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Novel pyrrolo-quinazolino-quinoline analogues of the natural alkaloids and their inclusion molecular complexes in the native cyclodextrins: experimental versus theoretical study

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Abstract

A series ten novel analogs based on a novel template pyrrolo-quinazolino-quinolines, containing Luotonin-A (Luot-A) and 14-aza-camptothecin (14-aza-CPT) molecular core as well as their inclusion complexes in the native α- (α-CD), β- (β-CD) and γ- (β-CD) cyclodextrins were obtained. The physical properties of the alkaloids and corresponding molecular complexes with cyclodextrins are elucidated experimentally by the electronic absorption and CD-spectroscopy, electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry and nuclear magnetic resonance method. The experimental data are supported by the theoretical quantum chemical calculations of the molecular and electronic structures as well as physical properties in condense phase.

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References

  1. Ma, Z., Hano, Y., Nomura, T., Chen, Y.: Two new pyrroloquinazolinoquinoline alkaloids from Peganum nigellastrum. Heterocycles 46, 541 (1997)

    Article  CAS  Google Scholar 

  2. Ma, Z., Hano, Y., Nomura, T., Chen, Y.: Two new quinazoline-quinoline alkaloids from Peganum nigellastrum. Heterocycles 51, 1883 (1999)

    Article  CAS  Google Scholar 

  3. Ali Tasneem, M., Rajanna, K., SaiPrakash, P.: An efficient and facile synthesis of 2-chloro-3-formyl quinolines from acetanilides in micellar media by Vils-meier-HaackCyclisation. Synlett 32, 251 (2001)

    Google Scholar 

  4. Amin, A., Mehta, D., Samarth, S.: Vasicineand related compounds. Prog. Drug. Res. 14, 218 (1970)

    Google Scholar 

  5. Johne, S.: Search for pharmaceutically interesting quinazoline derivatives: efforts and results (1969–1980). Prog. Drug. Res. 26, 259 (1982)

    CAS  Google Scholar 

  6. Govindachari, T., Ravindranath, K., Viswanathan, N.: Mappicine, a minor alkaloid from Mappia foetida miers. J. Chem. Soc. Perkin Trans. 1, 1215 (1974)

    Article  Google Scholar 

  7. Hertzberg, R., Caranfa, M., Holden, K., Jakas, D., Gallagher, G., Mattern, M.R., Mong, S., Bartus, J., Johnson, R., Kingsbury, W.J.: Modification of the hydroxylactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J. Med. Chem. 32, 715 (1989)

    Article  CAS  Google Scholar 

  8. Adamovics, J., Hutchinson, C.J.: Prodrug analogs of the antitumor alkaloid camptothecin. J. Med. Chem. 22, 310 (1979)

    Article  CAS  Google Scholar 

  9. Sawada, S., Yaegashi, T., Furuta, T., Yokokura, T., Miyasaka, T.: Chemical modification of an antitumor alkaloid, 20(S)-camptothecin: E-lactone ring-modified water-soluble derivatives of 7-ethylcamptothecin. Chem. Pharm. Bull. 41, 310 (1993)

    Article  CAS  Google Scholar 

  10. Nicholas, A., Wani, M., Manikumar, G., Wall, M., Kohn, K., Pommier, Y.: Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring E modified analogs of camptothecin. J. Med. Chem. 33, 972 (1990)

    Article  CAS  Google Scholar 

  11. Ejima, A., Terasawa, H., Sugimori, M., Ohsuki, S., Matsumoto, K., Kawato, Y., Yasuoka, M., Tagawa, H.: Antitumor agents. V. Synthesis and antileukemic activity of E-ring-modified (RS)-camptothecin analogues. Chem. Pharm. Bull. 41, 683 (1992)

    Article  Google Scholar 

  12. Cagir, A., Jones, S., Gao, R., Eisenhauer, B., Hecht, S.J.: Communication luotonin A. a naturally occurring human dna topoisomerase I poison. J. Am. Chem. Soc. 125, 13628 (2003)

    Article  CAS  Google Scholar 

  13. Dallavalle, S., Merlini, L.: A new synthesis of the cytotoxic alkaloid luotonine A. Tetrahedron Lett. 43, 1835 (2002)

    Article  CAS  Google Scholar 

  14. Yadav, J., Reddy, B.: Microwave-assisted rapid synthesis of the cytotoxic alkaloid luotonin A. Tetrahedron Lett. 43, 1905 (2002)

    Article  CAS  Google Scholar 

  15. Osborne, D., Stevenson, P.: Concise formal synthesis of luotonin A. Tetrahedron Lett. 43, 5469 (2002)

    Article  CAS  Google Scholar 

  16. Lee, E., Park, J., Jahng, Y.: A facile synthesis of simple alkaloids—synthesis of 2,3-polymethylene-4(3H)-quinazolinones and related alkaloids. Tetrahedron Lett. 44, 1883 (2003)

    Google Scholar 

  17. Chavan, S., Sivappa, R.: A short and efficient general synthesis of luotonin A, B and E. Tetrahedron 60, 9931 (2004)

    Article  CAS  Google Scholar 

  18. Liang, J., Cha, H., Jahng, Y.: Recent advances in the studies on luotonins. Molecules 16, 4861 (2011)

    Article  CAS  Google Scholar 

  19. Cortesi, R., Esposito, E., Maietti, A., Menegatti, E., Nastruzzi, C.: Formulation study for the antitumor drug camptothecin: liposomes, micellar solutions and a microemulsion. Int. J. Pharm. 159, 95 (1997)

    Article  CAS  Google Scholar 

  20. Burke, T., Staubus, A., Misra, A.: Liposomal stabilization of camptothecin’s lactone ring. J. Am. Chem. Soc. 114, 8318 (1992)

    Article  CAS  Google Scholar 

  21. Daoud, S., Fetouh, M., Giovanella, B.: Antitumor effect of liposome-incorporated camptothecin in human malignant xenografts. Anti Cancer Drugs 6, 83 (1995)

    Article  CAS  Google Scholar 

  22. Kang, J., Kumar, V., Yang, D., Chowdhury, P., Hohl, R.: Cyclodextrin complexation: influence on the solubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent. Eur. J. Pharm. Sci. 15, 163 (2002)

    Article  CAS  Google Scholar 

  23. Steffen, A., Thiele, B., Tietze, S., Strassnig, C., Kämper, A., Lengauer, T., Wenz, G., Apostolakis, J.: Apostolakis mproved cyclodextrin-based receptors for camptothecin by inverse virtual screening. Chem. Eur. J. 13, 6801 (2007)

    Article  CAS  Google Scholar 

  24. Foulon, C., Tedou, T., Queruau, T., Vaccher, C., Bonte, F., Goossens, J.: Assessment of the complexation degree of camptothecin derivatives and cyclodextrins using spectroscopic and separative methodologies. Tetrahedron Asymm. 20, 2482 (2009)

    Article  CAS  Google Scholar 

  25. Xiang, T., Anderson, B.: Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the presence of a chemically modified beta-cyclodextrin. Pharm. Res. 19, 1215 (2002)

    Article  CAS  Google Scholar 

  26. Tong, R., Cheng, J.: Controlled synthesis of camptothecin–polylactide conjugates and nanoconjugates. Bioconj. Chem. 21, 111 (2010)

    Article  CAS  Google Scholar 

  27. Mussardo, P., Corda, E., González-Ruiz, V., Rajesh, J., Girotti, S., Martín, M., Olives, A.: Study of non-covalent interactions of luotonin A derivatives and the DNA minor groove as a first step in the study of their analytical potential as DNA probes. Anal. Bioanal. Chem 400, 321 (2011)

    Article  CAS  Google Scholar 

  28. Szente, L., Szetjili, J.: Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in development. Adv. Drug Deliv. Rev. 36, 17–28 (1999)

    Article  CAS  Google Scholar 

  29. Szente, L., Vikmon, M., Szeman, J., Otta, K.S.T.P.: Methods to enhance the complexation efficiency of cyclodextrins. Pharm. Sci. 9, 243 (1999)

    CAS  Google Scholar 

  30. Thompson, D.: Cyclodextrins enabling excipients: their present and future use in pharmaceuticals. Crit. Rev. Ther. Drug Carr. Syst. 14, 1 (1997)

    Article  CAS  Google Scholar 

  31. Awouafack, M., Spiteller, P., Lamshöft, M., Kusari, S., Ivanova, B., Tane, P., Spiteller, M.J.: Antimicrobial isopropenyl-dihydrofuranoisoflavones from Crotalaria lachnophora. Nat. Prod. 74, 272 (2011)

    Article  CAS  Google Scholar 

  32. Awouafack, M., Kusari, S., Lamshöft, M., Ngamga, D., Tane, P., Spiteller, M.: Semi-synthesis of dihydrochalcone derivatives and their in vitro antimicrobial activities. Planta Medica 76, 640 (2010)

    Article  CAS  Google Scholar 

  33. Kusari, S., Zühlke, S., Spiteller, M.: An endophytic fungus from Camptotheca acuminata that produces camptothecin and analogues. J. Nat. Prod. 72, 2 (2009)

    Article  CAS  Google Scholar 

  34. Sawada, S., Okajama, S., Aijama, R., Nokata, K., Furuta, T., Yokokura, T., Sugino, E., Yamaguchi, K., Miyasaka, Y.: Synthesis and antitumor activity of 20(S) substituted camptothecin. Chem. Pharm. Bull. 39, 1446 (1991)

    Article  CAS  Google Scholar 

  35. Ivanova, B., Spiteller, M.: Conformation, optical properties, and absolute configuration of 2′,3′-isopropylideneadenosines: theoretical versus experimental study. J. Mol. Struct. 1004, 303 (2011)

    Article  CAS  Google Scholar 

  36. Ivanova, B., Spiteller, M.: Structure and properties of camptothecin derivatives, their protonated forms, and model interaction with the topoisomerase I-DNA complex. Biopolymers 97, 134 (2012)

    Article  CAS  Google Scholar 

  37. Aiyama, R., Nagai, H., Sawada, N., Yokokura, T., Itokawa, H., Nakanishi, M.: Determination of self-association of irinotecan hydrochloride (CPT-11) in aqueous solution. Chem. Pharm. Bull. 40, 2810–2813 (1992)

    Article  CAS  Google Scholar 

  38. Ivanova, B., Spiteller, M.J.: Experimental and theoretical spectroscopic and structural study of A-ring substituted camptothecins. Mol. Struct. 1012, 189 (2012)

    Article  CAS  Google Scholar 

  39. Ivanova, B., Spiteller, M.: Physical properties and molecular conformations of indole alkaloids and model protein interactions–theoretical versus experimental study. Nat. Prod. Commun. 7, 1 (2012)

    Google Scholar 

  40. Kumara, P., Zuehlke, S., Priti, V., Ramesha, B., Shweta, S., Ravikanth, B., Vasudeva, R., Santhoshkumar, Spiteller, M., Shaanker, R.: Fusarium proliferatum, an endophytic fungus from Dysoxylum binectariferum Hook.f, produces rohitukine, a chromane alkaloid possessing anti-cancer activity. Antonie van Leewenhoek Int. J. General Mol. Microbiol. 101, 323 (2012)

    Article  CAS  Google Scholar 

  41. Mason, J., Bergman, J.: Synthesis and biological activities of natural and non-natural quinazolines. Org. Biomol. Chem. 5, 2486 (2007)

    Article  CAS  Google Scholar 

  42. Yoon, K., Krull, K., Morton, C., Bornmann, W., Lee, R., Potter, P., Danks, M.: Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies. Mol. Cancer. Ther. 2, 1171 (2003)

    CAS  Google Scholar 

  43. Curran, D., Ko, S., Josien, H.: Cascade radical reactions of isonitriles: a second-generation synthesis of (20S)-camptothecin, topotecan, irinotecan, and GI-147211C. Angew. Chem. Int. Ed. 34, 2683 (1995)

    CAS  Google Scholar 

  44. Sawada, S., Yokokura, T., MIiyasaka, T.: Synthesis of CPT-11. Ann. New York Acad. Sci. 803, 13 (1996)

    Article  CAS  Google Scholar 

  45. Sawada, H., Watanabe, T., Yokokura, T.: Structure-activity relationships of N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N’-(3,4-dimethylphenyl)piperazine and analogues as inhibitors of acyl-CoA: cholesterol O-acyltransferase. Chem. Pharm. Bull. 49, 830 (2001)

    Article  Google Scholar 

  46. Sawada, D., Tsukuda, Y., Saito, H., Takagi, K., Horie, K., Ochiai, E., Takenouchi, K., Kittaka, K.: Synthesis and biological evaluation of 4-substituted vitamin d and 14-epi-previtamin d analogs. Chem. Pharm. Bull. 57, 1431 (2009)

    Article  CAS  Google Scholar 

  47. Sawada, K., Okada, S., Kuroda, A., Watanabe, S., Sawada, Y., Tanaka, H.: 4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III. Chem. Pharm. Bull. 49, 799 (2001)

    Article  CAS  Google Scholar 

  48. Rahman, A., Kim, D., Liang, J., Lee, E., Na, Y., Jun, K., Kwon, Y., Jahng, Y.: Synthesis and biological properties of luotonin a derivatives. Bull. Korean Chem. Soc. 29, 1988 (2008)

    Article  CAS  Google Scholar 

  49. Samori, C., Guerrini, A., Varchi, G., Zunino, F., Beretta, G., Femoni, C., Bombardelli, E., Fontana, G., Battaglia, A.: Thiocamptothecin. J. Med. Chem. 51, 3040 (2008)

    Article  CAS  Google Scholar 

  50. Cinelli, M., Cordero, B., Dexheimer, T., Pommier, Y., Cushman, M.: Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: investigating the hypothesis of shared structure-activity relationships. Bioorg. Med. Chem. 15, 7145 (2009)

    Article  Google Scholar 

  51. Rahier, N., Cheng, K., Gao, R., Eisenhauer, B., Hecht, S.: Synthesis of 14-azacamptothecin, a water-soluble topoisomerase i poison. Org. Lett. 7, 835 (2005)

    Article  CAS  Google Scholar 

  52. Elban, M., Sun, V., Eisenhauer, B., Gao, R., Hecht, S.: Synthesis and biological evaluation of 10,11-methylenedioxy-14-azacamptothecin. Org. Lett. 8, 3513 (2006)

    Article  CAS  Google Scholar 

  53. Dodds, H., Haaz, M., Riou, J., Robert, J., Rivori, L.: Identification of a new metabolite of CPT-11 (irinotecan): pharmacological properties and activation to SN-38. J. Pharmacol. Exp. Therap. 286, 578 (1998)

    CAS  Google Scholar 

  54. Rivory, L., Haaz, M., Canal, P., Lokiec, F., Armand, J., Robert, J.: Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials. Clin. Cancer. Res. 3, 1261 (1997)

    CAS  Google Scholar 

  55. Santos, A., Zanetta, S., Cresteil, T., Deroussent, A., Pein, P., Raymond, E., Vernillet, L., Risse, M., Boige, V., Gouyette, A., Vassal, V.: Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin. Cancer Res. 6, 2012 (2000)

    CAS  Google Scholar 

  56. Cole, R. (ed.): Electrospray and MALDI Mass Spectrometry, 2nd edn. Wiley, New York (2010)

    Google Scholar 

  57. Srimany, A., Ifa, D., Naik, H., Bhat, V., Cooks, R., Pradeep, T.: Direct analysis of camptothecin from nothapodytes nimmoniana by desorption electrospray ionization mass spectrometry (DESI-MS). Analyst 136, 3066 (2011)

    Article  CAS  Google Scholar 

  58. Frisch M, et al.: Gaussian 09w, Gaussian Inc., Pittsburgh (2009)

  59. Dalton 2.0 Program package

  60. Zhao, Y., Truhlar, D.: Density functionals with broad applicability in chemistry. Acc. Chem. Res. 41, 157 (2008)

    Article  CAS  Google Scholar 

  61. Schultz, N., Zhao, Y., Truhlar, D.: Benchmarking approximate density functional theory for s/d excitation energies in 3d transition metal cations. J. Comput. Chem. 29, 185 (2008)

    Article  CAS  Google Scholar 

  62. Zhao, Y., Truhlar, D.: The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215 (2008)

    Article  CAS  Google Scholar 

  63. Hay, H., Wadt, W.: Ab initio effective core potentials for molecular calculations. Potentials for the transition metal atoms Sc to Hg. J. Chem. Phys. 82, 270 (1985)

    Article  CAS  Google Scholar 

  64. Woon, D., Dunning, T.: Gaussian basis sets for use in correlated molecular calculations. III. The atoms aluminum through argon. J. Chem. Phys. 98, 1358 (1993)

    Article  CAS  Google Scholar 

  65. Ivanova, B., Spiteller, M.: Physical optical properties and crystal structures of organic 5-sulfosalicylates—Theoretical and experimental study. J. Mol. Struct. 1003, 1 (2011)

    Article  CAS  Google Scholar 

  66. Office Program Package. http://de.openoffice.org

  67. Stephens, P., McCann, D., Cheeseman, J., Frisch, M.: Determination of absolute configurations of chiral molecules using ab initio time-dependent density functional theory calculations of optical rotation: how reliable are absolute configurations obtained for molecules with small rotations? Chirality 17, S52 (2005)

    Article  CAS  Google Scholar 

  68. Stephens, P., Devlin, F., Cheeseman, J., Frisch, M., Bortolini, O., Besse, P.: Determination of absolute configuration using ab initio calculation of optical rotation. Chirality 15, S57 (2003)

    Article  CAS  Google Scholar 

  69. Yildiz, A., Selvin, P.: Fluorescence imaging with one nanometer accuracy:  application to molecular motors. Acc. Chem. Res. 38, 574 (2005)

    Article  CAS  Google Scholar 

  70. Kelley, C.: Iterative Methods for Optimization, SIAM Frontiers in Applied Mathematics. 18, (1999)

  71. Madsen, K., Nielsen, H., Tingleff, O.: Informatics and Mathematical Modelling, 2nd edn. DTU Press, Denmark (2004)

    Google Scholar 

  72. Marquardt, D.: An algorithm for least-squares estimation of nonlinear parameters. J. Soc. Ind. Appl. Math. 11, 431 (1963)

    Article  Google Scholar 

  73. Lamshoeft, M., Ivanova, B., Spiteller, M.: Chemical identification and determination of sulfonamides in n-component solid mixtures within THz-region—Solid-state Raman spectroscopic and mass spectrometric study. Talanta 85, 2562 (2011)

    Article  CAS  Google Scholar 

  74. Ivanova, B., Spiteller, M.: On the chemical identification and determination of flavonoids in solid-state. Talanta. 30(94), 9–21 (2012)

    Google Scholar 

  75. Ivanova, B., Spiteller, M.: Quantitative analysis of solid binary mixtures-vibrational spectroscopy of β-lactam antibiotics within THz-region. J. Pharmaceut. Biomed. Anal. 2012. doi:10.1016/j.jpba.2011.10.028

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Acknowledgments

The authors thank the Deutscher Akademischer Austausch Dienst (DAAD), the Deutsche Forschungsgemeinschaft (DFG), the central instrumental laboratories for structural analysis at University of Dortmund (Germany) and the analytical and computational laboratories at the Institute of Environmental Research (INFU) at same University.

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  1. Institut für Umweltforschung, Universität Dortmund, Otto-Hahn-Strasse 6, 44221, Dortmund, Germany

    Bojidarka Ivanova & Michael Spiteller

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  1. Bojidarka Ivanova
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Correspondence to Bojidarka Ivanova.

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Ivanova, B., Spiteller, M. Novel pyrrolo-quinazolino-quinoline analogues of the natural alkaloids and their inclusion molecular complexes in the native cyclodextrins: experimental versus theoretical study. J Incl Phenom Macrocycl Chem 76, 87–98 (2013). https://doi.org/10.1007/s10847-012-0176-y

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