2004 62 8, 783 788 ACTA CHIMICA SINICA Vol 62, 2004 No 8, 783 788 Zn 2 +, Cu 2 + Ni 2 + Ξ Ξ ( 030006) Zn 2 +, Cu 2 +, Ni 2 + :Zn 2 +, Cu 2 +, Ni 2 +, N, N, N, N,, Studies on the Structures and Antihyperglycemic Effects of Zn 2 +, Cu 2 +, Ni 2 + 2Metformin Complexes ZHU, Miao2Li LU, Li2Ping YANG, Pin Ξ ( Institute of Molecular Science, Chemical Biology and Molecular Engineering Laboratory of Education Ministry, Shanxi University, Taiyuan 030006) Abstract The structures and charge distribution as well as antihyperglycemic effects of 1,12dimethylbiguanide (metformin) metal ( Zn 2 +, Cu 2 + and Ni 2 + ) complexes were investigated Metformin can complex with Zn 2 + at bridging N, forming a rare monodentate complex, but complex with Cu 2 + and Ni 2 + at terminal N atoms, giving rise to bidentate complexes The charge distribution calculated by DFT and ab initio methods indicates that the bridging N atom has more negative charge than terminal N atoms The antihyperglycemic effects of metformin metal complexes show that the monodentate complex has no effect and bidentate complexes still keep the activity but less efficient than metformin alone This result suggests that the bridging N atom of metformin be important for its antihyperglycemic effect Keywords complexes of metal2metformin, charge distribution, antihyperglycemic effect,,, ( 5 10 mg/ d),,,,,,, 1957,, [1 3] 1980,Coulston Dandona [1] [3] Ξ E2mail : yangpin @sxu edu cn Received December 12, 2003 ; revised January 31, 2004 ; accepted March 8, 2004 (No 20171031) (No 20011007) 2002
784 Vol 62, 2004, ( %) : C 15 91, H 4 01, N 23 20 ; ( %) : C 15 70, H, 4 19, N 23 09 IR C = N : 1660 1635 5 ( s), 1617 2 ( s),, 2000 1533 3 (s) cm - 1, 28 % [4], X2ray, [Cu(C 4 H 10 N 5 ) 2 ] 8H 2 O (4) 8 25 g 1 1 1,, C, H, N Perkin2Elmer 240B 80 24 h 7 35 g, 46 % ; 1 H, 13 C NMR DRX 300 MHz, C 8 CuH 32 N 10 O 6, ( %) : C 22 45, H 7 48, N 32 Hewlett Packard 8453 ; 72 ; ( %) : C 22 35, H 7 33, N 32 41 ; : KBr Shimadzu 8300 FT2IR ; X24 max = 549 nm ; IR C = N : 1672 2 (s), 1636 51 (s) cm - 1 ;ph Beckman 39848, 1 0 mol/ L KOH ph 9 11, Beckman 50 ph, SCMAR [5] 4,, A R C P ([Ni (C 4 H 10 N 5 ) 2 ] (5) 4, 63 % A R ), C 8 H 20 N 10 Ni, ( %) : C 30 05, H 6 40, N 44 47 ; Gassian98 [6] ( %) : C 29 79, H 6 93, N 43 73 ; IR C = N : 1683 7 [7] 0 2 ml/ 10 g 5 d 5 (s), 1646 1 (s), 1612 4 (s) cm - 1, N H : 1569 9 (s) cm - 1 14 h,,, 4 [8] 1 3 1 2 ph (C 4 H 12 N 5 ) + Cl - (1) 30 0 g 27 0 g 1 0 mmol L - 1 (25 0 0 1), I = 0 1 C 2 H 4 N 2 140 ml (1 9 V mol/ L (NaClO 4 ) 0 1153 mol/ L NaOH V), 5 h ( < 150 ),, 1 ph 2 5 12, mol/ L HCl ph 5,,, 4 1 :lg K 1 = 12 9,, (lg K 1 = 10 4 12 8) [9],, 21 45 g, 35 2 % Zn 2 +, Cu 2 +, Ni 2 + :,,m p 223 5 225 C 4 N 5 H 11 HCl, ( %) :C 29 01, H 7 30, N 42 28 ; ( %) :C 29 19, H 7 94, N 42 73 ; UV2vis max : 233 nm ( = 12518 10 4 L mol - 1 cm - 1 ) ; IR C = N : 1640 1623 0 ( s), 1580 1569 9 ( s) cm - 1 ; 1 H NMR (DMSO2d 6 ) : 2 92 [ N2 (CH 3 ) ], 6 73, 7 23 (NH 2 ) ; 13 C NMR (DMSO2d 6 ) : 37165 [N(CH 3 ) ], 158 45 [ C( N) N(CH 3 ) 2 ], 160 06 [ C( N) N],,,,, X2ray 1 5 (C 4 H 12 N 5 ) + NO3 - (2) 1 5 1 NaOH,, ( ) :, HNO 3 ph 5, ( 0105110) ; : Sigma,, X2ray ; 2 1 8 5 g, 1 0 mol/ L KOH ph,, 3 h, lg K = 13 3, 19 0, 20 4 1 4 Gassian98, RHF/ 62 31G(d), B3LYP/ 6231G( d) B3PW91/ 6231G( d), [ 10 13 ], :,, ; 0 45 % ; : [ ZnCl 3 (C 4 H 12 N 5 ) ] (3) 16 55 g, (020801) : 25 ml ; 10 ml, ( ),, 1 mol/ L HCl, GB14922294 II, : ( ) A002001, 2 h,, [ ZnCl 3 ( C 4 H 12 N 5 ) ] (3), [ Cu ( C 4 H 10 N 5 ) 2 ],,, 24 h 8H 2 O (4), [Ni (C 4 H 10 N 5 ) 2 ] (5) 3 % 19 82 g, 65 6 % C 4 H 12 Cl 3 N 5 Zn, 60 mmol/ L 3 %
No 8 :Zn 2 +, Cu 2 + Ni 2 + 785 60 mmol/ L 2 2 1 5 2 2 2 1 100, (28 2) g, 10, 1 [ : ( 45 mg/ kg (0 1 ml/ 10 g) ) ], [13], 2 ( 14 h, 3 d ),72 h, X2ray, 13 mmol/ L,,, N(14), N(18) : 3 4 5 6, (012 ml/ 10 g), (3 % RHF : C(15) > C(10) > C(6) > C(9) > N( 17) > N( 4) > N(16) ), 1, 5 d 14 h, > N( 18) > N( 14),, B3LYP : C(15) > C (10) > C (6) > C (9) > N( 4) > N( 17) > 2 2 1 1 [14 ], 2 5 [10 13 ] C N C N 0 1474, 0 1265 nm [15], C N,Zn ( I) ( II) ( 1), I, (67 5 ), [13,14,16,17],Zn 2 + OH -, II [11, II,12], N Cu N 0 1906 0 1955 nm, 0 1934 nm, ( 1,102 ) Cu N (0 2001 0 2031 nm) [18] ;Ni N 0 1805 0 1899 nm, 011851 nm,,, C(10) N(18),, d d 8, d, 0 69, 0 72, [11,,12] N(18), +, C(10) N(18), X2ray,,, [17,19 21] N(16) > N( 14) > N( 18) B3pw91 : C (15) > C (10) > C (6) > C (9) > N( 4) > N( 17) > N(16) > N( 14) > N( 18) 2 C 4 H 12 N 5 + Figure 2 A label diagram for C 4 H 12 N + 5 C(10) C(15), C N(18), C(10) N(18),, C(10) C(15), ( 1 0), N(18), N (17), RHF,B3LYP B3PW91 N(17) 2 2 2 1 6231G(d) 3a, Figure 1 Monodentate and bidentate models of metformin complexes, Cu N
786 Vol 62, 2004 1 RHF DFT C 4 H 12 N 5 + Table 1 Calculated net charge of C 4 H 12 N + 5 in RHF and DFT methods Atom RHF/ 6231G(d) B3LYP/ 6231G(d) B3pw91/ 6231G(d) N(4) 0 024 ( - 0 059) 0 076 ( - 0 004) 0 075 ( - 0 006) C(6) 0 382 (0 356) 0 303 (0 276) 0 314 (0 281) C(9) 0 355 (0 314) 0 282 (0 247) 0 291 (0 249) C( 10) 0 747 ( 0 903) 0 557 ( 0 700) 0 571 ( 0 721) N(14) - 0 698 ( - 0 652) - 0 454 ( - 0 407) - 0 488 ( - 0 433) C( 15) 0 868 ( 0 966) 0 648 ( 0 730) 0 670 ( 0 759) N(16) - 0 019 ( - 0 069) 0 033 ( - 0 020) 0 033 ( - 0 020) N(17) 0 026 ( - 0 026) 0 075 (0 029) 0 072 (0 023) N( 18) - 0 685 ( - 0 734) - 0 520 ( - 0 551) - 0 539 ( - 0 575) (0 81) 2 3 Cu N, C N [ Ni ( C 4 H 10 2 N 5 ) 2 ] RHF/ 6231G( d), 2 3 2 ( 1 2 3b, Ni, mmol/ kg ),, ( - 0 79) 6 mmol/ L, C (0 92) 23 mmol/ L,, [ (33 32 9 92) mmol/ L ] (24 41 5 20) mmol/ L, ( P < 0 05) (26 60 13 15) (26 08 11 53) mmol/ L,, P < 0 05, (33 76 4 03) mmol/ L, ( 3 0 6 mmol/ kg ), 3, (48 05 10 55) mmol/ L, 3 4 1 d 8, 2 4 2 4 1 Zn 2 +, Cu 2 +, Ni 2 + ( Zn 2 + lg K = 13 3 ; Cu 2 +,lg K = 19 0, Ni 2 + lg K = 20 4) [ Ni (C 4 H 10 N 5 ) 2 ] > [ Cu ( C 4 H 10 N 5 ) 2 ] H 2 O > [ ZnCl 3 (C 4 H 12 N 5 ) ],,, 2 4 2 3 (a) 4 (b) 5 :Zn 2 + N Figure 3 A lable diagram and calculated atomic charge for 4 (a) and 5, (b), N ZnCl 3 -, N
No 8 :Zn 2 +, Cu 2 + Ni 2 + 787 Group 2 ( x s) Table 2 Antihyperglycemic effects of metformin complexes ( x s) Before treatment After treatment Normal control 14 5 68 1 42 a 14 6 07 1 20 a Model control 9 23 92 5 58 9 33 32 9 92 Metformin 11 23 05 4 73 11 24 41 5 20 b 3 11 23 91 5 03 3 33 76 4 03 4 11 23 63 5 58 3 26 60 13 15 5 9 23 11 4 66 9 26 08 11 53 a P < 0 001 and b P < 0 05 compared to model control group Group 3 3 ( x s) Table 3 Antihyperglycemic effects of the complex 3 ( x s) Before treatment After treatment Normal control 11 6 64 1 03 a 11 5 59 1 12 a Model control 10 28 75 3 50 9 37 37 8 81 3 10 27 70 6 06 10 48 05 10 55 b a P < 0 001 and b P < 0 05 compared to model control group ; N (,, 2002, 10 (3), 220 ), N(1), N(4) Cu 2 + Ni 2 +, N 3 N 9 (7), 443 (in Chinese) :N(8) - 0 091, N(9) - 0 026, N(11) 0 015 ; (,,,, 2000, 9 (7), 443 ) 4 N - 0 81 ; 5 N 5 Sun, H2W Program SCMAR, Central Laboratory, Nankai - 0 79 N,University, Tianjing, 1997 (in Chinese) N [ N ( 4) (, SCMAR,,, 1997 ) - 0 059, N ( 16) - 0 069, N ( 17) - 0 026, N ( 18) 6 Frisch, M J ; Trucks, G W ; Schlegel, H B ; Scuseria, G E ; Robb, M A ; Cheeseman, J R ; Zakrzewski, V G ; - 0 734 ] : Montgomery, J A Jr ; Stratmann, R E ; Burant, J C ;, Dapprich, S ; Millam, J M ; Daniels, A D ; Kudin, K N ;, N Strain, M C ; Farkas, O ; Tomasi, J ; Barone, V ; Cossi,, M ; Cammi, R ; Mennucci, B ; Pomelli, C ; Adamo, C ; Clifford, S ; Ochterski, J ; Petersson, G A ; Ayala, P Y ; N Cui, Q ; Morokuma, K ; Malick, D K ; Rabuck, A D ;,, Raghavachari, K ; Foresman, J B ; Cioslowski, J ; Ortiz, J V ; Baboul, A G ; Stefanov, B B ; Liu, G ; Liashenko,,, A ; Piskorz, P ; Komaromi, I ; Gomperts, R ; Martin, R L ; Fox, D J ; Keith, T ; Al2Laham, M A ; Peng, C Y ; References 1 Coulston, L ; Dandona, P Diabetes 1980, 29 (8), 665 2 Lynch, C J ; Patson, B J ; Goodman, S A ; Trapolsi, D ; Kimball, S R Am J Physiol Endocrinol Metab 2001, 281, E25 3 Chen, L2L Chin J Clin Nutr 2002, 10 ( 3), 220 ( in Chinese) 4 Han, Y ; Tu, S2Z ; Wang, Q2J Chin New Drugs J 2000, Nanayakkara, A ; Challacombe, M ; Gill, P M W ; Johnson, B ; Chen, W ; Wong, M W ; Andres, J L ; Gonzalez, C ; Head2Gordon, M ; Replogle, E S ; Pople, J A Gaussian 98, Revision A 9, Gaussian, Inc, Pittsburgh PA, 1998 7 Chen, Q2M Acta Pharm Sinica 1985, 21 ( 16), 410 ( in Chinese) (,, 1985, 21 (16), 410 ) 8 Xu, S2Y Methodology of Pharmacological Experimental, 2nd
788 Vol 62, 2004 ed, People s Medical Publishing House, Beijing, 1991, 1269 (in Chinese) (, ( ),, E59 (2), m91, 1991, 1269 ) 9 Ray, P Chem Rev 1961, 61, 313 10 Zhu, M2L ; Lu, L2P ; Jin, X2L ; Yang, P Acta Crystallogr 2002, C58 (3), m158 11 Zhu, M2L ; Lu, L2P ; Yang, P ; Jin, X2L Acta Crystallogr 2002, E58 (5), m217 12 Zhu, M2L ; Lu, L2P ; Yang, P ; Jin, X2L Acta Crystallogr 2002, E58 (6), m272 13 Zhu, M2L ; Lu, L2P ; Yang, P Acta Crystallogr 2003, E59 (4), o586 14 Hariharan, M ; Rajan, S S ; Srinivasan, R Acta Crystallogr 1989, C45, 911 15 Lide, D R Tetrahedron 1962, 17, 125 16 Zhu, M2L ; Yang, P ; Lu, L2P Acta Crystallogr 2003, 17 He, Z2L ; Zhu, M2L ; Ma, G2B Acta Crystallogr 2002, E58 (5), m647 18 Lu, L2P ; Zhu, M2L ; Yang, P J Inorg Biochem 2003, 95 (1), 31 19 Lu, L2P ; Zhu, M2L Acta Crystallogr 2003, E59 ( 12), m1086 20 Lu, L2P ; Zhu, M2L ; Yang, P Acta Crystallogr 2004, C60 (1), m18 21 Yang, P ; Zhu, M2L Chem Res Appl 1992, 4 (3), 20 (in Chinese) (,,, 1992, 4 (3), 20 ) (A0312128 PAN, B F ; FAN, Y Y )