Two natural products, Camptothecin (1, Figure 1), an alkaloid isolated from the Chinese tree Camptotheca acuminate Dence,1 and Evodiamine (2), an alkaloid isolated from the dried fruit of Evodia rutaecarpa (Juss.) Benth (E. rutaecarpa),2 are characterized by antitumoral activity, targeting the DNA topoisomerase I,3-5 an ubiquitous and essential enzyme for topological DNA modification during a number of critical cellular process in mammals.6 However, their therapeutic application is hindered because of poor aqueous solubility and high in vivo hepatoxicity. Subsequently, the structural modification of the natural Camptothecin and Evodiamine is crucial for the improvement of their pharmacological and pharmacokinetic profile.7-10 Figure 1. Structure of camptothecin and evodiamine and images taken from modeling studies.11 In our interest, for the synthesis of various derivatives of the natural compounds we focused on position 7 of the Camptothecin, and on position 5 of the Evodiamine moiety (Figure 2). Experimental In the case of Camptothecin, the reactivity of position 7 gave us the possibility to obtain 7-hydroxymethyl camptothecin that by reaction with hydrobromic acid resulted in the corresponding bromoderivative. We then turned our attention toward the formation of C-S bond that resulted as a not trivial issue. The solution of the problem gave us the possibility to obtain 3 different compounds stable enough to be submitted to different biological assays. Antiproliferative activity and topoisomerases inhibition were investigated and the results moved us to study the cellular response to the DNA damage and their influence on angiogenesis. With a similar approach a library of 11 compounds has been prepared by introduction of a carboxylic group at position 5 of evodiamine. The biological data have been compared with the suggestion deriving from modeling studies. Figure 2. Results and discussion In the case of camptothecin derivatives, the results of cellular studies and the molecular modeling analysis indicated that the 7-modified camptothecin derivatives fully maintained the biological activity and the same feature of drug-target interaction of the natural compound. This conclusion is also supported by the biochemical characterization indicating a comparable ability to induce DNA damage. These observations support the view that the 7-position is favourable for safe introduction of suitable side chains without detrimental effects. In the case of evodiamine derivatives the preliminary results regarding the antoproliferative activity require further investigation that are ongoing. References [1] Wall, M.E., Wani, M.C., Cook, C.E., Palmer, K.H., McPhail, A.T., Sim, G.A., J. Am. Chem. Soc., 88 (1966), 3888-3890. [2] Asahina, A., Kashiwaki, K., Yakugaku Zasshi, 405 (1915), 1293; Chem. Abstr., 10 (1916), 607. [3] Hsiang, Y.H., Hertzberg, R., Hetch, S.M., Liu, L.F., J. Biol. Chem., 260 (1985), 14873-14878. [4] Liu, L.F., Desai, S.D., Li, T.K., Mao, Y., Sun, M., Sim, S.P., Ann. N. Y. Acad. Sci., 922 (2000), 1-10. [5] Dong, G., Sheng, C., Wang, S., Miao, Z., Yao, J., Zhang, W., J. Med. Chem., 53 (2010), 7521-2531. [6] Pommier, Y., Nat. Rev. Cancer, 6 (2006), 789-802. [7] Driver, R.W., Yang, L.X., Mini-Rev. Med. Chem., 5 (2005), 425–439. [8] Li, Q.Y., Zu, Y.G., Shi, R.Z., Yao, L.P., Curr. Med. Chem., 13 (2006), 2021–2039. [9] Thomas, C.J., Rahier, N.J., Hecht, S.M., Bioorg. Med. Chem., 12 (2004), 1585–1604. [10] Chen, Z., Hu, G., Li, D., Chen, J., Li, Y., Zhou, H., Xie, Y., Bioorg. Med. Chem., 17 (2009), 2351–2359. [11] The image of the docked position of evodiamine has been taken from Dong, G., Sheng, C.; Wang, S., Miao, Z., Yao, J., Zhang, W. J. Med. Chem 53 (2010), 7521-7531.

Natural Products as Scaffolds for the Modulation of Topoisomerase I / D. Passarella, M. Christodoulou, S. Borrelli. ((Intervento presentato al convegno COST ACTION CM 0804 - Chemistry and Target Identification of Natural Products tenutosi a București nel 2012.

Natural Products as Scaffolds for the Modulation of Topoisomerase I

D. Passarella
Primo
;
M. Christodoulou
Secondo
;
S. Borrelli
Ultimo
2013

Abstract

Two natural products, Camptothecin (1, Figure 1), an alkaloid isolated from the Chinese tree Camptotheca acuminate Dence,1 and Evodiamine (2), an alkaloid isolated from the dried fruit of Evodia rutaecarpa (Juss.) Benth (E. rutaecarpa),2 are characterized by antitumoral activity, targeting the DNA topoisomerase I,3-5 an ubiquitous and essential enzyme for topological DNA modification during a number of critical cellular process in mammals.6 However, their therapeutic application is hindered because of poor aqueous solubility and high in vivo hepatoxicity. Subsequently, the structural modification of the natural Camptothecin and Evodiamine is crucial for the improvement of their pharmacological and pharmacokinetic profile.7-10 Figure 1. Structure of camptothecin and evodiamine and images taken from modeling studies.11 In our interest, for the synthesis of various derivatives of the natural compounds we focused on position 7 of the Camptothecin, and on position 5 of the Evodiamine moiety (Figure 2). Experimental In the case of Camptothecin, the reactivity of position 7 gave us the possibility to obtain 7-hydroxymethyl camptothecin that by reaction with hydrobromic acid resulted in the corresponding bromoderivative. We then turned our attention toward the formation of C-S bond that resulted as a not trivial issue. The solution of the problem gave us the possibility to obtain 3 different compounds stable enough to be submitted to different biological assays. Antiproliferative activity and topoisomerases inhibition were investigated and the results moved us to study the cellular response to the DNA damage and their influence on angiogenesis. With a similar approach a library of 11 compounds has been prepared by introduction of a carboxylic group at position 5 of evodiamine. The biological data have been compared with the suggestion deriving from modeling studies. Figure 2. Results and discussion In the case of camptothecin derivatives, the results of cellular studies and the molecular modeling analysis indicated that the 7-modified camptothecin derivatives fully maintained the biological activity and the same feature of drug-target interaction of the natural compound. This conclusion is also supported by the biochemical characterization indicating a comparable ability to induce DNA damage. These observations support the view that the 7-position is favourable for safe introduction of suitable side chains without detrimental effects. In the case of evodiamine derivatives the preliminary results regarding the antoproliferative activity require further investigation that are ongoing. References [1] Wall, M.E., Wani, M.C., Cook, C.E., Palmer, K.H., McPhail, A.T., Sim, G.A., J. Am. Chem. Soc., 88 (1966), 3888-3890. [2] Asahina, A., Kashiwaki, K., Yakugaku Zasshi, 405 (1915), 1293; Chem. Abstr., 10 (1916), 607. [3] Hsiang, Y.H., Hertzberg, R., Hetch, S.M., Liu, L.F., J. Biol. Chem., 260 (1985), 14873-14878. [4] Liu, L.F., Desai, S.D., Li, T.K., Mao, Y., Sun, M., Sim, S.P., Ann. N. Y. Acad. Sci., 922 (2000), 1-10. [5] Dong, G., Sheng, C., Wang, S., Miao, Z., Yao, J., Zhang, W., J. Med. Chem., 53 (2010), 7521-2531. [6] Pommier, Y., Nat. Rev. Cancer, 6 (2006), 789-802. [7] Driver, R.W., Yang, L.X., Mini-Rev. Med. Chem., 5 (2005), 425–439. [8] Li, Q.Y., Zu, Y.G., Shi, R.Z., Yao, L.P., Curr. Med. Chem., 13 (2006), 2021–2039. [9] Thomas, C.J., Rahier, N.J., Hecht, S.M., Bioorg. Med. Chem., 12 (2004), 1585–1604. [10] Chen, Z., Hu, G., Li, D., Chen, J., Li, Y., Zhou, H., Xie, Y., Bioorg. Med. Chem., 17 (2009), 2351–2359. [11] The image of the docked position of evodiamine has been taken from Dong, G., Sheng, C.; Wang, S., Miao, Z., Yao, J., Zhang, W. J. Med. Chem 53 (2010), 7521-7531.
mag-2013
Settore CHIM/06 - Chimica Organica
Natural Products as Scaffolds for the Modulation of Topoisomerase I / D. Passarella, M. Christodoulou, S. Borrelli. ((Intervento presentato al convegno COST ACTION CM 0804 - Chemistry and Target Identification of Natural Products tenutosi a București nel 2012.
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