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Influence of Sugar Residue on the Cytotoxicity and Solubility of Several Aryl-indolo[2,3-a]pyrrolo[3,4-c]carbazoles and the Corresponding Maleimides
Corresponding Author(s) : Yingxia Li
Asian Journal of Chemistry,
Vol. 25 No. 3 (2013): Vol 25 Issue 3
Abstract
Indolo[2,3-a]carbazoles and the corresponding maleimides form two structurally related classes of compounds endowed with diverse biological activities. In the work we investigated the influence of sugar residue on the cytotoxicity and solubility of several aryl-indolo[2,3- a]pyrrolo[3,4-c]carbazoles and the corresponding maleimides. The results indicated that introduce a monosaccharide on a planar aromatic molecule to increase the solubility is not always effective, whereas the sugar moiety do have a profound impact on the mechanism of action for these types of compounds.
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- (a) Y. Wada, H. Nagasaki and M. Tokuda, J. Org. Chem., 72, 2008 (2007); (b) M.G. Saulnier, B.N. Balasubramanian and B.H. Long, J. Med. Chem., 48, 2258 (2005); (c) J.D. Chisholm and D.L. Van Vranken, J. Org. Chem., 65, 7541 (2000); (d) F. Anizon, L. Belin and P. Moreau, J. Med. Chem., 40, 3456 (1997).
- T. Tamaoki, H. Nomoto and Y. Takahashi, Biochem. Biophys. Res. Commun., 135, 397 (1986).
- D.E. Nettleton, T.W. Doyle and B. Krishnan, Tetrahedron Lett., 26, 4011 (1985).
- F. Anizon, L. Belin and P. Moreau, J. Med. Chem., 40, 3456 (1997).
- (a) G. Zhu, S. Conner and X.C. Zhou, Bioorg. Med. Chem. Lett., 13, 1231 (2003); (b) S. Routier, P. Peixoto and J.Y. Mérour, J. Med. Chem., 48, 1401 (2005); (c) A. Bourderioux, P. Kassis and J.-Y. Mérour, Tetrahedron, 64, 11012 (2008).
- C. Sanchez-Martinez, C. Shih and M.M. Faul, Bioorg. Med. Chem. Lett., 13, 3835 (2003).
- N. Ding, X.G. Du and W. Zhang, Bioorg. Med. Chem. Lett., 21, 3531 (2011).
- (a) G.P. Song, H.C. Liu and W. Zhang, Bioorg. Med. Chem., 18, 5183 (2010); (b) M. Gui, D.K. Shi and M. Huang, Invest. New Drug, 28, 1 (2010).
- (a) M.M. Faul, L.L. Winneroski and C.A. Kumrich, J. Org. Chem., 63, 6053 (1998); (b) M.M. Faul, L.L. Winneroski and C.A. Kumrich, Tetrahedron Lett., 40, 1109 (1999).
- 3a: 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 11.13 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8.55 (d, J = 8.1 Hz, 1H), 7.75-7.68 (m, 2H), R2 NH2 O 5a R2 = CH3 5b R2 = OCH3 (i) N OO ONHO N OR2NHN O OR2+R1R1R16b R1= O MBOPMBO OPMBO PMBOOPMBOPMBOOPMB PMBOPMBOPMBO6c R1 =6d R1 =7d R1 =R2 = OCH3O PMBOOPMB PMBO OPMBOOPMBOPMBOOPMB PMBOPMBOPMBOO PMBOPMBO OPMB7c R1 =R2 = CH37f R1 =R2 = OCH37e R1 =R2 = CH33d R1 =R2 = OCH3O HOOHHOOHOOHOHOOH HOHOHOO HOOH HO3c R1 =R2 = CH34b R1=R2 = OCH34a R1 =R2 = CH3NHO N OR2H(iii)7a R1 = H, R2 = CH37b R1 = H, R2 = OCH33a R1 = H, R2 = CH33b R1 = H, R2 = OCH36a R1 = HNHO N OR2R18d R1 =R2 = OCH3O HOOH HOOHOOHOHOHO OHHOHOO HOHO OH8c R1 =R2 = CH34b R1 =R2 = OCH34a R1 =R2 = CH3(ii) (iii)Scheme-I: Synthesis of indolo[2,3-α]pyrrolo[3,4-c]carbazoles, aryl-indolyl maleimides and their glycosides. Conditions: (i) t-BuOK, THF, 12 % for 7a,17 % for 7b, 44 % for 7c, 36 % for 7d; (ii) DDQ, CH2Cl2/H2O (v:v = 10:1), 77 % for 8c, 81 % for 8d, 31 % for 4a over 2 steps, 16 % for 4b over2 steps, (iii) 57 % for 3a, 40 % for 3b, 65 % for 3c, 35 % for 3d. 7.60 (d, J = 7.1 Hz, 1H), 7.55 (s, 1H), 7.37 (d, J = 7.5 Hz, 1H), 3.04 (s,3H); 13C NMR (100 MHz, DMSO-d6) δ 170.3, 170.2, 141.6, 140.2,136.2, 131.1, 130.7, 127.5, 126.5, 126.4, 124.7, 124.2, 121.3, 120.8,120.7, 120.2, 111.7, 111.5, 25.7; API-ESMS: calcd. (%) for [M + H]+:m/z 301.1, found (%) 301.1. 3b: 1H NMR (400 MHz, DMSO-d6) δ12.81 (s, 1H), 10.97 (s, 1H), 9.03 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 8.1Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.54 (t, J =7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H),3.99 (s,3H); 13C NMR (100 MHz, DMSO-d6) δ 170.1, 168.0, 156.8, 140.6,140.2, 130.1, 129.0, 126.6, 124.8, 121.4, 120.7, 120.0, 118.3, 114.7,112.1, 111.8, 108.4, 55.8; API-ESMS: calcd. (%) for [M + H]+: m/z317.1, found (%) 317.1. 3c: 1H NMR (400 MHz, DMSO-d6) δ 11.19(s, 1H), 9.18 (d, J = 7.6 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.29 (d, J =8.5 Hz, 1H), 7.74-7.68 (m, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.45 (t, J =7.2 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 6.41 (s, 1H), 5.66 (d, J = 4.9 Hz,1H), 5.06 (d, J = 5.4 Hz, 1H), 5.01 (d, J = 6.0 Hz, 1H), 4.64 (s, 1H),3.82 (s, 1H), 3.56-3.48 (m, 1H), 3.47-3.38 (m, 1H), 3.01 (s, 3H), 1.16(d, J = 5.9 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 175.1, 175.0,146.8, 146.7, 141.3, 135.7, 134.9, 132.5, 132.3, 130.7, 130.0, 129.1,127.4, 127.2, 126.5, 126.4, 123.8, 119.6, 92.8, 80.6, 78.1, 77.3, 76.6,30.7, 23.1; API-ESMS: calcd. (%) for [M + H]+: m/z 447.1, found (%)447.1. 3d: 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.21 (d, J =7.8 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.77 (t,J = 8.2 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.38-7.27 (m, 2H), 6.49 (s,1H), 5.65 (s, 1H), 5.13 (m, 2H), 4.61 (s, 1H), 4.01 (s, 3H), 3.82 (s, 1H),3.53 (s, 1H), 3.46 (d, J = 6.0 Hz, 1H), 1.19 (d, J = 5.9 Hz, 3H); 13CNMR (100 MHz, DMSO-d6) δ 175.0, 172.7, 162.0, 146.7, 145.2, 134.3,130.6, 130.5, 126.5, 126.2, 123.8, 121.0, 120.0, 113.1, 92.5, 80.6, 78.1,77.3, 76.6, 61.1, 23.1; API-ESMS: calcd. (%) for [M + H]+: m/z 463.2,found. (%) 463.1.
- 4a: 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.11 (s, 1H), 7.47(d, J = 8.3 Hz, 1H), 7.29 (dd, J = 10.7, 5.6 Hz, 1H), 7.24-7.16 (m, 3H),7.03 (t, J = 7.7 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.18 (d, J = 8.2 Hz,1H), 5.56 (d, J = 9.2 Hz, 1H), 5.12 (d, J = 3.7 Hz, 1H), 5.07 (d, J = 7.6Hz, 1H), 4.89 (d, J = 6.1 Hz, 1H), 4.02 (s, 1H), 3.96 (t, J = 8.5 Hz, 1H),3.82- 3.69 (m, 2H), 3.60 (dd, J = 9.9, 4.5 Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 172.3, 172.2, 137.3, 136.5, 133.6, 131.5, 131.0,130.9, 130.5, 130.1, 128.9, 125.5, 122.4, 120.6, 120.5, 111.5, 111.4,105.5, 105.4, 82.5, 82.2, 71.4, 68.7, 66.6, 65.2, 20.0; API-ESMS: calcd.(%) for [M + H]+: m/z 435.1, found. (%) 435.1. 4b: 1H NMR (400MHz, DMSO-d6) δ 11.02 (s, 1H), 8.01 (s, 1H), 7.56 (d, J = 8.21 Hz,1H), 7.37 (t like, J = 7.44 Hz, 1H), 7.15 (m, 1H), 7.05 (t, J = 7.43 Hz,1H), 6.94 (m, 2H), 6.64 (t, J = 7.24 Hz, 1H), 6.31(d, J = 8.22 Hz, 1H),5.50 (d, J = 9.0 Hz, 1H), 5.33 (d, J = 5.08 Hz, 1H), 5.21 (d, J = 4.69Hz, 1H), 5.15 (d, J = 5.09 Hz, 1H), 4.59 (s, 1H), 3.68 (m, 3H), 3.48 (s,3H), 3.27 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 172.4, 172.0,157.6, 137.4, 136.4, 133.3, 131.1, 130.6, 128.9, 125.4, 125.3, 122.1,120.4, 120.3, 120.1, 111.8, 111.6, 105.9, 85.0, 79.6, 77.4, 71.9, 69.7,60.8, 55.1; API-ESMS: calcd for [M + H]+: m/z 481.2, found. (%)481.1; [M + Na]+: m/z 503.1, found. (%) 503.2.
References
(a) Y. Wada, H. Nagasaki and M. Tokuda, J. Org. Chem., 72, 2008 (2007); (b) M.G. Saulnier, B.N. Balasubramanian and B.H. Long, J. Med. Chem., 48, 2258 (2005); (c) J.D. Chisholm and D.L. Van Vranken, J. Org. Chem., 65, 7541 (2000); (d) F. Anizon, L. Belin and P. Moreau, J. Med. Chem., 40, 3456 (1997).
T. Tamaoki, H. Nomoto and Y. Takahashi, Biochem. Biophys. Res. Commun., 135, 397 (1986).
D.E. Nettleton, T.W. Doyle and B. Krishnan, Tetrahedron Lett., 26, 4011 (1985).
F. Anizon, L. Belin and P. Moreau, J. Med. Chem., 40, 3456 (1997).
(a) G. Zhu, S. Conner and X.C. Zhou, Bioorg. Med. Chem. Lett., 13, 1231 (2003); (b) S. Routier, P. Peixoto and J.Y. Mérour, J. Med. Chem., 48, 1401 (2005); (c) A. Bourderioux, P. Kassis and J.-Y. Mérour, Tetrahedron, 64, 11012 (2008).
C. Sanchez-Martinez, C. Shih and M.M. Faul, Bioorg. Med. Chem. Lett., 13, 3835 (2003).
N. Ding, X.G. Du and W. Zhang, Bioorg. Med. Chem. Lett., 21, 3531 (2011).
(a) G.P. Song, H.C. Liu and W. Zhang, Bioorg. Med. Chem., 18, 5183 (2010); (b) M. Gui, D.K. Shi and M. Huang, Invest. New Drug, 28, 1 (2010).
(a) M.M. Faul, L.L. Winneroski and C.A. Kumrich, J. Org. Chem., 63, 6053 (1998); (b) M.M. Faul, L.L. Winneroski and C.A. Kumrich, Tetrahedron Lett., 40, 1109 (1999).
3a: 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 11.13 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8.55 (d, J = 8.1 Hz, 1H), 7.75-7.68 (m, 2H), R2 NH2 O 5a R2 = CH3 5b R2 = OCH3 (i) N OO ONHO N OR2NHN O OR2+R1R1R16b R1= O MBOPMBO OPMBO PMBOOPMBOPMBOOPMB PMBOPMBOPMBO6c R1 =6d R1 =7d R1 =R2 = OCH3O PMBOOPMB PMBO OPMBOOPMBOPMBOOPMB PMBOPMBOPMBOO PMBOPMBO OPMB7c R1 =R2 = CH37f R1 =R2 = OCH37e R1 =R2 = CH33d R1 =R2 = OCH3O HOOHHOOHOOHOHOOH HOHOHOO HOOH HO3c R1 =R2 = CH34b R1=R2 = OCH34a R1 =R2 = CH3NHO N OR2H(iii)7a R1 = H, R2 = CH37b R1 = H, R2 = OCH33a R1 = H, R2 = CH33b R1 = H, R2 = OCH36a R1 = HNHO N OR2R18d R1 =R2 = OCH3O HOOH HOOHOOHOHOHO OHHOHOO HOHO OH8c R1 =R2 = CH34b R1 =R2 = OCH34a R1 =R2 = CH3(ii) (iii)Scheme-I: Synthesis of indolo[2,3-α]pyrrolo[3,4-c]carbazoles, aryl-indolyl maleimides and their glycosides. Conditions: (i) t-BuOK, THF, 12 % for 7a,17 % for 7b, 44 % for 7c, 36 % for 7d; (ii) DDQ, CH2Cl2/H2O (v:v = 10:1), 77 % for 8c, 81 % for 8d, 31 % for 4a over 2 steps, 16 % for 4b over2 steps, (iii) 57 % for 3a, 40 % for 3b, 65 % for 3c, 35 % for 3d. 7.60 (d, J = 7.1 Hz, 1H), 7.55 (s, 1H), 7.37 (d, J = 7.5 Hz, 1H), 3.04 (s,3H); 13C NMR (100 MHz, DMSO-d6) δ 170.3, 170.2, 141.6, 140.2,136.2, 131.1, 130.7, 127.5, 126.5, 126.4, 124.7, 124.2, 121.3, 120.8,120.7, 120.2, 111.7, 111.5, 25.7; API-ESMS: calcd. (%) for [M + H]+:m/z 301.1, found (%) 301.1. 3b: 1H NMR (400 MHz, DMSO-d6) δ12.81 (s, 1H), 10.97 (s, 1H), 9.03 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 8.1Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.54 (t, J =7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H),3.99 (s,3H); 13C NMR (100 MHz, DMSO-d6) δ 170.1, 168.0, 156.8, 140.6,140.2, 130.1, 129.0, 126.6, 124.8, 121.4, 120.7, 120.0, 118.3, 114.7,112.1, 111.8, 108.4, 55.8; API-ESMS: calcd. (%) for [M + H]+: m/z317.1, found (%) 317.1. 3c: 1H NMR (400 MHz, DMSO-d6) δ 11.19(s, 1H), 9.18 (d, J = 7.6 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.29 (d, J =8.5 Hz, 1H), 7.74-7.68 (m, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.45 (t, J =7.2 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 6.41 (s, 1H), 5.66 (d, J = 4.9 Hz,1H), 5.06 (d, J = 5.4 Hz, 1H), 5.01 (d, J = 6.0 Hz, 1H), 4.64 (s, 1H),3.82 (s, 1H), 3.56-3.48 (m, 1H), 3.47-3.38 (m, 1H), 3.01 (s, 3H), 1.16(d, J = 5.9 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 175.1, 175.0,146.8, 146.7, 141.3, 135.7, 134.9, 132.5, 132.3, 130.7, 130.0, 129.1,127.4, 127.2, 126.5, 126.4, 123.8, 119.6, 92.8, 80.6, 78.1, 77.3, 76.6,30.7, 23.1; API-ESMS: calcd. (%) for [M + H]+: m/z 447.1, found (%)447.1. 3d: 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.21 (d, J =7.8 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.77 (t,J = 8.2 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.38-7.27 (m, 2H), 6.49 (s,1H), 5.65 (s, 1H), 5.13 (m, 2H), 4.61 (s, 1H), 4.01 (s, 3H), 3.82 (s, 1H),3.53 (s, 1H), 3.46 (d, J = 6.0 Hz, 1H), 1.19 (d, J = 5.9 Hz, 3H); 13CNMR (100 MHz, DMSO-d6) δ 175.0, 172.7, 162.0, 146.7, 145.2, 134.3,130.6, 130.5, 126.5, 126.2, 123.8, 121.0, 120.0, 113.1, 92.5, 80.6, 78.1,77.3, 76.6, 61.1, 23.1; API-ESMS: calcd. (%) for [M + H]+: m/z 463.2,found. (%) 463.1.
4a: 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.11 (s, 1H), 7.47(d, J = 8.3 Hz, 1H), 7.29 (dd, J = 10.7, 5.6 Hz, 1H), 7.24-7.16 (m, 3H),7.03 (t, J = 7.7 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.18 (d, J = 8.2 Hz,1H), 5.56 (d, J = 9.2 Hz, 1H), 5.12 (d, J = 3.7 Hz, 1H), 5.07 (d, J = 7.6Hz, 1H), 4.89 (d, J = 6.1 Hz, 1H), 4.02 (s, 1H), 3.96 (t, J = 8.5 Hz, 1H),3.82- 3.69 (m, 2H), 3.60 (dd, J = 9.9, 4.5 Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 172.3, 172.2, 137.3, 136.5, 133.6, 131.5, 131.0,130.9, 130.5, 130.1, 128.9, 125.5, 122.4, 120.6, 120.5, 111.5, 111.4,105.5, 105.4, 82.5, 82.2, 71.4, 68.7, 66.6, 65.2, 20.0; API-ESMS: calcd.(%) for [M + H]+: m/z 435.1, found. (%) 435.1. 4b: 1H NMR (400MHz, DMSO-d6) δ 11.02 (s, 1H), 8.01 (s, 1H), 7.56 (d, J = 8.21 Hz,1H), 7.37 (t like, J = 7.44 Hz, 1H), 7.15 (m, 1H), 7.05 (t, J = 7.43 Hz,1H), 6.94 (m, 2H), 6.64 (t, J = 7.24 Hz, 1H), 6.31(d, J = 8.22 Hz, 1H),5.50 (d, J = 9.0 Hz, 1H), 5.33 (d, J = 5.08 Hz, 1H), 5.21 (d, J = 4.69Hz, 1H), 5.15 (d, J = 5.09 Hz, 1H), 4.59 (s, 1H), 3.68 (m, 3H), 3.48 (s,3H), 3.27 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 172.4, 172.0,157.6, 137.4, 136.4, 133.3, 131.1, 130.6, 128.9, 125.4, 125.3, 122.1,120.4, 120.3, 120.1, 111.8, 111.6, 105.9, 85.0, 79.6, 77.4, 71.9, 69.7,60.8, 55.1; API-ESMS: calcd for [M + H]+: m/z 481.2, found. (%)481.1; [M + Na]+: m/z 503.1, found. (%) 503.2.