Synthesis and spectral characterizations of vanadyl(II) and chromium(III) mixed ligand complexes containing metformin drug and glycine amino acid

Metformin is one of the most effective drugs for the treatment of type II diabetes. Two new mixed ligand complexes of vanadyl(II) and chromium(III) ions with the general formula [VOL1L2]SO4 and [CrL1L2(Cl)2]Cl, respectively, where L1 is the metformin and L2 is the glycine amino acid, have been synthesized in MeOH solvent with 1:1:1 stoichiometry and characterized by several spectroscopic techniques. The spectroscopic data suggested that the [VOL1L2]SO4 complex possesses a square pyramidal geometry, where the [CrL1L2(Cl)2]Cl complex possesses an octahedral geometry. The L1 ligand coordinated to the VO(II) and Cr(III) ions via the N atoms of the imino (‒C]NH) groups, where the L2 ligand coordinated via the O atom of the carboxylate group (COO) and the N atom of the amino group (NH2). The interaction of ligands L1 and L2 with the metal ions leads to complexes that have organized nanoscale structures with a main diameter of ∼14 nm for the [CrL1L2(Cl)2]Cl complex and ∼40 nm for the [VOL1L2]SO4 complex.


Introduction
Metal complexes are an important class of compounds with applications in various fields such as medicine, material sciences, biology, and catalysis [1,2]. These class of compounds may have different geometries, which make them potentially biologically active and used as anticancer, antifungal, and antibacterial agents. For example, carboplatin, oxaliplatin, and cisplatin, which are platinum-based metallodrugs, are considered anticancer drugs for treating several solid tumors such as ovarian, bladder, and testicular cancers. Platinum-based metallodrugs kill tumor cells by damaging DNA, which inhibit tumor cell division [3][4][5][6][7][8].
Nevertheless, the adverse side effects and acquired resistance associated with several metallodrugs prevent their effectiveness and widespread applications [9][10][11][12]. Because of that, significant attempts have been made to replace metallodrugs by developing innovative drugs with negligible side effects, enhanced efficiency, and decreased drug resistance and toxicity profiles. One of these attempts involves the design of new metal-based drugs by coordinating metal ions with biologically active ligands. Ions of transition metals play an important role in the fields of biochemistry and medicine, and their complexes are extensively used as therapeutic agents and drugs for the treatment of various human diseases, including neurological disorders, diabetes, inflammation, infection control, lymphomas, and carcinomas. Two interesting properties of transition metals enabling the design of metallodrugs with promising biological benefits exhibited: (i) different oxidation states and (ii) the ability to interact with several metalbinding sites [13][14][15].
Metformin (C 4 H 11 N 5 ) is a well-known AMP-activated protein kinase (AMPK) activator and well-known oral hypoglycemic drug, which has been in clinical use for over half a century, particularly in obese and overweight people. It is the most widely prescribed antidiabetic drug worldwide and the first-line therapy for non-insulindependent diabetes and metabolic syndrome. Besides its use in oral hypoglycemic medication for type II diabetes, metformin confers protection against a series of diseases through the activation of AMPK. This drug has antihyperglycemic and anticancer properties, and it strongly enhances insulin sensitivity in the body, increases the glucose uptake by peripheral tissues through stimulation of intracellular AMPK, and inhibits gluconeogenesis in the liver. This drug has multiple beneficial effects, such as the following: (i) Does not increase the risk for hypoglycemia (ii) Reduces weight gain (iii) Lowers blood lipid levels (iv) Lowers blood glucose levels.
Further research on the complexation of metformin with metal ions, especially in mixed ligand complexes, is still important for establishing good knowledge and a better understanding of the binding modes of metformin in this type of complex as a key point for developing new metformin-based metallodrugs. Therefore, this study was done to present the synthesis and speculated formula of two mixed ligand complexes of vanadyl(II) and chromium(III) ions with the general formula [VOL 1 L 2 ]SO 4 and [CrL 1 L 2 (Cl) 2 ]Cl, respectively, where L 1 is the metformin and L 2 is the glycine amino acid ( Figure 1) and to observe the X-ray diffraction patterns, phase purity, surface morphologies, and particle shapes of the synthesized mixed ligand complexes.

Instruments and chemicals
The spectrometers such as Perkin-ElmerLambda 25 UV/Vis spectrophotometer, Shimadzu FT-IR spectrophotometer, and Jeol JES-FE2XG electron spin resonance spectrometer were used to scan the UV-visible, IR, and ESR spectra at the room temperature, respectively. The microscopes such as JEOL JEM-1200 EX II transmission electron microscope (TEM) and Quanta FEG 250 scanning electron microscope (SEM) were applied to picture the TEM and SEM images, respectively. Perkin-Elmer 2400CHN elemental analyzer was applied to collect the elemental data. X'Pert Philips X-ray powder diffractometer was applied to collect the XRD spectra of the complexes, where HACH digital conductivity meter and magnetic susceptibility balance were applied for the molar conductivity and magnetic measurements, respectively. Solvents and chemicals were purchased from Merck KGaA company (Darmstadt, Germany) in analytical grade and used without further modification: metformin hydrochloride (C 4 H 11 N 5 ·HCl ≥97%), glycine (NH 2 CH 2 COOH ≥99%), VOSO 4 ·xH 2 O 97%, and CrCl 3 ·6H 2 O ≥98%.

Syntheses
Mixed ligand complexes [VOL 1 L 2 ]SO 4 and [CrL 1 L 2 (Cl) 2 ]Cl were synthesized as follows: To a methanolic solution of L 1 (metformin) (1 mmol in 10 mL), 1 mmol of L 2 (glycine) dissolved in MeOH solvent (10 mL) was added. The solution was stirred well for 10 min. Then, 1 mmol of VOSO 4 ·H 2 O dissolved in MeOH solvent (10 mL) was added to prepare the VOL 1 L 2 complex, and the pH of the mixture was adjusted to ∼8 with the ammonia solution (5%). The resultant homogenous greenish-blue solution was refluxed with stirring for 30 min at 65°C. On cooling the reactant media, the greenish-blue-colored precipitate was separated, which was recrystallized from the MeOH solvent. The final product was filtered, washed with MeOH and CH 3 OCH 3 , and then dried in an oven at 70°C. The [CrL 1 L 2 (Cl) 2 ]Cl complex was similarly synthesized as described for the VOL 1 L 2 complex using 1 mmol of CrCl 3 ·6H 2 O resulting in a dark greencolored product. The products were next characterized by analytical, thermal, and different spectral methods.     [40]. Accordingly, the observed bands can be assigned to 2 B 2 → 2 E, 2 B 2 → 2 B 1 , and 2 B 2 → 2 A 2 transitions, respectively. One more band is observed at the region 36,364 cm −1 , which may be due to the transition of the metformin linkages [40]. For the chromium complex, two peaks at 16,667 and 23,529 cm −1 were assigned to 4 A 2g → 4 T 2g and 4 A 2g → 4 T 1g (f) d-d transitions, respectively. The appearance of these two bands confirms octahedral (O h ) geometry for this complex [40]. The other band exhibited at the region 37,736 cm −1 is assigned to the transition of the metformin linkages.

Free ligands
A free L 1 molecule has three significant vibrational bands    The amino group of L 2 molecule can lose a hydrogen ion and become negatively charged or can accept a hydrogen ion and become positively charged, this is called as the zwitterion structure of L 2 molecule in solution.  Table 1 reports the band assignments for the important IR bands in free ligands and the mixed ligand complexes, where their IR spectra are shown in Figure 3. In the [VOL 1 L 2 ]SO 4 complex, the bands due to the ν(N-H) vibrations of the ligands were located at 3,394 and 3,173 cm −1 . The IR spectrum of [CrL 1 L 2 (Cl) 2 ]Cl complex showed a very wide absorption band ranged from 3,600 to 2,560 cm −1 due to the overlapping of bands due to the ν (N-H)

ESR spectral results
The Jeol JES-FE2XG electron spin resonance spectrometer was used to scan the powder ESR spectrum of the VOL 1 L 2 complex, and the obtained spectrum is presented in Figure 5. Electron spin resonance spectrum of vanadyl(II) complex in the polycrystalline state was recorded on   ESR spectrometer using 2,2-diphenyl-1-picrylhydrazyl DPPH ( Figure 5) free radical as "g" marker (g = 2.0027) at the room temperature. The Hamiltonian spectral data obtained from this spectrum are presented in Table 2. The powder ESR spectrum and the values of g and A for the [VOL 1 L 2 ]SO 4 complex agree with a square pyramidal geometry [46]. Equations (1) and (2) were used to calculate the values of anisotropic (A) and isotropic (g).
Equations (3) and (4) were used to calculate the covalency of the β 2 ; in plane π-and α 2 ; in plane σ-bonding [47,48]: β A P A P g g g 7 6 --5 14 -9 14 2 e = / ( where E is the electronic transition energy, λ = 135 cm −1 , and P = 128 × 10 −4 cm −1 . It is reported in the literature that a g || value more than 2.3 for a metal-ligand bind with ionic character and less than 2.3 for a covalent character [49]. The g || value for the [VOL 1 L 2 ]SO 4 complex was 1.99, suggesting a covalent character of the ligand-metal bond. The α 2 value for the complex was found much smaller than the β 2 value.

XRD, SEM, and TEM results
To observe the X-ray diffraction patterns, phase purity, surface morphologies, and particle shapes of the [VOL 1 L 2 ] SO 4 and [CrL 1 L 2 (Cl) 2 ]Cl complexes, XRD, SEM, and TEM techniques were used. Analyses of the XRD spectra ( Figure 6), SEM micrographs (Figure 7), and TEM micrographs ( Figure 8) of these complexes provided the following observations:

Conclusion
In this work, we sought to synthesize and characterize two mixed ligand complexes containing drug metformin as L 1 and glycine amino acid as L 2 with the metal ions of Cr(III) and VO(II). The interaction via a 1:1:1 (L 1 :L 2 :Metal ion) stoichiometry yielded two complexes: a greenishblue-colored complex formulated as [VOL 1 L 2 ]SO 4 with a square pyramidal geometry and a dark green-colored complex formulated as [CrL 1 L 2 (Cl) 2 ]Cl with an octahedral structure. Spectroscopic results indicated that L 1 ligand coordinated to the VO(II) and Cr(III) ions via the N atoms of the imino (-C]NH) groups, where the L 2 ligand coordinated via the O atom of the carboxylate group (COO) and the N atom of the amino group (NH 2 ). SEM and TEM results indicated that the complexes had organized nanoscale structures with a main diameter of ∼14 nm for the [CrL 1 L 2 (Cl) 2 ]Cl complex and ∼40 nm for the [VOL 1 L 2 ]SO 4 complex.