OJSTA  Vol.2 No.4 , October 2013
Regioselective Synthesis and Biological Evaluation of 1-Hydroxyl Modified Ailanthinone Derivatives as Antimalarials

The triterpene quassinoid ailanthinone is a structurally intricate natural product possessing highly potent antimalarial activity against multidrug resistance plasmodium parasites. Although the mechanism of action of ailanthinone is not completely understood, it is presumed to disrupt regular ribosomal functions by inhibiting parasite protein synthesis. Natural scarcity and low solubility of many quassinoids have impeded their development as potential clinical candidates, but exquisite potency of ailanthinone against Plasmodium remains compelling in the global fight against malaria. Herein, we report the highly selective synthesis of 1-hydroxyl derivatives of ailanthinone, including ester, carbonate, carbamate and sulfonate derivatives. The key feature of the synthesis is a one-step regioselective modification of the 1-hydroxyl group in favor of two other hydroxyl groups at C12 and C13. Derivatives were obtained via direct reaction with acyl/sulfonyl chlorides in the presence of a tertiary amine base without any protection-deprotection. In vitro antimalarial evaluations of these derivatives were compared with chloroquine and mefloquine against the Plasmodium falciparum clones, D6, W2, and TM91C235. The results demonstrate that modification of the 1-hydroxyl group is achievable, and the antimalarial activity of these derivatives relative to the parent product is significantly retained, thus paving the way for synthesis of derivatives with improved biological availability and/or increased potency.

Cite this paper
M. Chordia, W. McCalmont, K. Smith and P. Smith, "Regioselective Synthesis and Biological Evaluation of 1-Hydroxyl Modified Ailanthinone Derivatives as Antimalarials," Open Journal of Synthesis Theory and Applications, Vol. 2 No. 4, 2013, pp. 91-96. doi: 10.4236/ojsta.2013.24012.
[1]   B. C. Joshi, R. P. Sharma and A. Khare, “Ailanthus Quassinoids and Their Biological Activity,” Natural Product Communications, Vol. 2, No. 8, 2007, pp. 869-880.

[2]   Z. Guo, S. Vangapandu, R. W. Sindelar, L. A. Walker and R. D. Sindelar, “Biologically Active Quassinoids and Their Chemistry: Potential Leads for Drug Design,” Current Medicinal Chemistry, Vol. 12, No. 2, 2005, pp. 173-190. http://dx.doi.org/10.2174/0929867053363351

[3]   S. C. Bhatnagar, A. J. Caruso and J. Polonky, “Biologically-Active Quassinoids-Synthetic Methodology for the Conversion of Chaparrin into Glaucarbolone Esters and Quassinoid Analogs,” Tetrahedron, Vol. 43, No. 15, 1987, pp. 3471-3480.

[4]   J. Polonsky, “Quassinoid Bitter Principles. II,” Progress in the Chemistry of Organic Natural Products, Vol. 47, 1985, pp. 221-264.

[5]   R. M. Ekong, G. C. Kirby, G. Patel, J. David Phillipson and D. C. Warhurst, “Comparision of the in Vitro Activities of Quassinoids with Activity against PlasmodiumFalciparum, Anisomycine and Some Other Inhibitors of Eukaryotic Protein-Synthesis,” Biochemical Pharmacology, Vol. 40, No. 2, 1990, pp. 297-301.

[6]   I. Muhammad and V. Samoylenko, “Antimalarial Quassinoids: Past, Present and Future,” Expert Opinion on Drug Discovery, Vol. 2, 2007, pp. 1065-1084.

[7]   H.-S. Kim, Y. Shibata, N. Ko, N. Ikemoto, Y. Ishizuka, et al., “Potent in Vivo Antimalarial Activity of 3,15-di-OAcetylbruceolide against Plasmodium Berghei Infection in Mice,” Parasitology International, Vol. 48, 2000, pp. 271-274. http://dx.doi.org/10.1016/S1383-5769(99)00023-9

[8]   N. Murakami, M. Sugimoto, M. Kawanishi, S. Tamura, H. S. Kim, et al., “New Semisynthetic Quassinoids with in Vivo Antimalarial Activity,” Journal of Medical Chemistry, Vol. 46, No. 4, 2003, pp. 638-641.

[9]   G. C. Kirby, M. J. O’Neill, J. D. Phillipson and D. C. Warhurst, “In Vitro Studies on the Mode of Action of Quassinoids with Activity Chloroquine-Resistant Plasmodium Falciparum,” Biochemical Pharmacology, Vol. 38, No. 24, 1989, pp. 4367-4374.

[10]   J. D. Chulay, J. D. Haynes and C. L. Diggs, “Plasmodium-Falciparum—Assessment of in Vitro Growth by [H-3]-Labeled Hypoxanthine Incorporation,” Experimental Parasitology, Vol. 55, No. 1, 1983, pp. 138-146.

[11]   W. K. Milhous, N. F. Weatherly, J. H. Bowdre and R. E. Desjardins, “In Vitro Activities of and Mechanisms of Resistance to Antifol Antimalarial Drugs,” Antimicrobial Agents Chemotherapy, Vol. 27, No. 4, 1985, pp. 525-530.

[12]   M. Ogura, G. A. Cordell, D. Kinghorn and N. R. Farnsworth, “Potential Anti-Cancer Agents 6. Constituents of Ailanthus-Excelsa (Simaroubaceae),” Lloydia, Vol. 40, 1977, pp. 579-584.

[13]   D. J. Morré, P. A. Grieco and D. M. Morré, “Mode of Action of the Anticancer Quassinoids—Inhibition of the Plasma Membrane NADH Oxidase,” Life Sciences, Vol. 63, 1998, pp. 595-604.