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Publicly Available Published by De Gruyter April 29, 2012

First total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the Leishmania topoisomerase IB enzyme

  • Néstor M. Carballeira , Michelle Cartagena , Fengyu Li , Zhongfang Chen , Christopher F. Prada , Estefania Calvo-Alvarez , Rosa M. Reguera and Rafael Balaña-Fouce

The fatty acids (±)-2-methoxy-6Z-heptadecenoic acid, (±)-2-methoxy-6-hepta-decynoic acid, and (±)-2-methoxyheptadecanoic acid were synthesized and their inhibitory activity against the Leishmania DNA topoisomerase IB enzyme (LdTopIB) determined. Both 2-OMe-17:1 fatty acids were synthesized from 4-bromo-1-pentanol, the olefinic fatty acid in 10 steps and in 7 % overall yield, while the acetylenic fatty acid in 7 steps and in 14 % overall yield. The 2-OMe-17:0 acid was prepared in 6 steps and in 42 % yield from 1-hexa-decanol. The 2-OMe-17:1 acids inhibited LdTopIB, with the acetylenic acid displaying an EC50 = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit LdTopIB. The (±)-2-methoxy-6Z-heptadecenoic acid preferentially inhibited LdTopIB over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of LdTopIB and either the double or triple bonds of the fatty acids. Toxicity toward Leishmania donovani promastigotes was also investigated, resulting in the order acetylenic > olefinic > saturated with the (±)-2-methoxy-6-heptadecynoic acid displaying an EC50 = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C17:1 fatty acids toward L. donovani promastigotes, but improves their selectivity index.


Conference

IUPAC Congress, IUPAC Congress, CONGRESS, IUPAC Congress, 43rd, San Juan, Puerto Rico, 2011-07-30–2011-08-07


References

1 10.1016/j.ijid.2011.03.021, T. S. Tiuman, A. O. Santos, T. Ueda-Nakamura, B. P. Filho, C. V. Nakamura. Int. J. Infect. Dis.15, 525 (2011).Search in Google Scholar PubMed

2 D. L. Sacks, P. V. Perkin. Am. J. Trop. Med. Hyg.34, 456 (1985).Search in Google Scholar

3 J. S. Glasser, C. K. Murray. Am. J. Trop. Med. Hyg.84, 566 (2011).Search in Google Scholar

4 10.1590/S0036-46652009000400011, I. D. Vélez, L. M. Colmenares, C. A. Muñoz. Rev. Inst. Med. Trop. Sao Paulo51, 231 (2009).Search in Google Scholar PubMed

5 G. Chaudhuri, K. Ghoshal, A. B. Banerjee. Indian J. Med. Res.84, 361 (1986).Search in Google Scholar

6 L. V. Cunningham, B. H. Kazan, S. S. Kuwahara. J. Gen. Microbiol.70, 491 (1972).Search in Google Scholar

7 10.1007/s11745-009-3345-z, N. M. Carballeira, M. M. Cartagena, C. Fernández Prada, C. Fernández-Rubio, R. Balaña-Fouce. Lipids44, 953 (2009).Search in Google Scholar PubMed PubMed Central

8 10.1074/jbc.M203991200, H. Villa, A. R. Otero-Marcos, R. M. Reguera, R. Balaña-Fouce, C. García-Estrada, Y. Pérez-Pertejo, B. L. Tekwani, P. J. Myler, K. D. Stuart, M. A. Bjornsti, D. Ordóñez. J. Biol. Chem.278, 3521 (2003).Search in Google Scholar PubMed

9 10.1021/np990529d, N. M. Carballeira, M. Pagán. J. Nat. Prod.63, 666 (2000).Search in Google Scholar PubMed

10 Spectral data for the (±)-2-methoxy-6-heptadecynoic acid (2). IR (neat) νmax: 3365, 2926, 2855, 1734, 1457, 1380, 1119 cm–1; 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.83 (1H, t, J = 4.6 Hz), 3.44 (3H, s, OCH3), 2.20 (2H, t, J = 7.0 Hz), 2.12 (2H, t, J = 6.9 Hz), 1.62 (2H, q, J = 7.2 Hz), 1.25 (18H, brs, CH2), 0.87 (3H, t, J = 6.9 Hz, CH3); 13C NMR (CDCl3, 125 MHz) δ (ppm): 176.97 (C-1), 81.07 (C-7), 79.72 (C-2), 79.02 (C-6), 58.24 (C-2'), 31.88 (C-15), 31.36 (C-13), 29.57 (C-12), 29.52 (C-14), 29.30 (C-9), 29.14 (C-11), 28.88 (C-3), 24.44 (C-16), 22.66 (C-4), 18.71 (C-5), 18.45 (C-8), 14.09 (C-17). HRMS calcd for C18H32O3 [M + H]+ 297.2424, found 297.2423.Search in Google Scholar

11 Spectral data for the (±)-2-methoxy-6Z-heptadecenoic acid (1). IR (neat) νmax: 3330, 3005, 2928, 2856, 1720, 1650, 1458, 1380, 969, 778 cm–1; 1H NMR (CDCl3, 500 MHz) δ (ppm): 5.35 (2H, m), 3.78 (1H, t, J = 6.7 Hz), 3.42 (3H, s, –OCH3), 2.01 (4H, m), 1.76 (2H, m), 1.23 (18H, brs, CH2), 0.85 (3H, t, J = 7.0 Hz, CH3); 13C-NMR (CDCl3, 125 MHz) δ (ppm): 176.87 (C-1), 131.26 (C-7), 129.04 (C-6), 80.46 (C-2), 58.28 (C-2'), 31.88 (C-15), 31.81 (C-3, C-9), 29.67 (C-10), 29.61 (C-11), 29.53 (C-12), 29.41 (C-13), 29.31 (C-14), 27.23 (C-8), 26.71 (C-5), 24.83 (C-4), 22.67 (C-16), 14.13 (C-17). HRMS Calcd for C18H35O3 [M + H]+ 299.2581, found 299.2583.Search in Google Scholar

12 Spectral data for the (±)-2-methoxyheptadecanoic acid (3). IR (neat) νmax: 3420, 2922, 2852, 1716, 1457, 1381, 1090 cm–1; 1H-NMR (CDCl3, 500 MHz) δ (ppm): 3.79 (1H, t, J = 5.0 Hz), 3.46 (3H, s, OCH3), 1.52 (2H, m), 1.28 (26H, brs, CH2), 0.87 (3H, t, J = 6.7 Hz, CH3); 13C-NMR (CDCl3, 125 MHz) δ (ppm): 175.89 (C-1), 80.27 (C-2), 58.34 (C-2'), 32.22 (C-15), 31.93 (C-3), 29.70 (C-12, C-13), 29.67 (C-10, C-11), 29.63 (C-9), 29.55 (C-8), 29.42 (C-7), 29.37 (C-6), 29.32 (C-5), 29.08 (C-14), 24.82 (C-4), 22.70 (C-16), 14.13 (C-17).Search in Google Scholar

13 10.1016/j.tetlet.2010.09.083, N. M. Carballeira, N. Montano, R. M. Reguera, R. Balaña-Fouce. Tetrahedron Lett.51, 6153 (2010).Search in Google Scholar PubMed PubMed Central

14 10.1016/j.abb.2009.04.007, S. Castelli, A. Campagna, O. Vassallo, C. Tesauro, P. Fiorani, P. Tagliatesta, F. Oteri, M. Falconi, H. K. Majumder, A. Desideri. Arch. Biochem. Biophys.486, 103 (2009).Search in Google Scholar PubMed

15 C. A. Deakyne, M. Meot-Ner. J. Am. Chem. Soc.107, 474 (1985).Search in Google Scholar

16 10.1021/cr9603744, J. C. Ma, D. A. Dougherty. Chem. Rev.97, 1303 (1997).Search in Google Scholar PubMed

17 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox. Gaussian 09, Gaussian, Inc., Wallingford, CT (2009).Search in Google Scholar

18 10.1103/PhysRev.46.618, C. Möller, M. S. Plesset. Phys. Rev.46, 618 (1934).Search in Google Scholar

19 10.1063/1.443164, G. D. Purvis, R. J. Bartlett. J. Chem. Phys.76, 1910 (1982).Search in Google Scholar

20 10.1016/S0009-2614(89)87395-6, K. Raghavachari, G. W. Trucks, J. A. Pople, M. Head-Gordon. Chem. Phys. Lett.157, 479 (1989).Search in Google Scholar

21 10.1063/1.464480, J. D. Watts, J. Gauss, R. J. Bartlett. J. Chem. Phys.98, 8718 (1993).Search in Google Scholar

22 E. D. Glendening, A. E. Reed, J. E. Carpenter, F. Weinhold. NBO Version 3.1.Search in Google Scholar

Online erschienen: 2012-4-29
Erschienen im Druck: 2012-4-30

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