubio O, Vélez Castro H, Frontana Uribe B, Cardenas J. Nemorosone, the major constituent of floral resins of Clusia rosea. Phytochemistry. 2001;57:279-83 pubmed
    ..Our studies concluded that an interchange occurred in the assignment of the benzoyl moiety position with an isoprenyl group in that structure. ..
  31. Suzuki T, Kitamura S, Khota R, Sugihara K, Fujimoto N, Ohta S. Estrogenic and antiandrogenic activities of 17 benzophenone derivatives used as UV stabilizers and sunscreens. Toxicol Appl Pharmacol. 2005;203:9-17 pubmed
    ..Hydroxylated benzophenones exhibited estrogenic activity in human breast cancer cell line MCF-7, but their activities varied markedly...
  32. Jorga K, Fotteler B, Banken L, Snell P, Steimer J. Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies. Br J Clin Pharmacol. 2000;49:39-48 pubmed
    ..The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone. ..
  33. Kumar S, Sharma S, Chattopadhyay S. High-performance liquid chromatography and LC-ESI-MS method for identification and quantification of two isomeric polyisoprenylated benzophenones isoxanthochymol and camboginol in different extracts of Garcinia species. Biomed Chromatogr. 2009;23:888-907 pubmed publisher
    ..method has been developed for the identification and quantification of two isomeric polyisoprenylated benzophenones, isoxanthochymol and camboginol, in the extracts of the stem bark, seeds and seed pericarps of Garcinia indica ..
  34. Murata R, Yatsuda R, dos Santos M, Kohn L, Martins F, Nagem T, et al. Antiproliferative effect of benzophenones and their influence on cathepsin activity. Phytother Res. 2010;24:379-83 pubmed publisher
    The antiproliferative activity of two prenylated benzophenones isolated from Rheedia brasiliensis, the triprenylated garciniaphenone and the tetraprenylated benzophenone 7-epiclusianone, was investigated against human cancer cell lines...
  35. Chattopadhyay S, Kumar S. Identification and quantification of two biologically active polyisoprenylated benzophenones xanthochymol and isoxanthochymol in Garcinia species using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;844:67-83 pubmed
    ..LC/ESI-MS/MS) method was developed for the identification and quantification of two polyisoprenylated benzophenones xanthochymol and isoxanthochymol in the extracts of the fruit rinds, stem bark, seed pericarps and leaves of ..
  36. Hernández I, Fernandez M, Cuesta Rubio O, Piccinelli A, Rastrelli L. Polyprenylated benzophenone derivatives from Cuban propolis. J Nat Prod. 2005;68:931-4 pubmed
    ..All the structures, including relative configurations, were elucidated by spectroscopic methods and computer-generated molecular modeling. ..
  37. Jung Y, Lee J, Kim J, Yoon J, Cho H, Chung B. Photoactivable antibody binding protein: site-selective and covalent coupling of antibody. Anal Chem. 2009;81:936-42 pubmed publisher
  38. Martins F, Assis D, Dos Santos M, Camps I, Veloso M, Juliano M, et al. Natural polyprenylated benzophenones inhibiting cysteine and serine proteases. Eur J Med Chem. 2009;44:1230-9 pubmed publisher
    ..and triprenylated compounds epiclusianone (2) and garciniaphenone (3), respectively, the other natural benzophenones that also inhibited significantly the four enzymes...
  39. Bourrain J, Amblard P, Beani J. Contact urticaria photoinduced by benzophenones. Contact Dermatitis. 2003;48:45-6 pubmed
  40. Lokvam J, Braddock J, Reichardt P, Clausen T. Two polyisoprenylated benzophenones from the trunk latex of Clusia grandiflora (Clusiaceae). Phytochemistry. 2000;55:29-34 pubmed
    The polyisoprenylated benzophenones, chamones I and II, were isolated from the trunk latex of Clusia grandiflora (Clusiaceae) growing in southeastern Venezuela...
  41. Diaz Carballo D, Malak S, Bardenheuer W, Freistuehler M, Reusch H. Cytotoxic activity of nemorosone in neuroblastoma cells. J Cell Mol Med. 2008;12:2598-608 pubmed publisher
    ..Finally, nemorosone induced a considerable down-regulation of N-myc protein levels in parental LAN-1 and an etoposide resistant sub-line at the same drug-concentrations. ..
  42. Nguyen L, Venkatraman G, Sim K, Harrison L. Xanthones and benzophenones from Garcinia griffithii and Garcinia mangostana. Phytochemistry. 2005;66:1718-23 pubmed
    ..Their structures were established on the basis of spectroscopic studies and chemical correlation...
  43. Gonzalez H, Farbrot A, Larko O, Wennberg A. Percutaneous absorption of the sunscreen benzophenone-3 after repeated whole-body applications, with and without ultraviolet irradiation. Br J Dermatol. 2006;154:337-40 pubmed
    ..There was no significant difference between the two groups (P < 0.99, t-test). We show that a large amount of BZ-3 is absorbed. BZ-3 is accumulated in the body as the volunteers excreted BZ-3 5 days after the last application. ..
  44. Turek T, Gaon I, Distefano M, Strickland C. Synthesis of farnesyl diphosphate analogues containing ether-linked photoactive benzophenones and their application in studies of protein prenyltransferases. J Org Chem. 2001;66:3253-64 pubmed
    ..These results clearly demonstrate the utility of these compounds as photoaffinity labeling analogues for the study of a variety of protein prenyltransferases and other enzymes that employ FPP or GGPP as their substrates. ..
  45. Giakoumaki S, Roussos P, Bitsios P. Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism. Neuropsychopharmacology. 2008;33:3058-68 pubmed publisher
    ..These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function. ..
  46. Molina Molina J, Escande A, Pillon A, Gomez E, Pakdel F, Cavailles V, et al. Profiling of benzophenone derivatives using fish and human estrogen receptor-specific in vitro bioassays. Toxicol Appl Pharmacol. 2008;232:384-95 pubmed publisher
  47. Tarazona I, Chisvert A, León Z, Salvador A. Determination of hydroxylated benzophenone UV filters in sea water samples by dispersive liquid-liquid microextraction followed by gas chromatography-mass spectrometry. J Chromatogr A. 2010;1217:4771-8 pubmed publisher
    ..Finally, the validated method was applied to the analysis of sea water samples. ..
  48. Kunz P, Fent K. Estrogenic activity of UV filter mixtures. Toxicol Appl Pharmacol. 2006;217:86-99 pubmed
    ..These results show that significant interactions occur in UV filter mixtures, which is important for the hazard and risk assessments of these personal care products. ..
  49. Kumar S, Chattopadhyay S. High-performance liquid chromatography and LC-ESI-MS method for the identification and quantification of two biologically active polyisoprenylated benzophenones xanthochymol and isoxanthochymol in different parts of Garcinia indica. Biomed Chromatogr. 2007;21:139-63 pubmed
    ..Compounds (1) and (2) were qualitatively and quantitatively analyzed in the above three samples of Garcinia indica. The overall analytical procedure is rapid and reproducible and is considered for the analysis of the above two compounds...
  50. Muller T, Kuhn W. Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson's disease patients. Eur J Clin Pharmacol. 2006;62:447-50 pubmed
    ..This may hypothetically reduce homocysteine mediated progress of neuronal degeneration and the risk for onset of dementia, vascular disease and polyneuropathy in levodopa treated PD patients in the long term. ..
  51. Shan D, Lee S, Chao L, Yeh S. Gait analysis in advanced Parkinson's disease--effect of levodopa and tolcapone. Can J Neurol Sci. 2001;28:70-5 pubmed
    ..The results of our gait analysis confirmed that in parkinsonian patients with fluctuating motor symptoms levodopa/benserazide, but not tolcapone, produced a substantial improvement. ..
  52. Revesz L, Blum E, Di Padova F, Buhl T, Feifel R, Gram H, et al. SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with oral activity. Bioorg Med Chem Lett. 2004;14:3601-5 pubmed
    Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis...
  53. Jorga K, Fotteler B, Heizmann P, Gasser R. Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase. Br J Clin Pharmacol. 1999;48:513-20 pubmed
    ..5% of tolcapone was excreted unchanged); glucuronidation is the most important route of metabolism. The relatively long duration of excretion is caused by the long half-life of 3-OMT. ..