DIMERIC DIAMINOCATIONIC β-CYCLODEXTRIN DERIVATIVES Текст научной статьи по специальности «Фундаментальная медицина»

Cyclodextrins Циклодекстрины

Макрогэтэроцмклы

http://macroheterocycles.isuct.ru

Communication Сообщение

DOI: 10.6060/mhc181110s

Dimeric Diaminocationic p-Cyclodextrin Derivatives

Dmitry A. Shipilov,a@ Galina I. Kurochkina,a Aleksander K. Akhlebinin,b Natalia V. Kutyasheva,a and Mikhail K. Gracheva

Moscow State University of Education, 129164 Moscow, Russia bTsiolkovsky Kaluga State University, 248023 Kaluga, Russia @Corresponding author E-mail: [email protected]

Dimeric f-cyclodextrins derivatives being of interest as potential carriers (inclusion compounds and conjugates) of drugs for pharmacological studies in various directions have been obtained using various alkylenediamines and monohalogen substituted f-cyclodextrin derivatives. The position ofsubstituents in carbohydrate fragments of CDs was unambiguously determined by various variants of 1H and 13C NMR spectroscopy and by elemental analysis.

Keywords: Dimeric derivatives, cationic cyclodextrins, regiodirected synthesis, and 13C NMR spectroscopy.

Димерные диаминокатионные производные р—циклодекстрина

Д. А. Шипилов,а@ Г. И. Курочкина,1 А. К. Ахлебинин,ь Н. В. Кутяшева,1 М. К. Грачев1

Московский педагогический государственный университет, 129164 Москва, Россия ьКалужский государственный университет им. К. Э. Циолковского, 248023 Калуга, Россия @Е-таИ: [email protected]

С использованием различных алкилендиаминов и моногалогензамещенных производных в-циклодекстрина получены димерные производные, представляющие интерес как потенциальные носители (соединения включения и конъюгаты) лекарственных средств для фармакологических исследований в разных направлениях. Строение полученных димерых циклодекстриновых производных надежно подтверждено различными вариантами спектроскопии ЯМР Н и 13С, а также элементным анализом.

Ключевые слова: Димерные производные, катионные производные, регионаправленный синтез, Щ и 13С ЯМР спектроскопия.

Introduction

Cyclodextrins (CDs) and some their derivatives have found wide practical application mainly due to the unique ability to form inclusion compounds of the "guest-host" type with numerous "guests".[1-4] Earlier, we turned our attention to the dimeric cyclodextrins derivatives, in which two residues of the P-cyclodextrin (Figure 1) are connected by a bridge.[5,6] In comparison with native CDs and mono-modified CDs, dimeric CDs exhibit the significantly high binding abilities and molecular selectivity through the cooperative binding of two adjacent CD units.[7] This fascinating property enables them to be employed successfully in several

areas of chemistry as an excellent model system mimicking substrate-specific interaction of enzymes.[8,9] Consequently, a number of dimeric P-CDs have been designed and synthesized to examine and compare the molecular binding affinity of native P-CD and dimeric P-CDs and also to gain insights into factors governing the inclusion complexation phenomena between the host dimeric P-CDs and guest molecules.1[10,11] Moreover, the linker can supply a well-organized pseudo-cavity that in turns provides additional binding interactions with accommodated guest molecules.[11] Thus, dimeric CDs could be successfully utilized in carriers,[12] catalysis,[8] templated synthesis,[13] photochemical materials^14,1^ solubilizers,[16] etc. The dimeric complex, in com-

D. A. Shipilov et al.

parison with the monomeric complex, has an enhanced synergistic effect on the inclusion of "guests" in its cyclodextrin cavity,[17"19] which could help for more efficient and targeting site delivery.

Cationic cyclodextrin derivatives, in which one or more hydroxyls are replaced by a group bearing a positive charge, could enhance the ability of native CDs to penetrate biological barriers, e.g. the blood-brain barrier,[20] to embed in biological membranes,[2122] and serve as carriers for DNA delivery (vectorization) under gene therapy.[23-26] These properties of cationic cyclodextrins, after the formation of inclusion complexes or conjugates with pharmacologically important compounds, are used in pharmacology for more efficient and targeting site delivery of the drug (prodrug) (see, for example,[27]).

Experimental

'H and 13C NMR spectra were recorded on a JEOL ECX-400 spectrometer at the frequencies 399.78 and 100.53 MHz, respectively. The 'H and 13C chemical shifts are presented relative to tet-ramethylsilane. Elemental analyses were performed on a FlashEA 1112 HT instrument. Thin layer chromatography was performed on aluminum plates with fixed layer of SiO2 (Silufol UV-254), eluent: acetonitrile:chloroform (1:1). Commercial P-cyclodextrin "Wacker" (USA) was dried in vacuum (1 Torr) for 10 h at 90 °C over P2O5 prior to use.

Di-6,6'-dideoxy-6,6'-(propane-1,3-diyldiaminium cyclodextrin iodide (6). To a solution of 1.00 g (0.80 mmol) of mono(6-iodo-6-deoxy)-P-cyclodextrin 1 in 15 mL of DMF was added at stirring 0.030 g (0.40 mmol) of propane-1,3-diamino 2. The solution was stirred for 40 h at 120-130 °C. The reaction mixture was concentrated to 5 mL, diluted with 25 mL of acetone, the mixture was stirred, the separated precipitate was filtered off, washed successively with chloroform (2x5 mL), ethanol (2x5 mL), acetone (2x5 mL), ethyl ether (2x5 mL), and dried in a vacuum (1 mm Hg) for 4 h at 80 °C. Yield 0.75 g (66 %). M.p. 259-261°C (decomp.). R, = 0.71. Found, %: C 40.81, H 5.93, N 1.19. C H T NOCS. Calcu-

j J J 8/ 148 22 68

lated, %: C 40.76, H 5.82, N 1.09. 1H NMR ([D6]DMSO) 8H ppm:

1.82 m (2H, NCH2CH2), 2.16 m (4H, NCH2), 3.17-3.74 m (84H, C2H-C5H, C6H2), 4.48 br.s (12H, C6OH), 4.78 br.s (14H, C1H), 5.73 br.s (32H, N+H2, C2OH-C3OH). 13C NMR ([D6]DMSO) SC ppm: 29.6 (NCH2CH2), 37.5 (NCH2), 49.9 (C6'), 60.4 (C6), 70.1 (C5'), 72.5 (C5), 72.9 (C2), "73.4 (C3), 82.0 (C4), 102.4 (C1).

Di-6,6'-dideoxy-6,6'-(butane-1,4-diyldiaminium cyclodextrin iodide (7) was prepared similarly to compound 6 from mono(6-iodo-6-deoxy)-P-cyclodextrin 1 (1.00 g, 0.80 mmol) and butane-1,4-diamino 3 (0.035 g, 0.40 mmol). Yield 0.75 g (66 %). M.p. 261-263 °C (decomp.). Rf = 0.67. Found, %: C 41.11, H 5.73, N 1.12. CSSH, T NO,,. Calculated, %: C C 41.00, H 5.87, N

88 150 2 2 68

1.09. 1H NMR ([D6]DMSO) 8H ppm: 1.38 m (4H, NCH2CH2), 2.53 m (4H, NCH2), 3.17-3.74 m (84H, C2H-C5H, C6H2), 4.48 br.s (12H, C6OH), 4.78 br.s (14H, C1H), 5.73 br.s (32H, N+H2, C2OH-C3OH). 13C NMR ([D6]DMSO) 5C ppm: 25.3 (NCH2CH2), 46.3 (NCH2), 49.9 (C6'), 60.4 (C6), 70.1 (C5'), 72.6 (C5), 73.0 (C2), 73.6 (C3), 82.0 (C4), 102.4 (C1).

Di-6,6'-dideoxy-6,6'-(pentane-1,5-diyldiaminium)-fi-cyclodextrin iodide (8) was prepared similarly to compound 6 from mono(6-iodo-6-deoxy)-P-cyclodextrin 1 (1.00 g, 0.80 mmol) and pentane-1,5-diamino 4 (0.040 g, 0.40 mmol). Yield 0.80 g (70 %). M.p. 264-266 °C (decomp.). Rf = 0.63. Found, %: 41.27, H 5.83, N 1.18. C89^52I2N2O68. Calculated, %: C 41.24, H 5.91, N 1.08. 1H NMR ([D6]DMS O) 8H ppm: 1.29 m (2H, NCH2CH2CH2), 1.40 m (4H, NCH2CH2), 2.53 m (4H, NCH2), 3.17-3.74 m (84H, C2H-C5H, C6H2), 4.48 br.s (12H, C6OH), 4.78 br.s (14H, C1H), 5.73 br.s (32H, N+H2, C2OH-C3OH). 13C NMR ([D6]DMSO) SC ppm: 27.3 (NCH-2CH2CH2), 35.2 (NCH2CH2), 46.3 (NCH2), 49.9 (C6'), 60.4 (C6), 70.1 (C5'), 72.6 (C5), 73.0 (C2), 73.6 (C3), 82.0 (C4), 102.4 (C1).

Di-6,6'-dideoxy-6,6'-(hexane-1,6-diyldiaminium)-fi-cyclodextrin iodide (9) was prepared similarly to compound 6 from mono(6-iodo-6-deoxy)-P-cyclodextrin 1 (1.00 g, 0.80 mmol) and hexane-1,6-diamino 5 (0.035 g, 0.40 mmol). Yield 0.94 g (89 %). M.p. 268-270 °C (decomp.), Rf = 0.60. Found, %: C 41.32, H 5.89, N 1.01. C90H154I2N2O68. Calculated, %: C 41.48, H 5.96, N 1.07. 1H NMR ([D6]DMSO) 8H ppm: 1.20 m (4H, NCH2CH2CH2), 1.32 m (4H, NCH2CH2), 2.60 m (4H, NCH2), 3.17-3.74 m (84H, C2H-C5H, C6H2), 4.48 br.s (12H, C6OH), 4.78 br.s (14H, C1H), 5.73 br.s (32H, N+H2, C2OH-C3OH). 13C NMR ([D6]DMSO) 5C ppm: 26.7 (NCH-2CH2CH2), 29.7 (NCH2CH2), 37.5 (NCH2), 49.9 (C6'), 60.4 (C6), 70.1 (C5'2, 72^ (C5), 72.9 (CC2), 73.4 (C3), 82.0 (C4), 102.4 (C1).

Dimeric Diaminocationic P-Cyclodextrin Derivatives

Figure 2. Scheme of the syntheses of dimeric diaminocationic P-cyclodextrin derivatives 6-9.

Results and Discussion

Conclusions

In the present work, we have considered the possibility of synthesizing dimeric diaminocationic p-cyclodextrin derivatives. For this we used the procedure proposed for the synthesis of monocathionic derivatives:[28] iodo derivative 1 alkylated the diamines 2-5 with different number of methylene units to obtain dimeric diaminocationic p-cyclodextrin derivatives 6-9, respectively (Figure 2). The syntheses were carried out in DMF at 120-130 °C for 40 h to receive in high yield compounds 6-9 with the positive charge on the side of the primary hydroxy groups of the cyclodextrin scaffold. It is interesting to note the dependence of the increase in the melting point and the decrease in chromatographic mobility with an increase in the number of methylene units in the bridge between the two cyclodextrins (see Experimental).

The structure of compounds 6-9 was confirmed by 'H and 13C NMR data. For example, for compound 9, the central hexamethylene diamine bridge binds the same cyclodextrin substituents, and therefore the methylene fragments at positions 1 and 6, 2 and 5, 3 and 4 are pairwise equivalent, which is reflected in the form of three broadened singlets in the 'H NMR spectrum. The regiodirection of the substitution of the primary hydroxy groups was revealed from the 13C NMR data. To be able to integrate the carbon signals in the 13C NMR spectra of compounds 6-9 the registration was performed at a large delay between the pulses (8 s). The 13C NMR spectra of compounds 6-9 contain the signals of nuclei of unsubstituted C-6 atoms at 5 60.4 ppm and characteristic minor upfield signals of C-6' nuclei bearing the N+ substituent at 5 49.9 ppm. The OH proton positions were identified by their considerable shift (by 0.3-0.8 ppm) at elevated temperature (80 oC). The correctness of the signals assignment of all obtained compounds 6-9 was additionally confirmed by the analysis of 2D NMR spectra of homo- (HOMOCOR {'H-'H}) and heteronuclear (HETCOR {'H-13C}) correlations (Figure 3) and registering in the DEPT mode.

Thus, the obtained dimeric derivatives are of interest as potential carriers (inclusion compounds and conjugates) of drugs for pharmacological studies in different directions. This research reveals possible ways of obtaining dimeric complexes of p-cyclodextrin with important pharmaceutical preparations.

Acknowledgements. This work was performed under financial support of the Russian Foundation for Basic Research (Project no. 19-03-00278).

References

Bilensoy E., Hincal A.A. Expert Opinion on Drug Delivery 2009, 6, 1161-1173.

Laza-Knoerr A.L., Gref R., Couvreur P. Journal of Drug Targeting 2010, 18, 645-656.

Pinho E., Grootveld M., Soares G., Henriques M. Carbohydr. Polym. 2014, 101, 121-135.

Valente A.J.M., Soderman O. Adv. Colloid Interface Sci. 2014, 205, 156-176.

Malenkovskaya M.A., Vasyanina L.K., Grachev M.K. Russ. J. Gen. Chem. 2015, 85, 1681-1685.

Grachev M.K., Malenkovskaya M.A., Vasyanina L.K. J. Inclusion Phenom. Macrocycl. Chem. 2015, 83, 209-2014. Breslow R., Halfon S., Zhang B. Tetrahedron 1995, 51, 377-388.

Breslow R., Dong S.D. Chem. Rev. 1998, 98, 1997-2012. Marinescu L., Bols M. Trends Glycosci. Glycotechnol. 2009, 21, 309-323.

10. Liu Y., Yang Y.W., Chen Y., Ding F. Bioorg. Med. Chem. 2005, 13, 963-971.

11. Liu Y., Chen Y. Acc. Chem. Res. 2006, 39, 681-691.

12. Baugh S.D.P., Yang Z., Leung D.K., Wilson D.M., Breslow R. J. Am. Chem. Soc. 2001, 123, 12488-12494.

13. van Bommel K.J.C., de Jong M.R., Metselaar G.A., Verboom W., Huskens J., Hulst R., Kooijman H., Spek A.L., Reinhoudt D.N. Chem. Eur. J. 2001, 7, 3603-3615.

D. A. Shipilov et al.

Figure 3. 2D NMR spectra of heteronuclear (HETCOR {'H-13C}) correlations of derivative 9 (fragment).

14. Mulder A., Jukovic A., Huskens J., Reinhoudt D.N. Org. Biomol. Chem. 2004, 2, 1748-1755.

15. Mulder A., Jukovic A., Lucas L.N., van Esch J., Feringa

B.L., Huskens J., Reinhoudt D.N. Chem. Commun. 2002, 22, 2734-2735.

16. Filippone S., Heimanna F., Rassat A. Chem. Commun. 2002, 14, 1508-1509.

17. Liu Y., Chen G.-S., Li L., Zhang H.-Y., Cao D.-X., Yuan Y.-J. J. Med. Chem. 2003, 46, 4634-4637.

18. Aykaf A., Martos-Maldonado M.C., Casas-Solvas J.M., García-Fuentes L., Vargas-Berenguel A. J. Drug Del. Sci. Tech. 2012, 22, 270-272.

19. Grachev M.K., Malenkovskaya M.A., Vasyznina L.K. J. Incl. Phenom. Macro. Chem. 2015, 83, 209-214.

20. Zafar N., Fessi H., Elaissari A. Int. J. Pharm. 2014, 461, 351-366.

21. Cryan S.A., Holohan A., Donohue R., Darcy R., O'Driscoll

C.M. Eur. J. Pharm. Sci. 2004, 21, 625-633.

22. Sallas F., Darcy R. Eur. J. Org. Chem. 2008, 2008(6), 957-969.

23. Cryan S.A., Donohue R., Ravoo B.J., Darcy R., O'Driscoll

C.M. J. DrugDeliv. Sci. Tec. 2004, 14, 57-62.

24. Mével M., Yaouanc J.J., Laurent P., Clément J.C., Cartier

D., Jaffrès P.A., Montier T., Delépine P., Le Gall T., Lehn P., Pichon C., Midoux R, Férec C. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 460-468.

25. Mével M., Lamarche F., Clément J.C., Yaouanc J.J., Laurent P., Burel L., Giamarchi P., Montier T., Delépine P., Lehn P., Jaffrès P.A., Férec C. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 745-746.

26. Bienvenu C., Martínez Á., Jiménez Blanco J.L., Di Giorgio C., Vierling P., Mellet C.O., Defaye J., García Fernández J.M. Org. Biomol. Chem. 2012, 10, 5570-5581.

27. Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedi-cine: Current and Future Industrial Applications (Bilensoy

E., Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc, 2011. p. 251-274.

28. Shipilov D.A., Kurochkina G.I., Sergievich A.A., Grachev M.K. Macroheterocycles 2017, 10, 238-242.

Received 11.11.2018 Accepted 28.12.2018