N-glycosidesindolo[2,3,-a]pyrrolo[3,4,-c]carbazole derivatives chemical structure influence on antitumor activity

Introduction . The report considers the prospect of rational approach to the new anticancer agents creation based on indolocarbazole derivatives.

Objective . To conduct a comparative study of 12 domestic N-glycosides, indolo[2,3-a]pirrolo[2,3-a]carbazole derivatives in the course of “structure – activity” bond analysis.

Materials and methods . The investigation of influence of 12 carbohydrate – containing indolocarbazoles, synthesized in N. N. Blokhin Russian Cancer Research Center of the Ministry of Health of Russia, performed on models of solid transplantable mouse tumors: lung Lewis epidermoid carcinoma and B16 melanoma. The antitumor effect was assessed by Lewis epidermoid carcinoma and B16 melanoma tumor growth inhibition (TGI %) criterion.

Results . A variety of indolocarbazoles modifications allowed revealing the dependence of their antitumor properties on the structure of both, the aglycone and the glycoside residue. Imino-nitrogen interchange of atoms in upper heterocycle influences on indocarbazole derivatives antitumor activity change. During a comparative study of 12 N-glycosides indolocarbazole derivatives on lung Lewis epidermoid carcinoma and B16 melanoma models, 8 derivatives showed antitumor activity.

Conclusion . The formulated concepts on the modification features in indolocarbazole derivatives structure can be used for more active compounds creation with greater action selectivity. 

1. Онкология: справочник практического врача. Под ред. И.В. Поддубной. М.: МЕДпресс-информ., 2009. 768 с. [Oncology: Referencepractitioner. Edn. I.V. Poddubnaya. M.: MEDpressinform., 2009. 768 p. (In Russ.)].

2. Семенов А.А. Природные противоопухолевые соединения (структура и механизм действия). Новосибирск: Наука, 1979. 222 с. [Natural antitumor compounds (structure and mechanism of action). Novosibirsk: Nauka, 1979. 222 p. (In Russ.)].

3. Bailly C. Topoisomerase I poisons and suppressors as anticancer drugs. Curr Med Chem 2000;7(1):39–58.

4. Pereira E.R., Belin L., Sancelme M. et al. Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties. J Med Chem 1996;39(22):4471–7.

5. Pindur U., Kim Y.S., Mehrabani F. Advances in indolo[2,3-a]carbazole chemistry: design synthesis of protein kinase C and topoisomerase I inhibitors. Curr Med Chem 1999;6(1):29–69.

6. Deslandes S., Chassaing S., Delfourne E. Marine pyrrolocarbazoles and analogues: synthesis and kinase inhibition. Mar Drugs 2009;7(4):754–86. DOI: 10.3390/md7040754.

7. Omura S., Ywai Y., Hirano A. et al. A new alkaloid AM-2282 of Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J Antibiot 1977;30(4):275–82.

8. Nettleton D.E., Doyle T.W., Krishnan B. et al. Isolation and structure of rebeccamycin – a new antitumor antibiotic from nocardia aerocoligenes. Tetrahedron Lett 1985;26:4011–4. DOI.org/10.1016/ S0040-4039(00)89280-1.

9. Wada Y., Nagasaki H., Tokuda M. et al. Synthesis of N-protected staurosporinones. J Org Chem 2007;72(6): 2008–14. DOI: 10.1021/jo062184r.

10. Prudhomme M. Biological Targets of antitumor indolocarbazoles bearing a sugar moiety. Curr Med Chem AntiCancer Agents 2004;4(6):509–21.

11. Gescher A. Analogs of staurosporine: potential anticancer drugs? Gen Pharmacol 1998;31:721–8.

12. Zembower D.E., Zhang H., Lines wala J.P. et al. Indolocarbazole poisons of human topoisomerase I: regioisomeric analogues of ED-110. Bioorg Med Chem 1999;9:145–50.

13. Urasaki Y., Laco G., Takebayashi Y. et al. Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506 and its topoisomerase I binding site. Cancer Res 2001;61(2):504–8.

14. Ohkubo M., Kojiri K., Kondo H. et al. Synthesis and biological activities of topoisomerase i inhibitors, 6-N-amino analogues of NB-506. Bioorg Med Chem Lett 1999;9(9):1219–24.

15. Preobrazhenskaya M.N., Korbukh I.A. The synthesis and reactions of pyrrole, pyrazole, triazole, indole, indazole and benzotriazole nucleosides and nucleotides. In: Chemistry of Nucleosides and Nu cleo tides. Сh. 3. Ed. L.B. Townsend. New York, London: Plenum Press, 1993. Pp. 1–105.

16. Мельник С.Я. Синтез и изучение гликозидов, производных бисиндола и родственных индоло[2,3-а]карбазолов. Под ред. М.И Давыдова, А.Ю. Барышникова Экспериментальная онкология на рубеже веков. М., 2003. С. 281–93. [Melnik S.Ya. Synthesis and study of glycosides, bisindole derivatives and related indolo[2,3-a]carbazoles. Ed. Davydov M.I., Baryshnikov A.Yu. Experimental oncology at the turn of the century. Moscow, 2003. P. 281–93 (In Russ.)].

17. Экспериментальная оценка противоопухолевых препаратов в СССР и США. Под ред. З.П. Софьиной, А.Б. Сыркина (СССР), А. Голдина, А. Кляйна (США). М.: Медицина, 1980. 295 с. [Experimental evaluation ofantitumor drugsin the USSR and the USA. Ed. Z.P. Sofina, A.B. Syrkin (USSR), A. Goldin, A. Klein (USA), M.: Medicine, 1980:296 p. (In Russ.)].

18. Трещалина Е.М., Жукова О.С., Герасимова Г.К. и др. Методические рекомендации по доклиническому изучению противоопухолевой активности лекарственных средств. В кн.: Руководство по проведению доклинических исследований лекарственных средств. Ч. 1. Под ред. А.Н. Миронова, Н.Д. Бунятян, А.Н. Васильева и др. М.: Гриф и К, 2012;39:642–57. [Treshchalina Н.M., Zhukova O.S., Gerasimova G.K. et al. Guidelines for preclinical study of the antitumor activity of drugs. In the book: Guidelines for conducting preclinical studies of drugs. Part 1. Ed. A.N. Mironov, N.D. Bunyatyan, A.N. Vasil’yev et al. M.: Grief and K, 2012;39:642–57 (In Russ.)].

19. Голубева И.С., Яворская Н.П., Эктова Л.В. и др. Сравнение противоопухолевой активности производных индолокарбазола с углеводными остатками галактозой, арабинозой и заместителями по имидному атому азота. Российский биотерапевтический журнал 2017;16(s1):23. [Golubeva I.S., Yavorskaya N.P., Ektova L.V. et al. Comparison of the antitumor activity of indolocarbazole derivatives with carbohydrate residues galactose, arabinose and substituents on the imide nitrogen atom. Rossiysky bioterapevtichesky zhurnal = Russian Biotherapeutic Journal 2017;16(S):23 (In Russ.)].