Zn 2 +, Studies on the Structures and Antihyperglycemic Effects of Zn 2 +, Cu 2 +, Ni 2 + 2Metformin Complexes. ZHU, Miao2Li LU, Li2Ping YANG, Pin Ξ

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1 , ACTA CHIMICA SINICA Vol 62, 2004 No 8, Zn 2 +, Cu 2 + Ni 2 + Ξ Ξ ( ) 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 ) 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 : edu cn Received December 12, 2003 ; revised January 31, 2004 ; accepted March 8, 2004 (No ) (No ) 2002

2 784 Vol 62, 2004, ( %) : C 15 91, H 4 01, N ; ( %) : C 15 70, H, 4 19, N IR C = N : ( s), ( s),, (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 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 ; : KBr Shimadzu 8300 FT2IR ; X24 max = 549 nm ; IR C = N : (s), (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 ; Gassian98 [6] ( %) : C 29 79, H 6 93, N ; IR C = N : [7] 0 2 ml/ 10 g 5 d 5 (s), (s), (s) cm - 1, N H : (s) cm h,,, 4 [8] ph (C 4 H 12 N 5 ) + Cl - (1) 30 0 g 27 0 g 1 0 mmol L - 1 ( ), I = 0 1 C 2 H 4 N ml (1 9 V mol/ L (NaClO 4 ) mol/ L NaOH V), 5 h ( < 150 ),, 1 ph , mol/ L HCl ph 5,,, 4 1 :lg K 1 = 12 9,, (lg K 1 = ) [9],, g, 35 2 % Zn 2 +, Cu 2 +, Ni 2 + :,,m p C 4 N 5 H 11 HCl, ( %) :C 29 01, H 7 30, N ; ( %) :C 29 19, H 7 94, N ; UV2vis max : 233 nm ( = L mol - 1 cm - 1 ) ; IR C = N : ( s), ( s) cm - 1 ; 1 H NMR (DMSO2d 6 ) : 2 92 [ N2 (CH 3 ) ], 6 73, 7 23 (NH 2 ) ; 13 C NMR (DMSO2d 6 ) : [N(CH 3 ) ], [ C( N) N(CH 3 ) 2 ], [ C( N) N],,,,, X2ray 1 5 (C 4 H 12 N 5 ) + NO3 - (2) NaOH,, ( ) :, HNO 3 ph 5, ( ) ; : Sigma,, X2ray ; g, 1 0 mol/ L KOH ph,, 3 h, lg K = 13 3, 19 0, Gassian98, RHF/ 62 31G(d), B3LYP/ 6231G( d) B3PW91/ 6231G( d), [ ], :,, ; 0 45 % ; : [ ZnCl 3 (C 4 H 12 N 5 ) ] (3) g, (020801) : 25 ml ; 10 ml, ( ),, 1 mol/ L HCl, GB 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 % g, 65 6 % C 4 H 12 Cl 3 N 5 Zn, 60 mmol/ L 3 %

3 No 8 :Zn 2 +, Cu 2 + Ni mmol/ L , (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) : , (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) > [14 ], 2 5 [10 13 ] C N C N , 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 nm, nm, ( 1,102 ) Cu N ( nm) [18] ;Ni N nm, 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) G(d) 3a, Figure 1 Monodentate and bidentate models of metformin complexes, Cu N

4 786 Vol 62, 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) ( ) ( ) ( ) C(6) (0 356) (0 276) (0 281) C(9) (0 314) (0 247) (0 249) C( 10) ( 0 903) ( 0 700) ( 0 721) N(14) ( ) ( ) ( ) C( 15) ( 0 966) ( 0 730) ( 0 759) N(16) ( ) ( ) ( ) N(17) ( ) (0 029) (0 023) N( 18) ( ) ( ) ( ) (0 81) 2 3 Cu N, C N [ Ni ( C 4 H 10 2 N 5 ) 2 ] RHF/ 6231G( d), ( 1 2 3b, Ni, mmol/ kg ),, ( ) 6 mmol/ L, C (0 92) 23 mmol/ L,, [ ( ) mmol/ L ] ( ) mmol/ L, ( P < 0 05) ( ) ( ) mmol/ L,, P < 0 05, ( ) mmol/ L, ( mmol/ kg ), 3, ( ) mmol/ L, d 8, 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 ) ],,, (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

5 No 8 :Zn 2 +, Cu 2 + Ni Group 2 ( x s) Table 2 Antihyperglycemic effects of metformin complexes ( x s) Before treatment After treatment Normal control a a Model control Metformin b a P < 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 a a Model control b a P < 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) , N(9) , N(11) ; (,,,, 2000, 9 (7), 443 ) 4 N ; 5 N 5 Sun, H2W Program SCMAR, Central Laboratory, Nankai N,University, Tianjing, 1997 (in Chinese) N [ N ( 4) (, SCMAR,,, 1997 ) , N ( 16) , N ( 17) , N ( 18) 6 Frisch, M J ; Trucks, G W ; Schlegel, H B ; Scuseria, G E ; Robb, M A ; Cheeseman, J R ; Zakrzewski, V G ; ] : 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), 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, Chen, Q2M Acta Pharm Sinica 1985, 21 ( 16), 410 ( in Chinese) (,, 1985, 21 (16), 410 ) 8 Xu, S2Y Methodology of Pharmacological Experimental, 2nd

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