Electronic Supplementary Information: Ternary oxovanadium(iv) complexes of ONO-donor Schiff base and polypyridyl derivatives as protein tyrosine phosphatase inhibitors: synthesis, characterization and biological activities Caixia Yuan a, Liping Lu a,b, Xiaoli Gao a, Yanbo Wu a, Maolin Guo b, Ying Li c, Xueqi Fu c, Miaoli Zhu a,d Table S1 Crystallographic data and structure refinement for complexes 1 and 2 Empirical formula Mr/g mol -1 Crystal size/mm T/K Crystal system Space group a/ Å b/ Å c/ Å α/ β/ γ/ V/ Å 3 Z Calc. Density/ g cm -3 F(000) µ/mm 1 θ Range/ Index range Total refl./ unique refl. Obs. Refl. [I >2 sigma(i )] Data / restraints / parameters R 1, wr 2 [I>2σ(I)] Residuals/ eå -3 GOF Complex 1 0.25bpy C 26.5 H 19 N 3.5 O 4 V 501.39 0.25 0.22 0.20 298(2) Triclinic P 1 11.350 (4) 14.201 (5) 15.097 (6) 99.462(8) 97.022(7) 90.904(7) 2380.6(15) 4 1.399 1030 0.46 2.1-25.0-13 h 13; -16 k 16; 0 l 17 8124/8124 3309 8124 / 0 / 631 0.062, 0.125 0.386/-0.438 0.798 Complex 2 0.33H 2 O C 26 H 17.67 N 3 O 4.33 V 492.37 0.40 0.40 0.10 298(2) Rhombohedral R 3 34.468 (8) 34.468 (8) 9.998 (3) 90.00 90.00 120.00 10287 (5) 18 1.431 4542 0.474 2.1-25.0-40 h 40; -40 k 30; -11 l 7 13278/3986 2084 3986 / 6 / 318 0.057, 0.110 0.988/-0.196 0.939 1
Table S2 Selected bond lengths (Å)and angles( o ) for complexes 1 0.25bpy and 2 0.33H 2 O 1 0.25bpy 2 0.33H 2 O V1 O1 1.595 (3) V2 O5 1.601 (3) V1 O1 1.589 (3) V1 O2 1.928 (4) V2 O6 1.942 (3) V1 O2 1.957 (3) V1 O3 1.964 (3) V2 O7 1.967 (3) V1 O3 1.978 (3) V1 N1 2.059 (4) V2 N4 2.063 (4) V1 N3 2.091 (4) V1 N2 2.134 (4) V2 N6 2.131 (4) V1 N1 2.141 (4) V1 N3 2.322 (4) V2 N5 2.321 (4) V1 N2 2.365 (4) O1 V1 O2 102.49 (16) O5 V2 O6 102.11 (16) O1 V1 O2 103.53 (16) O1 V1 O3 102.46 (15) O5 V2 O7 101.89 (15) O1 V1 O3 99.84 (16) O2 V1 O3 155.05 (15) O6 V2 O7 156.00 (13) O2 V1 O3 156.51 (13) O1 V1 N1 99.40 (16) O5 V2 N4 98.22 (15) O1 V1 N3 101.33 (16) O2 V1 N1 88.12 (17) O6 V2 N4 88.96 (14) O2 V1 N3 89.31 (13) O3 V1 N1 87.81 (15) O7 V2 N4 88.15 (14) O3 V1 N3 88.45 (14) O1 V1 N2 93.05 (16) O5 V2 N6 93.46 (15) O1 V1 N1 94.78 (15) O2 V1 N2 88.62 (16) O6 V2 N6 86.58 (13) O2 V1 N1 85.47 (13) O3 V1 N2 90.06 (13) O7 V2 N6 91.46 (14) O3 V1 N1 90.26 (14) N1 V1 N2 167.53 (16) N4 V2 N6 168.14 (14) N3 V1 N1 163.82 (14) O1 V1 N3 165.60 (15) O5 V2 N5 165.62 (15) O1 V1 N2 167.55 (15) O2 V1 N3 78.28 (15) O6 V2 N5 79.63 (13) O2 V1 N2 80.33 (13) O3 V1 N3 77.56 (13) O7 V2 N5 77.00 (13) O3 V1 N2 76.31 (13) N1 V1 N3 95.00 (15) N4 V2 N5 96.08 (14) N1 V1 N3 90.48 (14) N2 V1 N2 72.56 (15) N6 V2 N7 72.32 (14) N2 V1 N2 73.56 (13) 2
Fig. S1 The cell packing of complex 1 0.25bpy Fig. S2 The cell packing of complex 2 0.33H 2 O 3
Table S3 UV-vis spectral data at 298 K in DMSO for the complexes and ligands Complex/ligand λmax/nm(ε/dm3 mol-1 cm-1) 1 793sh (36), 577 (113), 513 (162), 401 (6175), 314 (9,915), 282 (24,719) 2 741sh (14), 515sh (239), 411 (8,747), 312 (16,876), 294 (25,341) 3 776sh (14), 517sh (214), 425 (3,556), 397 (5,559), 339 (9,955), 301 (22,997) 4 779sh (20), 520sh (176), 415 (6,946), 382 (19,383), 362 (16,979), 296 (34,300) 5 777sh (18), 519sh (207), 423 (3841), 388 (12,145), 366 (10,543), 296 (20,801) bpy 285(20,849) phen 268(67,644) dpq 342(5,797), 325(7,285), 281(20,201), 263(31,088) dppz 381(8272), 360(7,949), 295(14,206), 269(35,554), dppm 386(8,398), 365(7,287), 296(12,786), 271(29,102), SAA 332(12.935), 261(14,123) Fig. S3(A) ESI-MS spectrum of complex 1. 4
Fig. S3(B) ESI-MS spectrum of complex 2. Fig. S3(C) ESI-MS spectrum of complex 3. 5
Fig. S3(D) ESI-MS spectrum of complex 4. Fig. S3(E) ESI-MS spectrum of complex 5. 6
Molecular modeling of interactions between complex 2 and PTP1B Our enzyme kinetics studies (Fig.8) suggest that the oxovanadium complexes are classical reversible competitive inhibitors of PTP1B. This inhibition mode implies that they may bind to PTP1B at the active site of the enzyme. Modeling studies were performed to probe the possible interactions of complex 2 at the active site of PTP1B. Molecular modeling was carried out on a SGI workstation using Insight II and Discover programs within the Biosym software package. The coordinates of the PTP1B X-Ray crystal structure (PDB ID: 1ONY) [S1] was used in the modeling studies. Hydrogen atoms were added using the Biopolymer module of the Insight II program, followed by energy minimization and optimization in extensible systematic force field (ESFF). Then the inhibitor (complex 2, coordinates from the x-ray structure) was introduced. The inhibitor was initially placed at the entrance of the baggy structure with the catalytic site at the bottom and this position was regarded as insertion depth 0. Next the inhibitor was manually docked, at a depths of 2 Å of each step, into the catalytic site of PTP1B in ESFF and the energy was minimized. At the beginning of each minimization, the steeped descend method in the ESFF was used until the rootmean-square derivative (RMSD) was less than 5 kcal/mol. The method of minimization was then converted to conjugate gradient procedure until the RMSD was less than 0.05 kcal/mol or the minimization steps exceed 1000. An exception is made for the structural model at the end of the insertion; the energy was further optimized until the RMSD was less than 0.01 kcal/mol. Fig. S4 A carton presentation of the model showing complex 2 (VO(SAA)(phen), shown in ball and stick) bound in the active site of PTP1B (shown the surface, the sulfur atom of the active site residue Cys215 is highlighted as a yellow ball). 7
The modeling studies suggest that the oxovanadium itself, can be well fitted into the active site cleft of PTP1B (Fig. S4). In the model, the vanadyl oxygen is close to the sulphur atom of the active site cysteine (Cys215), at a distance 3.38 Å. Two hydrogen-bonds may also be formed between the two oxygens of carboxyl of the complex and the nitrogens of the Arg221 residue in the enzyme (O carboxyl oxygen Narg 221, 3.13 Å and O carbozyl oxygen Narg 221, 3.07Å) (Fig. S5). Fig. S5 Expanded view showing the interactions between complex 2 and the residues in the enzyme active site. Reference: [S1] Liu G.; Szczepankiewicz B. G.; Pei Z.; Janowich D. A.; Xin Z.; Hadjuk P. J.; Abad-Zapatero C.; Liang H.; Hutchins C. W.; Fesik S. W.; Ballaron S. J.; Stashko M. A.; Lubben T.; Mika A. K.; Zinker B. A.; Trevillyan J. M.; Jirousek M. R. J. Med. Chem. 2003, 46, 2093-2103 8