Synthesis, in vitro antiproliferative and anti-mycobacterium tuberculosis activities of novel β-carboline derivatives

A series of β-carboline derivatives with amino or guanidinium were synthesized and evaluated in vitro against anti-Mycobacterium tuberculosis and for antiproliferative activities against nine human cancer cell lines. The compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline (24.9 μg mL-1) and 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline (26.9 μg mL-1) were the most active against M. Tuberculosis (MTB). Compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline and 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline, which had the same substituted groups, inhibited the growth of all human tumor cell lines with growth inhibitory activity (GI50) values from 1.37 to 9.20 mmol L-1. Also in this series, compounds 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline demonstrated significant activity against NCI/ADR cells. Among compounds with a terminal guanidine group, compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (27.8 μg mL-1) and 1-(3-nitrophenyl)-3-carboxamide(ethyl) guanidine β-carboline (37.4 μg mL-1) demonstrated the greatest activity against MTB. Additionally, compounds 1-(4-methoxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (GI50 = 0.45 mmol L-1) effectively inhibited growth and was highly selective against NCI/ADR. The in silico study revealed that 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline compounds follow the rules established by Lipinski, suggesting that this compound has no problems with oral bioavailability.27813981405CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESSem informaçãoSem informaçã

Synthesis, In Vitro Antiproliferative And Anti-mycobacterium Tuberculosis Activities Of Novel β-carboline Derivatives

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)A series of β-carboline derivatives with amino or guanidinium were synthesized and evaluated in vitro against anti-Mycobacterium tuberculosis and for antiproliferative activities against nine human cancer cell lines. The compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline (24.9 μg mL-1) and 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline (26.9 μg mL-1) were the most active against M. Tuberculosis (MTB). Compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline and 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline, which had the same substituted groups, inhibited the growth of all human tumor cell lines with growth inhibitory activity (GI50) values from 1.37 to 9.20 mmol L-1. Also in this series, compounds 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline demonstrated significant activity against NCI/ADR cells. Among compounds with a terminal guanidine group, compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (27.8 μg mL-1) and 1-(3-nitrophenyl)-3-carboxamide(ethyl) guanidine β-carboline (37.4 μg mL-1) demonstrated the greatest activity against MTB. Additionally, compounds 1-(4-methoxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (GI50 = 0.45 mmol L-1) effectively inhibited growth and was highly selective against NCI/ADR. The in silico study revealed that 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline compounds follow the rules established by Lipinski, suggesting that this compound has no problems with oral bioavailability. © 2016 Sociedade Brasileira de Química.27813981405CAPES, Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCNPq, Conselho Nacional de Desenvolvimento Científico e TecnológicoCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Synthesis And Evaluation Of New β-carboline-3-(4-benzylidene)- 4h-oxazol-5-one Derivatives As Antitumor Agents

In the present work, we report the synthesis and in vitro anticancer and antimicrobial activity evaluation of a new series of 1-substituted-β- carboline derivatives bearing a 4-benzylidene-4H-oxazol-5-one unity at C-3. The compound 2-[1-(4- methoxyphenyl)-9H-β-carbolin-3-yl]-4-(benzylidene)-4H- oxazol-5-one (11) was the most active derivative, exhibiting a potent cytotoxic activity against glioma (U251), prostate (PC-3) and ovarian (OVCAR-03) cancer cell lines with IC 50 values of 0.48, 1.50 and 1.07 μM, respectively. An in silico study of the ADME properties of the novel synthesized β-carboline derivatives was also performed. © 2012 by the Authors.17561006113Cao, R., Peng, W., Wang, Z., Xu, A., B-carboline alkaloids: Biochemical and pharmacological functions (2007) Curr. Med. 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Pharmacology And Toxicology Of Peumus Boldus And Baccharis Genistelloides [farmacologia E Toxicologia De Peumus Boldus E Baccharis Genistelloides]

There are a great number of medicinal plants without any scientific confirmation about their efficacy and safety. This paper is a short review about two medicinal plants, "boldo do chile" (Peumus boldus) and "carqueja" (Baccharis genistelloides). Pharmacological studies have confirmed several popular indications for P. boldus and B. genistelloides, besides have established a relationship between isolated compounds from these extracts and the pharmacological effects observed. On the other hand, toxicological researches have pointed out that P. boldus tea should not be consumed during a long period (potential hepatotoxicity) and by pregnant, especially during the first three months. Moreover, B. genistelloides tea must be prohibited for pregnant because of confirmed abortive action, and for patients using medicines for blood pressure disorders. These studies point out the continuous necessity of more studies about medicinal plants; only with this knowledge it will be possible a safe and efficient use.182295300Abad, M.J., Bermejo, P., Gonzales, E., Iglesias, I., Irurzun, A., Carrasco, L., Antiviral activity of Bolivian plant extracts (1999) Gen Pharmacol, 32, pp. 499-503Agra, M.F., França, P.F., Barbosa-Filho, J.M., Synopsis of the plants known as medicinal and poisonous in Northeast of Brazil (2007) Rev Bras Farmacogn, 17, pp. 114-140Almeida, E.R., Melo, A.M., Xavier, H., Toxicological evaluation of the hydro-alcohol extract of the dry leaves of Peumus boldus and boldine in rats (2000) Phytother Res, 14, pp. 99-102Alonso JR 1998. Tratado de Fitomedicina - bases clínicas y farmacológicas. ISIS Ediciones S. R. L., Buenos Aires, Argentina. 350-354Backhouse, N., Delporte, C., Givernau, M., Cassels, B.K., Valenzuela, A., Speisky, H., Antiinflammatory and antipyretic effects of boldine (1994) Agents and Actions, 42, pp. 114-117Barbosa-Filho, J.M., Vasconcelos, T.H.C., Alencar, A.A., Batista, L.M., Oliveira, R.A.G., Guedes, D.N., Falcão, H.S., Modesto-Filho, J., Plants and their active constituents from South, Central, and North America with hypoglycemic activity (2005) Rev Bras Farmacogn, 15, pp. 392-413Barbosa-Filho, J.M., Piuvezam, M.R., Moura, M.D., Silva, M.S., Lima, K.V.B., Cunha, E.V.L., Fechine, I.M., Takemura, O.S., Anti-inflammatory activity of alkaloids: A twenty-century review (2006) Rev Bras Farmacogn, 16, pp. 109-139Basila, D., Yuan, C.-S., Effects of dietary supplements on coagulation and platelet function (2005) Thromb Res, 117, pp. 49-53Brandão, M.G.L., Cosenza, G.P., Moreira, R.A., Monte-Mor, R.L.M., Medicinal plants and other botanical products from the Brazilian Official Pharmacopoeia (2006) Rev Bras Farmacogn, 16, pp. 408-420Coelho, M.P.G., Reis, P.A., Gava, V.B., Marques, P.R., Gayer, C.R., Laranja, G.A.T., Felzenswalb, I., Sabino, K.C.C., Anti-arthritic effect and subacute toxicological evaluation of Baccharis genistelloides aqueous extract (2004) Toxicol Lett, 154, pp. 69-80Cordell, G.A., Colvard, M.D., Some thoughts on the future of ethnopharmacology (2005) J Ethnopharmacol, 100, pp. 5-14Corrêa, M.P., (1926) Dicionário das Plantas Úteis do Brasil e das Exóticas Cultivadas, p. 74. , Rio de Janeiro, Imprensa Nacional. II, págLima, V.L.A.G., Mélo, E.A., Lima, D.E.S., Total phenolic content in Brazilian teas (2004) Braz J Food Technol, 7, pp. 187-190Gielen, K., Goossens, A., Occupational allergic contact dermatitis from drugs in healthcare workers (2001) Contact Dermatitis, 45, pp. 273-279Gonzales, E., Iglezias, I., Carretero, E., Villar, A., Gastric cytoprotection of Bolivian medicinal plants (2000) J Ethnopharmacol, 70, pp. 329-333Gupta, M.P., 270 Plantas medicinales Iberoamericanas (1995) Editorial Presencia Ltda, p. 79. , Santafé de Bogotá, Colombia. 1a edición, págIzzo, A.A., Carlo, G.D., Borrelli, F., Ernst, E., Cardiovascular pharmacotherapy and herbal medicines: The risk of drug interaction (2005) Int J Cardiol, 98, pp. 1-14Jang, Y.Y., Song, J.H., Shin, Y.K., Han, E.S., Lee, C.S., Protective effect of boldine on oxidative mitochondrial damage in streptozotocin-induced diabetic rats (2000) Pharmacol Res, 42, pp. 361-371Jiménez, I., Garrido, A., Bannach, R., Gotteland, M., Speisky, H., Protective effects of boldine against free radical-induced erythrocyte lysis (2000) Phytother Res, 14, pp. 339-343Kang, J.J., Cheng, Y.W., Fu, W.M., Studies on neuromuscular blockade by boldine in the mouse phrenic nerve-diaphragm (1998) Jpn J Pharmacol, 76, pp. 207-212Kringstein, P., Cederbaum, A.I., Boldine prevents human liver microsomal lipid peroxidation and inactivation of cytochrome P4502E1 (1995) Free Radical Biol Med, 18, pp. 559-563Kuroyanagi, M., Fujita, K., Mihoko, K., Matsumoto, S., Ueno, A., Fukushima, S., Katsuoka, M., Studies on the constituents of Baccharis genistelloides (1985) Chem Pharm Bul, 33, pp. 5075-5078Lima, V.L.A.G., Mélo, E.A., Lima, D.E.S., Total phenolic content in Brazilian teas (2004) Braz J Food Technol, 7, pp. 187-190Lima, I.O., Oliveira, R.A.G., Lima, E.O., Farias, N.M.P., de Souza, E.L., Atividade antifúngica de óleos essenciais sobre espécies de Candida. (2006) Rev Bras Farmacogn, 16, pp. 197-201Mendes, B.G., Machado, M.J., Falkenberg, M., Triagem de glicolipídios em plantas medicinais. (2006) Rev Bras Farmacogn, 16, pp. 568-575Monzón, S., Lezaun, A., Sáenz, D., Marquinez, Z., Bernedo, N., Uriel, O., Colas, C., Duce, F., Anaphylaxis to boldo infusion, a herbal remedy (2004) Allergy, 59, pp. 1019-1020O'Brien, P., Carrasco-Pozo, C., Speisky, H., Boldine and its antioxidant or health-promoting properties (2006) Chem Biol Interactions, 159, pp. 1-17Oliveira, A.C.P., Endringer, D.C., Amorin, L.A.S., Brandão, M.G.L., Coelho, M.M., Effect of the extract and fraction of Baccharis trimera and Syzygium cumini on glycaemia of diabetic and non-diabetic mice (2005) J Etnhopharmacol, 102, pp. 465-469Pedrazzi H 1997. In Alonso JR 1998. Tratado de Fitomedicina - bases clínicas y farmacológicas. ISIS Ediciones S. R. L., Buenos Aires, Argentina. 350-354Pietta, P., Mauri, P., Manera, E., Ceva, P., Determination of isoquinoline alkaloids from Peumus boldus by high-performance liquid chromatography (1988) J Chromatogr, 457, pp. 442-445Piscaglia, F., Leoni, S., Venturi, A., Graziella, F., Donati, G., Bolondi, L., Caution in the use of boldo in herbal laxatives: A case of hepatotoxicity (2005) Scand J Gastroenterol, 40, pp. 236-239Quezada, N., Ascencio, M., del Valle, J.M., Gomez, B., Antioxidant activity of crude extraxt, alkaloid fraction and flavonoid fraction from boldo (Peumus boldus Molina) leaves (2004) J Food Sci, 69, pp. C371-C376Rates, S.M.K., Plants as source of drugs (2001) Toxicon, 39, pp. 603-613Reiniger, I.W., de Oliveira, J.F., Caldeira-de-Araújo, A., Bernardo-Filho, M., Effect of Peumus boldus on the labeling of red blood cells and plasma proteins with Technetium-99m (1999) Appl Radiat Isot, 51, pp. 145-149Reiniger, I.W., da Silva, C.R., Felzenszwalb, I., de Mattos, J.C.P., de Oliveira, J.F., Dantas, F.J.S., Bezerra, R.J.A.C., Bernardo-Filho, M., Boldine action against the stannous chloride effect (1999) J Ethnopharmacol, 68, pp. 345-348Santanam, N., Penumetcha, M., Speisky, H., Parthasarathy, S., A novel alkaloid antioxidant, boldine and synthetic antioxidant, reduced form of RU486, inhibit the oxidation of LDL in vitro and atherosclerosis in vivo in LDLR -/- mice (2004) Atherosclerosis, 173, pp. 203-210Schmeda-Hirschmann, G., Rodriguez, J.A., Theoduloz, C., Astudillo, S.L., Feresin, G.E., Tapia, A., Free-radical scavengers and antioxidants from Peumus boldus (2003) Free Radical Res, 37, pp. 447-452Schwanz, M., Ferreira, J.J., Fröehlich, P., Zuanazzi, J.A.S., Henriques, A.T., Análise de metais pesados em amostras de Peumus boldus Mol. (Monimiaceae). (2008) Rev Bras Farmacogn, 18, pp. 98-101Speisky, H., Cassels, B.K., Boldo and boldine: An emerging case of a natural drug development (1994) Pharmacol Res, 29, pp. 1-12Suttisri, R., Kinghorn, A.D., Wright, A.D., Otto, S., Neoclerodane diterpenoids and other constituents from Baccharis genistelloides (1994) Phytochemistry, 35, pp. 446-446Torres, L.M.B., Gamberini, M.T., Roque, N.F., Landman, M.T.L., Souccar, C., Lapa, A.J., Diterpene from Baccharis trimera with a relaxant effect on rat vascular smooth muscle (2000) Phytochemistry, 55, pp. 617-619Verdi, L.G., Brighente, I.M.C., Pizzolati, M.G., Gênero Baccharis (Asteraceae): Aspectos químicos, econômicos e biológicos. (2005) Quim Nova, 28, pp. 85-94Vila, R., Valenzuela, L., Bello, H., Cañigueral, S., Montes, M., Adzet, T., Composition and antimicrobial activity of the essential oil of Peumus boldus leaves (1999) Planta Med, 65, pp. 178-179Vogel, H., Razmilic, I., Muñoz, M., Doll, U., San Martin, J., Studies of genetic variation of essential oil and alkaloid content in boldo (Peumus boldus) (1999) Planta Med, 65, pp. 90-91Youn, Y.C., Kwon, O.S., Han, E.S., Song, J.H., Shin, Y.K., Lee, C.S., Protective effect of boldine on dopamine-induced membrane permeability transition in brain mitochondria and viability loss in PC12 cells (2002) Biochem Pharmacol, 63, pp. 495-50

Asymmetric Total Synthesis And Antiproliferative Activity Of Goniothalamin Oxide Isomers

Goniothalamin oxide (1) is a styryl lactone which was isolated from bark and leaves of several Goniothalamus species. This natural product has some interesting biological properties such as larvicidal and tripanocidal activities. However, no studies on the antiproliferative profile of goniothalamin oxide (1) and its stereoisomers have been reported yet. Here, goniothalamin epoxide (1), isogoniothalamin epoxide (2) and their enantiomers were prepared via epoxidation of (R)-and (S)-goniothalamin (4). A 3:2 molar ratio in favor of goniothalamin oxide (1) and ent-1 was observed from (R)- and (S)-4, respectively, when 3-chloroperbenzoic acid (mCPBA) was employed while an increase to 6:1 molar ratio was achieved with (S,S)-Jacobsen's catalyst. Antiproliferative activity of these epoxides revealed that ent-isogoniothalamin oxide (ent-2) was the most active against the eight cancer cell lines studied. These results indicate that 6S, 7R and 8R absolute configurations are beneficial for the activity of these epoxides. © 2009.3725256Blázquez, M.A., Bermejo, A., Zafra-Polo, M.C., Cortes, D., (1999) Phytochem. Anal., 10, pp. 161-170de Fátima, A., Modolo, L.V., Conegero, L.S., Pilli, R.A., Ferreira, C.V., Kohn, L.K., de Carvalho, J.E., (2006) Curr. Med. Chem., 13, pp. 3371-3384de Fátima, A., Zambuzzi, W.F., Modolo, L.V., Tarsitano, C.A.B., Gadelha, F.R., Hyslop, S., de Carvalho, J.E., Pilli, R.A., (2008) Chem. Biol. Int., 176, pp. 143-150Martins, C.V.B., de Resende, M.A., Magalhães, T.F.F., Lima, B.H.S., Watanabe, G.A., Ruiz, A.L.T.G., de Carvalho, J.E., de Fátima, A., (2008) Lett. Drug. Des. Discov., 5, pp. 74-78Sam, T.W., Sew-Yeu, C., Matsjeh, S., Gan, E.K., Razak, D., Mohamed, A.L., (1987) Tetrahedron Lett., 28, pp. 2541-2544Lan, Y.H., Chang, F.R., Yu, J.H., Yang, Y.L., Chang, Y.L., Lee, S.J., Wu, Y.C., (2003) J. Nat. Prod., 66, pp. 487-490Goh, S.H., Ee, G.C.L., Chuah, C.H., Wei, C., (1995) Aust. J. Chem., 48, pp. 199-205de Fátima, A., Marquissolo, C., de Albuquerque, S., Carraro-Abrahão, A.A., Pilli, R.A., (2006) Eur. J. Med. Chem., 41, pp. 1210-1213Blagosklonny, M.V., (2005) Cell Cycle, 4, pp. 1518-1521Weisz, B., Meirow, D., Schiff, E., Lishner, M., (2004) Expert Rev. Anticancer Ther., 4, pp. 889-902Fuganti, C., Pedrocchi-Fantoni, G., Sarra, S., Servi, S., (1994) Tetrahedron: Asymmetry, 5, pp. 1135-1138Surivet, J.-P., Vatèle, J.-M., (1999) Tetrahedron, 55, pp. 13011-13028Peng, X., Li, A., Shen, H., Wu, T., Pan, X., (2002) J. Chem. Res.(S), pp. 330-332Pospíšil, J., Markó, I.E., (2006) Tetrahedron Lett., 47, pp. 5933-5937Bose, D.S., Reddy, A.V.N., Srikanth, B., (2008) Synthesis, pp. 2323-2326Monks, A., Scudeiro, D., Skehan, P., Shoemaker, R., Paull, K., Vistica, D., Hose, C., Boyd, M., (1991) J. Nat. Can. Inst., 83, pp. 757-766de Fátima, A., Pilli, R.A., (2003) Tetrahedron Lett., 44, pp. 8721-8724de Fátima, A., Pilli, R.A., (2003) Arkivoc, 10, pp. 118-126de Fátima, A., Kohn, L.K., Antônio, M.A., de Carvalho, J.E., Pilli, R.A., (2004) Bioorg. Med. Chem., 12, pp. 5437-5442de Fátima, A., Kohn, L.K., de Carvalho, J.E., Pilli, R.A., (2006) Bioorg. Med. Chem., 14, pp. 622-631Jacobsen, E.N., Zhang, W., Muci, A.R., Ecker, J.R., Deng, L., (1991) J. Am. Chem. Soc., 113, pp. 7063-7064Hosoya, N., Irie, R., Katsuki, T., (1993) Synlett, pp. 261-26

Steroids And Triterpenes From Eleocharis Acutangula And E. Sellowiana (cyperaceae)

From the hexane extract of the underground parts of Eleocharis acutangula (Roxb.) Schult., lup-20(29)-ene-3β,16β-diol and a mixture of campesterol, stigmasterol and sitosterol were isolated. The hexane extracts of aerial and underground parts of E. sellowiana Kunth furnished two new substances, namely neohop-13(18)-en-3α-ol and stigmast-22-en-3β,6β,9α-triol, together with a mixture of steroids, betulinic acid, stigmast-4-en-6β-ol-3-one and fern-9(11)-en-3α-ol. The molecular structures were determined by spectral analysis (1D- and 2D-NMR experiments and MS) and comparison with literature data. Copyright © 2004 John Wiley & Sons, Ltd.152125129Achari, B., Pal, A., Pakrashi, S.C., Studies on Indian medicinal plants. Part XXXVI: New D:E-cis neohopane derivatives from Alangium lamarckii (1975) Tetrahedron. Lett., 48, pp. 4275-4278Bridgeman, J.E., Cherry, P.C., Clegg, A.S., Evans, J.M., Jones, E.R.H., Kasal, A., Kumar, V., Woodgate, P.D.J., Microbiological hydroxylation of steroids. Proton magnetic resonance spectra of ketones, alcohols, and acetates in the androstane, pregnane and estrane series (1970) J. Chem. Soc. (C), (PART I), pp. 250-257Budzikiewicz, H., Wilson, J.M., Djerassi, C., Mass spectrometry in structural and stereochemical problems. XXXII. Pentacyclic triterpenes (1963) J. Am. Chem. Soc., 85, pp. 3688-3699Chakravarty, A.K., Masuda, K., Suzuki, H., Ageta, H., Unambiguous assignment of 13C chemical shifts of some hopane and migrated hopane derivatives by 2D-NMR (1994) Tetrahedron., 50, pp. 2865-2876Clifford, H.T., Harborne, J.B., Flavonoid pigmentation in sedges (Cyperaceae) (1969) Phytochemistry, 8, pp. 123-126Della Greca, M., Monaco, P., Previtera, L., Stigmasterols from Typha latifolia (1990) J. Nat. Prod., 53, pp. 1430-1435Faria, A.D., (1998), O Gênero Eleocharis R. Br. (Cyperaceae) no Estado de São Paulo. Masters thesis. Biology Institute, UNICAMP, Campinas, SP, BrazilKhastgir, H.N., Pradhan, B.P.J., Acid catalysed isomerisation of 3-epi-moretenyl acetate (1977) Indian Chem. Soc., 54, p. 922Merck, E., (1971) Dyeing Reagents for Thin Layer and Paper Chromatography, , Merck: DarmstadtMiles, D.H., Tunsuwan, K., Chittawong, V.J., Boll weevil anti-feedants from Eleocharis dulcis Trin (1994) Agric. Food Chem., 42, pp. 1561-1562Nakane, T., Arai, Y., Masuda, K., Ishizaki, Y., Ageta, H., Shiojima, K., Fern constituents: Six new triterpenoid alcohols from Adiantum capillus-veneris (1999) Chem. Pharm. Bull., 47, pp. 543-547Olea, R.S.G., Roque, N.F., Análise de misturas de triterpenos por RMN13C (1990) Quim Nova, 13, pp. 278-281Oyarzún, M.L., Garbarino, J.A., Gambaro, V., Guilhem, J., Pascard, C., Two triterpenoids from Boehmeria excelsa (1987) Phytochemistry, 26, pp. 221-223Pollio, A., Della Greca, M., Monaco, P., Pinto, G., Previtera, L., Lipid composition of the acidophilic alga Dunaliella acidophila (Volvocales, Chlorophyta). I. Non-polar lipids (1988) Biochim. Biophys. Acta, 963, pp. 53-60Quayyum, H.A., Mallik, A.U., Orr, D.E., Lee, P.F., Allelopathic potential of aquatic plants associated with wild rice: II. Isolation and identification of allelochemicals (1999) J. Chem. Ecol., 25, pp. 221-228Rubinstein, I., Goad, L.J., Clague, A.D.H., Mulheirn, L.J., The 220 MHz spectra of phytosterols (1976) Phytochemistry, 15, pp. 195-200Sholichin, M., Yamasaki, K., Kasai, R., Tanaka, O., 13C-Nuclear magnetic resonance of lupane-type triterpenes lupeol, betulin and betulinic acid (1980) Chem. Pharm. Bull., 28, pp. 1006-1008Stevens, K.L., Merrill, G.B., Growth inhibitors from spikerush (1980) J. Agric. Food Chem., 28, pp. 644-646Still, W.C., Kahn, M., Mitra, A., Rapid chromatographic technique for preparative separations with moderate resolution (1978) J. Org. Chem., 43, pp. 2923-2925Su, J., Peng, T., Long, K., Zeng, L., 24-Sigma-methyl-5α-cholestane-3α,6β,9α,25-tetrol 25-monoacetate, a novel polyhydroxylated steroid from the soft coral Sarcophyton tortuosum (1986) Steroids, 48, pp. 233-238Van Aller, R.T., Clark, L.R., Pessoney, G.F., Rogers, V.A., A prostaglandin-like fatty acid from a species in the Cyperaceae (1983) Lipids, 18, pp. 617-622Wenkert, E., Baddeley, G.V., Burfitt, I.R., Moreno, L.N., Carbon-13 nuclear magnetic resonance spectroscopy of naturally-occurring substances. LVII. Triterpenes related to lupane and hopane (1978) Org. Mag. Reson., 11, pp. 337-34

Nanocomplex Formation Between β-lactoglobulin Or Caseinomacropeptide And Green Tea Polyphenols: Impact On Protein Gelation And Polyphenols Antiproliferative Activity

The development of milk functional foods including health-promoting green tea polyphenols represents a challenge for the food industry since the formation of protein-polyphenol complexes may affect both protein technological properties and polyphenols biological activity. The present work aimed at the characterization of complexes formed between green tea polyphenols and either β-lactoglobulin (β-lg) or caseinomacropeptide (CMP), as well as to evaluate how this complexation may impact on protein gelation and polyphenol antiproliferative activity against tumor cell lines. Particle size and charge of protein-polyphenol complexes depend on protein nature and pH. At pH 6 they had the smallest size and were soluble. The presence of polyphenols accelerated the gelation of both β-lg and CMP, and mainly affected viscoelasticity of β-lg gels. Polyphenol complexation by proteins did not inhibit its anti-proliferative activity. Moreover, they exerted a better performance on some particular tumor cell lines. © 2012 Elsevier Ltd.44800809Baeza, R., Interacciones entre β-lactoglobulina y polisacáridos en coloides alimentarios (2003) Departamento de Industrias, Facultad de Ciencias Exactas y Naturales, p. 253. , Universidad de Buenos Aires. PhD. Buenos Aires, ArgentinaBaeza, R.I., Pilosof, A.M.R., Calorimetric studies of thermal denaturation of β-lactoglobulin in the presence of polysaccharides (2002) Lebensmittel-Wissenschaft und-Technologie, 35, pp. 393-399Bromley, E.H.C., Krebs, M.R.H., Donald, A.M., Aggregation across the length-scales in β-lactoglobulin (2005) Faraday Discussions, 128, pp. 13-27Burton, J., Skudder, P.J., (1987), Whey proteins. UK patent application GB 2188526 A1Clark, A.H., Kavanagh, G.M., Ross-Murphy, S.B., Globular protein gelation-theory and experiment (2001) Food Hydrocolloids, 15, pp. 383-400Clark, A.H., Ross-Murphy, S.B., Structural and mechanical properties of biopolymer gels (1987) Advances in Polymer Science, 83, pp. 57-192Class, S.D., Dalton, C.R., Hancock, B.C., Differential scanning calorimetry: Applications in drug development (1999) Pharmacology Science and Technology Today, 2 (8), pp. 311-319Chandra Mohan, K.V.P., Gunasekaran, P., Varalakshmi, E., Hara, Y., Nagini, S., In vitro evaluation of the anticancer effect of lactoferrin and tea polyphenol combination on oral carcinoma cells (2007) Cell Biology International, 31, pp. 599-608Charlton, A.J., Baxter, N.J., Lokman Khan, M., Moir, A.J.G., Haslam, E., Davies, A.P., Williamson, M.P., Polyphenol/peptide binding and precipitation (2002) Journal of Agricultural and Food Chemistry, 50, pp. 1593-1601Chen, C., Shen, G.X., Hebbar, V., Hu, R., Owuor, E.D., Kong, A.N.T., Epigallocatechin-3-gallate-induced stress signals in HT-29 human colon adenocarcinoma cells (2003) Carcinogenesis, 24, pp. 1369-1378Farías, M.E., Martinez, M.J., Pilosof, A.M.R., Casein glycomacropeptide pH dependent self-assembly and cold gelation (2010) International Dairy Journal, 20, pp. 79-88Frazier, R.A., Papadopoulou, A., Green, R.J., Isothermal titration calorimetry study of epicatechin binding to serum albumin (2006) Journal of Pharmaceutical and Biomedical Analysis, 41, pp. 1602-1605González de Mejía, E., Song, Y.S., Heck, C.I., Ramírez-Mares, M.V., Yerba mate tea (Ilex paraguariensis): Phenolics, antioxidant capacity and in vitro inhibition of colon cancer cell proliferation (2010) Journal of Functional Foods, 2, pp. 23-34Harbourne, N., Jacquier, J.C., O'Riordan, D., Effects of addition of phenolic compounds on the acid gelation of milk (2011) International Dairy Journal, 21 (3), pp. 185-191Harnsilawat, T., Pongsawatmanit, R., McClements, D.J., Characterization of β-lactoglobulin-sodium alginate interactions in aqueous solutions: A calorimetry, light scattering, electrophoretic mobility and solubility study (2006) Food Hydrocolloids, 20, pp. 577-585Haug, I.J., Skar, H.M., Vegarud, G.E., Langsrud, T., Draget, K.I., Electrostatic effects on β-lactoglobulin transitions during heat denaturation as studied by differential scanning calorimetry (2009) Food Hydrocolloids, 23 (8), pp. 2287-2293Hoffmann, M.A.M., Roefs, S.P.F.M., Verheul, M., van Mil, P.J.J.M., de Kruif, K.G., Aggregation of β-lactoglobulin studied by in situ light scattering (1996) Journal of Dairy Research, 63, pp. 423-440Huh, S.W., Bae, S.M., Kim, Y.-W., Lee, J.M., Namkoong, S.E., Lee, I.P., Kim, S.H., Ahn, W.S., Anticancer effects of (-)-epigallocatechin-3-gallate on ovarian carcinoma cell lines (2004) Gynecologic Oncology, 94 (3), pp. 760-768Jöbstl, E., Ó Connell, J., Fairclough, P.A., Williamson, M.P., Astringency - A molecular model for polyphenol/protein binding (2004) Fibre Diffraction Review, 12, pp. 66-69Khan, N., Mukhtar, H., Multitargeted therapy of cancer by green tea polyphenols (2008) Cancer Letters, 269, pp. 269-280Kreuß, M., Strixner, T., Kulozik, U., The effect of glycosylation on the interfacial properties of bovine caseinomacropeptide (2009) Food Hydrocolloids, 23 (7), pp. 1818-1826Kundu, T., Dey, S., Roy, M., Siddiqi, M., Bhattacharya, R.K., Induction of apoptosis in human leukemia cells by black tea and its polyphenol theaflavin (2005) Cancer Letters, 230, pp. 111-121Laemmli, U.K., Cleavage of structural proteins during the assembly of head of bacteriophague T4 (1970) Nature, 227, pp. 680-687Lambert, J.D., Lee, M.J., Diamond, L., Ju, J., Hong, J., Bose, M., Newmark, H.L., Yang, C.S., Dose-dependent levels of epigallocatechin-3-gallate in human colon cancer cells and mouse plasma and tissues (2006) Drug Metabolism and Disposition, 34, pp. 8-11Liang, L., Tajmir-Riahi, H.A., Subirade, M., Interaction of β-lactoglobulin with resveratrol and its biological implications (2008) Biomacromolecules, 9 (1), pp. 50-56Lin, H.-C., Chen, P.-C., Cheng, T.-J., Chen, R.L.C., Formation of tannin-albumin nano-particles at neutral pH as measured by light scattering techniques (2004) Analytical Biochemistry, 325, pp. 117-120Majhi, P.R., Ganta, R.R., Vanam, R.P., Seyrek, E., Giger, K., Dubin, P.L., Electrostatically driven protein aggregation: Beta-lactoglobulin at low ionic strength (2006) Langmuir, 22, pp. 9150-9159Martinez, M.J., Farías, M.E., Pilosof, A.M.R., The dynamics of heat gelation of casein glycomacropeptide - [beta]-lactoglobulin mixtures as affected by interactions in the aqueous phase (2010) International Dairy Journal, 20 (9), pp. 580-588Martinez, M.J., Farías, M.E., Pilosof, A.M.R., Casein glycomacropeptide pH-driven self-assembly and gelation upon heating (2011) Food Hydrocolloids, , Corrected ProofMonks, A., Scudiero, D., Skehan, P., Shoemaker, R., Paull, K., Vistica, D., Hose, C., Boyd, M., Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines (1991) Journal of the National Cancer Institute, 83 (11), pp. 757-766Naczk, M., Oickle, D., Pink, D., Shahidi, F., Protein precipitating capacity of crude canola tannins: Effect of pH, tannin, and protein concentrations (1996) Journal of Agricultural and Food Chemistry, 44, pp. 2144-2148Nakano, T., Ozimek, L., Purification of glycomacropeptide from dialyzed and non-dializable sweet whey by anion-exchange chromatography at different pH values (2000) Biotechnology Letters, 22, pp. 1081-1086Oku, N., Matsukawa, M., Yamakawa, S., Asai, T., Yahara, S., Hashimoto, F., Akizawa, T., Inhibitory effect of green tea polyphenols on membrane-type 1 matrix metalloproteinase, MT1-MMP (2003) Biological & Pharmaceutical Bulletin, 26 (9), pp. 1235-1238Ould Eleya, M.M., Turgeon, S.L., The effects of pH on the rheology of β-lactoglobulin/κ-carrageenan mixed gels (2000) Food Hydrocolloids, 14, pp. 245-251Pilosof, A.M.R., Gelificación (2000) Caracterización funcional y estructural de proteínas, pp. 75-95. , Eudeba, Buenos Aires, Argentina, A.M.R. Pilosof, G.B. Bartholomai (Eds.)Poncet-Legrand, C., Edelmann, A., Putaux, J.L., Cartalade, D., Sarni-Manchado, P., Vernhet, A., Poly (L-proline) interactions with flavan-3-ols units: Influence of the molecular structure and the polyphenol/protein ratio (2006) Food Hydrocolloids, 20, pp. 687-697Prigent, S.V.E., Gruppen, H., Visser, A.J.W.G., Van Koningsveld, G.A., De Jong, G.A.H., Voragen, A.G.J., Effects of non-covalent interactions with 5-O-caffeoylquinic acid (chlorogenic acid) on the heat denaturation and solubility of globular proteins (2003) Journal of Agricultural and Food Chemistry, 51, pp. 5088-5095Relkin, P., Differential scanning calorimetry: a useful tool for studying protein denaturation (1994) Thermochimica Acta, 246, pp. 371-386Relkin, P., Thermal unfolding of β-lactoglobulin, α-lactalbumin, and bovine serum albumin. 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Bioactivity-guided Isolation Of Cytotoxic Sesquiterpene Lactones Of Gochnatia Polymorpha Ssp. Floccosa

Phytochemical study of Gochnatia polymorpha (Less) Cabr. ssp. floccosa Cabr. trunk bark, guided by antiproliferative assays on 10 human cancer cell lines and the VERO cell line, yielded six known compounds identified as the triterpene bauerenyl acetate, the guaianolide 11α,13-dihydrozaluzanin C and the dimeric guaianolides 10-desoxygochnatiolide A, gochnatiolide A, 8-hydroxi-10-desoxygochnatiolide A and 8-hydroxigochnatiolide A. Extracts, fractions of extracts and isolated compounds were tested in vitro against a panel of human cancer cell lines, including U251 (glioma, CNS), UACC-62 (melanoma), MCF-7 (breast), NCI-ADR/RES (drug-resistant ovarian), 786.0 (kidney), NCI-H460 (lung, no small cells), PC-3 (prostate), OVCAR-3 (ovarian), HT-29 (colon), K562 (leukemia) and against the VERO no cancer cell line. Bauerenyl acetate was inactive, while 11α,13-dihydrozaluzanin C showed weak activity against UACC62 and the VERO cell line. The most active compounds were 10-desoxygochnatiolide A and gochnatiolide A, which inhibited the growth of kidney, melanoma, ovarian-resistant and glioma cell lines with values of TGI (total growth inhibition) varying 0.21-1.09 μg/mL. This is the first report about cytotoxic activity of dimeric lactones against cell lines. Copyright © 2011 John Wiley & Sons, Ltd.26710531056Bohlmann, F., Ahmed, M., Jakupovic, J., King, R.M., Robinson, H., Dimeric sesquiterpene lactones and kolavane derivatives from Gochnatia paniculata (1983) Phytochemistry, 22, pp. 191-195Bohlmann, F., Chen, Z., Guaianolides from Ainsliaea fragrans (1982) Phytochemistry, 21, pp. 2120-2122Bohlmann, F., Zdero, C., Schmeda-Hirschmann, G., Dimeric guainolides and other constituents from Gochnatia species (1986) Phytochemistry, 44, pp. 1175-1178. , et alCatalan, C., Vega, M.I., Lopez, M.L., Cuenca, M.R., Gedris, T.E., Herz, W., Coumarins and a kaurane from Gochnatia polymorpha ssp. polymorpha from Paraguay (2003) Biochem Syst Ecol, 31, pp. 417-422Farias, A.C.M., Silva, A.J.R., Tomassini, T.C.B., Constituents of Mochinea polymorpha (1984) J Nat Prod, 47, pp. 363-364Katinas, L., Pruski, J., Sancho, G., Telleria, M.C., The subfamily Mutisioideae (Asteraceae) (2008) Bot Rev, 74, pp. 469-716Moreira, A.S., Spitzer, V., Schapoval, E.E., Schenkel, E.P., Anti-inflammatory activity of extracts and fractions from the leaves of Gochnatia polymorpha (2000) Phytother Res, 14, pp. 638-640Piornedo, R.R., Souza, P., Stefanello, M.E.A., Strapasson, R.L.B., Zampronio, A.R., Kassuya, C.A.L., Anti-inflammatory activity of extracts and 11,13-dihydrozaluzanin C from Gochnatia polymorpha ssp. floccosa trunk bark in mice (2011) J Ethnopharmacol, 133, pp. 1077-1084Sacilotto, A.C.B., Vichnewski, W., Herz, W., Ent-kaurane diterpenes from Gochnatia polymorpha var. polymorpha (1997) Phytochemistry, 44, pp. 659-661Schlemper, V., Freitas, S.A., Schlemper, S.E.M., Antispasmodic effects of hydroalcoholic extract from Gochnatia polymorpha ssp. floccosa in the guinea pig ileum (2011) Res J Med Plant, 5, pp. 288-294Skehan, P., Storeng, R., Scudiero, D., New colorimetric cytotoxicity assay for anticancer-drug screening (1990) J Natl Cancer Inst, 82, pp. 1107-1118Silva, L.B., Strapasson, R.L.B., Riva, D., Salvador, M.J., Stefanello, M.E.A., Triterpenes from the flowers of Gochnatia polymorpha ssp. floccosa (Asteraceae) (2011) Braz J Pharmacogn, , DOI: 10.1590/S0102-695X2011005000031Stefanello, M.E.A., Salvador, M.J., Ito, I.Y., MacAri, P.A.T., Evaluation of antimicrobial and cytotoxic acitivity of extracts from Gochnatia polymorpha ssp. floccosa (2006) Braz J Pharmacogn, 16, pp. 525-530Zhang, S., Won, Y., Ong, C., Shen, H., Anti-cancer potential of sesquiterpene lactones: Bioactivity and molecular mechanisms (2005) Curr Med Chem, 5, pp. 239-24