Synthesis, Antiproliferative Activity In Cancer Cells And Theoretical Studies Of Novel 6α,7β-dihydroxyvouacapan-17β-oic Acid Mannich Base Derivatives

Natural products are great prototypes for the design of new anticancer agents. The plant-derived natural product 6α,7β-dihydroxyvouacapan- 17β-oic acid (1) is promising for the development of more potent antiproliferative agents against human cancer cells. Indeed, its lactone derivative 6α-hydroxyvouacapan-7β,17β-lactone (2), a non-natural furanoditerpene, exhibited higher anticancer activity than compound 1. Herein, we describe the synthesis and antiproliferative activity of six new Mannich derivatives of compound 2 against nine cancer cell lines. Overall, our results revealed that Mannich derivatives 3-8 were more potent than compound 2 in inhibiting the proliferation of cancer cells. Theoretical studies also supported our findings, revealing the nucleophilic character of furan ring as an important feature for antiproliferative activity of the studied Mannich derivatives. © 2010 Elsevier Ltd. All rights reserved.182381728177Newman, K.M., Cragg, G.M., (2007) J. Nat. Prod., 70, p. 461De 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, p. 3371Torrenegra, R., Bauerei, P., Achenbach, H., (1989) Phytochemistry, 28, p. 2219Marques, D.D., MacHado, M.I.L., Carvalho, M.G., Meleira, L.A.C., Braz-Filho, R., (1998) J. Braz. Med. Chem., 9, p. 295Braz-Filho, R., Gottlieb, O.R., Assumpão, R.M.V., (1971) Phytochemistry, 10, p. 2835Arriaga, A.M.C., De Castro, M.A.B., Silveira, E.R., Braz-Filho, R., (2000) J. Braz. Med. Chem., 11, p. 187Fascio, M., Mors, W.B., Gilbert, B., Mahajan, I.R., Monteiro, M.B., Dos Santos-Filho, D., Vichnewiski, W., (1976) Phytochemistry, 15, p. 201Duarte, I.D.G., Ferreira-Alves, D.L., Piló-Veloso, D., Nakamura-Craig, M., (1996) J. Ethnopharmacol., 55, p. 13Demuner, A.J., Barbosa, L.C.A., Piló-Veloso, D., Howarth, O.W., (1996) J. Nat. Prod., 59, p. 770Demuner, A.J., Barbosa, L.C.A., Piló-Veloso, D., Ferreira-Alves, D.L., Howarth, O.W., (1998) Aust. J. Chem., 51, p. 61Belinelo, V.J., Reis, G.T., Stefani, G.M., Ferreira-Alves, D.L., Piló-Veloso, D., (2002) J. Braz. Chem. Soc., 13, p. 830Rubinger, M.M.M., Piló-Veloso, D., Stefani, G.M., Ferreira-Alves, D.L., (1991) J. Braz. Chem. Soc., 2, p. 124Da Silva, M.C., Gayer, C.R., Lopes, C.S., Calixto, N.O., Reis, P.A., Passaes, C.P., Paes, M.C., Coelho, M.G.P., (2004) J. Pharm. Pharmacol., 56, p. 135King-Díaz, B., Pérez-Reyes, A., Dos Santos, F.J.L., Ferreira-Alves, D.L., Piló-Veloso, D., Uribe-Carbajal, S., Lotina-Hennsen, B., (2006) Pest. Biochem. Physiol., 84, p. 109King-Díaz, B., Dos Santos, F.J.L., Rubinger, M.M.M., Piló-Veloso, D., Lotina-Hennsen, B., (2006) Z. Naturforsch., 61, p. 227De Omena, M.C., Bento, E.S., De Paula, J.E., Sant'Ana, A.E.G., (2006) Vector-Borne Zoonotic. Dis., 6, p. 216Spindola, H.M., Servat, L., Denny, C., Rodrigues, R.A.F., Eberlin, M.N., Cabral, E., Sousa, I.M.O., Foglio, M.A., (2010) BMC Pharmacol., 10, p. 1Castelo-Branco, P.A., De Santos, F.J.L., Rubinger, M.M.M., Ferreira-Alves, D.L., Piló-Veloso, D., King-Díaz, B., Lotina-Hennsen, B., (2008) Z. Naturforsh., 63, p. 251Vieira, C.R., Marques, M.F., Soares, P.R., Matuda, L., De Oliveira, C.M.A., Kato, L., Da Silva, C.C., Guillo, L.A., (2008) Phytomedicine, 15, p. 528Euzébio, F.P., Santos, F.J.L., Piló-Veloso, D., Ruiz, A.L.T.G., Carvalho, J.E., Ferreira-Alves, D.L., Fatima, A., (2009) Bioorg. Chem., 37, p. 96Spindola, H.M., Carvalho, J.E., Ruiz, A.L.T.G., Rodrigues, R.A.F., Denny, C., Sousa, I.M.O., Tamashiro, J.Y., Foglio, M.A., (2009) J. Braz. Chem. Soc., 20, p. 569Rugiero, S.G., Rodrigues, B.L., Fernandes, N.G., Stefani, G.M., Piló-Veloso, D., (1997) Acta Crystallogr., Sect. C, 53, p. 982Mahajan, J.R., Monteiro, M.B., (1973) J. Chem. Soc., Perkin Trans. i, p. 520Monks, A., Scudeiro, D., Skehan, P., Shoemaker, R., Paull, K., Vistica, D., Hose, C., Boyd, M., (1991) J. Nat. Can. Inst., 83, p. 757Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Pople, J.A., (2003) Gaussian 2003 Revision B.04, , Gaussian, Inc.: Pittsburgh PADewar, M.J.S., Zoebish, E.G., Healy, E.F., Stewart, J.J.P., (1985) J. Am. Chem. Soc., 107, p. 3902Parr, R.G., Yang, W., (1989) Density Functional Theory of Atoms and Molecules, , Oxford New YorkLee, C., Yang, W., Parr, R.G., (1998) Phys. Rev. B, 37, p. 785Becke, A.D., (1998) Phys. Rev. A, 38, p. 3098Ditchfield, R., Hehre, W.J., Pople, J.A., (1971) J. Chem. Phys., 54, p. 724Hehre, W.J., Ditchfield, R., Pople, J., (1972) J. Chem. Phys., 56, p. 2257Hariharan, P.C., Pople, J.A., (1973) Theor. Chim. Acta, 28, p. 213Hariharan, P.C., Pople, J.A., (1974) Mol. Phys., 27, p. 209Gordon, M.S., (1980) Chem. Phys. Lett., 76, p. 163Vieira, F.T., De Lima, G.M., Wardell, J.L., Wardell, S.M.S.V., Krambrock, K., Alcântara, A.F.C., (2008) J. Org. Chem., 693, p. 198