Platinum-complexes permanently play an important role in the medical treatment of tumor cells. Since Pt has a soft-type Lewis acidic character, it forms the most stable complexes with S, P, N and I donor atoms, resulting planar (cisplatine) or octahedral (satraplatine) arrangement of ligands. In our research, new platinum complexes were synthesized with α-glyoximes, such as [Pt(diethyl-glyoxH)2(amine)2], where glyoxH = mono deprotonated glyoxime, amine = imidazole, 2-amino-pyrimidine or 3-hydroxy-aniline, and with Schiff bases, such as [Pt(3-heptanone)2(en)], [Pt(3-heptanone)2(1,2-pn)], [Pt(3-heptanone)2(1,3-pn)] (en = ethylenediamine, pn = propylenediamine). The Schiff bases were obtained with the condensation reaction between 3-heptanone and the corresponding diamines. The molecular structure of our products has been investigated by IR, UV–VIS and NMR spectroscopy, MS, thermoanalytical measurements (TG-DTG-DTA), and powder XRD. The biological activity study of compounds revealed their possible application in medical point of view since some of them proved to act as antibacterial agents and potential anticancer drugs. On the other hand, some members of the family of complexes can play catalytic role in organic chemistry transformations

Goga, Firuţa

Golban, Ligia Mirabela

Huszthy, Péter

Lang, Laura

Papp, Judit

Pokol, György

Szabó, Pál

Szalay, Roland

Várhelyi, Csaba

Várhelyi, Melinda

Várhelyi Csaba

Szalay Roland

Pokol György

Goga Firuţa

Papp Judit

Szabó Pál

Huszthy Péter

Golban Ligia Mirabela

Várhelyi Melinda

Lang Laura

University of Szeged

 24th International Symposium on Analytical and Environmental Problems 26 SYNTHESIS OF NOVEL Pt COMPLEXES WITH α-GLYOXIMES, SCHIFF BASES, AND THEIR PHYSICAL-CHEMICAL AND BIOLOGICAL STUDY  Csaba Várhelyi jr.1, Roland Szalay2, György Pokol3,5, Firuţa Goga1, Judit Papp4, Pál Szabó5, Péter Huszthy3, Ligia-Mirabela Golban1, Melinda Várhelyi1, Laura Lang1  1 Faculty of Chemistry and Chemical Engineering, “Babeş-Bolyai” University, RO-400 028 Cluj-N., Arany János str. 11, Romania 2 Institute of Chemistry, “Eötvös Loránd” University, H-1117 Budapest, Pázmány Péter str. 1/a, Hungary 3 Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, H-1111 Budapest, Műegyetem rkp. 3, Hungary 4 Faculty of Biology and Geology, “Babeş-Bolyai” University, RO-400 015 Cluj-Napoca, Gheorghe Bilaşcu str. 44, Romania 5 Hungarian Academy of Sciences - Research Centre for Natural Sciences, H-1117 Budapest, Magyar tudósok körútja 2, Hungary e-mail: vcaba@chem.ubbcluj.ro   Abstract Platinum-complexes permanently play an important role in the medical treatment of tumor cells. Since Pt has a soft-type Lewis acidic character, it forms the most stable complexes with S, P, N and I donor atoms, resulting planar (cisplatine) or octahedral (satraplatine) arrangement of ligands. In our research, new platinum complexes were synthesized with α-glyoximes, such as [Pt(diethyl-glyoxH)2(amine)2], where glyoxH = mono deprotonated glyoxime, amine = imidazole, 2-amino-pyrimidine or 3-hydroxy-aniline, and with Schiff bases, such as [Pt(3-heptanone)2(en)], [Pt(3-heptanone)2(1,2-pn)], [Pt(3-heptanone)2(1,3-pn)] (en = ethylenediamine, pn = propylenediamine). The Schiff bases were obtained with the condensation reaction between 3-heptanone and the corresponding diamines. The molecular structure of our products has been investigated by IR, UV–VIS and NMR spectroscopy, MS, thermoanalytical measurements (TG-DTG-DTA), and powder XRD. The biological activity study of compounds revealed their possible application in medical point of view since some of them proved to act as antibacterial agents and potential anticancer drugs. On the other hand, some members of the family of complexes can play catalytic role in organic chemistry transformations.  Introduction After cisplatin was discovered by Barnett Rosenberg due to its anti-tumor effect, and was introduced to the market as drug in 1978, beside the second generation Pt-drugs, as carboplatin, oxaliplatin [1, 2], it became the most important agent in cancer treatment.   During the study of relationships between the activity and the structure of Pt-complexes by Cleare and Hoeschele, they noted that the prerequisite of the metal complex to be an efficient drug is the ability of the platinum center to coordinate a bidentate amine ligand in cis position, or alternatively, two amine components containing minimum one NH group. Furthermore, the complexes must also contain two medium bonded leaving groups (e.g. chloride, sulfate, citrate, oxalate) [3].  The anti-tumor effect of cisplatin can be explained by the platinum coordination to the DNA, which makes a distortion in the helicoidal structure, resulting to the inhibition of  24th International Symposium on Analytical and Environmental Problems 27 replication and transcription of DNA. Finally, this process leads to the cell circuit stop and apoptosis [4].  It is also worth mentioning that Schiff bases are used in many fields, as in paint industry, however, due to their biological activity, they deserve more interest as antibacterial, antiviral, and anti-inflammatory agents. Some derivatives have anti-tumor effect, too.  Experimental Used materials: PtCl4, MeOH, EtOH, HCOOH, 3,4-hexanedione, hydroxylamine-hydrochloride, KOH, 3-heptanone, ethylenedianine, 1,2-propylene-diamine, 1,3-propylene-diamine, imidazole, 2-amino-pyrimidine, 3-hydroxy-aniline. Methods: - Preparation of diethyl-glyoxime In the first step 3,4-hexanedione was reacted with hydroxylamine-hydrochloride dissolved in water. To the hydroxylamine-hydrochloride solution equimolar amount of KOH was added in order to liberate the free amine from its salt. The reaction mixture was heated for 2–3 hours, and then the precipitated product was filtered off. After recrystallization from EtOH or MeOH, it was dried on air. - Synthesis of [Pt(diethyl-glyoxH)2(amine)2] complexes The platinum salt was reduced with formic acid before its use in the complex synthesis: PtCl4 + HCOOH  PtCl2 + CO2 + 2 HCl Diethyl-glyoxime was dissolved in EtOH or MeOH, than added to the aqueous solution of the reduced platinum salt (PtCl2). The mixture was heated for 2–3 hours. After cooling, the formed [Pt(diethyl-glyoxH)2] was filtered, washed with EtOH–water mixture (1:1), and dried on air. For the synthesis of complexes, the reaction mixture of the diethyl-glyoxime and PtCl2 was heated for 1 hour, than the corresponding amine (imidazole, 2-amino-pyrimidine, 3-hydroxy-aniline) was added, and heated further for 2 hours. After cooling the product was filtered, washed with EtOH–water mixture (1:1), and then dried on air. The reactions: KOH,  2 H2O+ 2 H2N-OH·HClCOC CH2OH2C CH3H3CCNC CH2NOHOHH2C CH3H3C + PtCl2 2HClCNCH2CN OOCNC CH2NOHOHPtH2C CH3CH2H3CH3CCH3+ 2 LLLCNCH2CN OOCNC CH2NOHOHPtH2C CH3CH2H3CH3CCH3L:NHNN NNH2NH2OH;, ,   - Synthesis of [Pt(3-heptanone)2(A)] (A = en, 1,2-pn, 1,3-pn) complexes The Schiff bases were prepared by the condensation reaction between 3-heptanone and the corresponding diamine (ethylenediamine, 1,2- and 1,3-propylenediamine) in EtOH solution. The mixture was heated at 70–80 °C for 2–3 hours. The solution obtained was directly used for the complex syntheses by adding the reduced platinum salt (PtCl2) dissolved in water. The product was filtered, washed with EtOH–water mixture (1:1), and then dried on air. For example, the reactions performed for the synthesis of [Pt(3-heptanone)2(en)] are: H2C C CH2 CH2 CH2 CH3OH3CH2C C CH2 CH2 CH2 CH3NH2CH2CNCH2C CH2 CH2 CH2 CH3H3CH3C2NH2H2CH2CNH2 2 H2O  24th International Symposium on Analytical and Environmental Problems 28 H2C C CH2 CH2 CH2 CH3NH2CH2CNCH2C CH2 CH2 CH2 CH3H3CH3CH2C C CH CH2 CH2 CH3NH2CH2CNCH2C CH CH2 CH2 CH3PtH3CH3C 2 HCl+ PtCl2  Results and discussion Microscopic characterization and the yield of prepared complexes are presented in Table 1. Table 1. Microscopic characterization, calculated molecular weight and the yield of prepared complexes. Nr. Compound Calc. mol. weight Yield (%) Microscopic  characterization 1. [Pt(diethyl-glyoxH)2] 481.41 59 Brown, triangle-based prisms 2. [Pt(diethyl-glyoxH)2 (imidazole)2] 617.56 56 Brown, square-based long crystals 3. [Pt(diethyl-glyoxH)2 (2-amino-pyrimidine)2] 671.61 54 Brown, long needles, triangle-based prisms 4. [Pt(diethyl-glyoxH)2 (3-hydroxy-aniline)2] 699.66 42 Black, shining, triangle-based prisms 5. [Pt(3-heptanone)2(en)] 445.50 5 Black, irregular microcrystals 6. [Pt(3-heptanone)2(1,2-pn)] 459.53 18 Black, triangle-based crystals 7. [Pt(3-heptanone)2(1,3-pn)] 459.53 13 Black, irregular microcrystals Infrared spectroscopic study The mid-IR spectra were recorded with a Bruker Alpha FTIR spectrometer (Platinum single reflection diamond ATR), at room temperature, in the wavenumber range of 4000–400 cm−1, and the far-IR range of 650–150 cm−1, respectively, on a Perkin–Elmer System 2000 FTIR spectrometer, operating with a resolution of 4 cm−1. The samples were measured in solid state (in powder form), respectively, in polyethylene pellets. The most important IR values for the selected complexes are presented in Table 2.  Table 2. IR data of the selected complexes.        Comp. cm-1 [Pt(diEt-glyoxH)2] [Pt(diEt-glyoxH)2 (imidazole)2] [Pt(diEt-glyoxH)2 (2-am.-pyrimid.)2] [Pt(diEt-glyoxH)2 (3-HO-aniline)2] ʋC-H 2975, 2938, 2876 m 2975, 2938, 2876 m 2975, 2937, 2875 m 2974, 2937, 2876 w ʋC=N 1535 s 1532 vs 1535 s 1534 s CH2 1459 s 1447 s 1459 s 1448 s CH3 1360 m 1360 s 1359 m 1358 w ʋN-O 1241 vs 1242 vs 1241 vs 1240 vs ʋN-OH 1107 s 1110 s 1106 s 1106 s τO-H 916 vs 918 vs 916 vs 915 vs C-H 712 s 715 s 712 s 710 s ʋPt-N 518 s 515, 512, 509 s 518, 515 s 516, 513, 501 s N-Pt-N 358 vs 356 vs 328 vs 324 vs (Abbreviations: vs = very strong, s = strong, m = medium, w = weak) Mass spectrometry Mass spectra of the samples were recorded by an Agilent/Technologies 6320 Mass Spectrometer using electrospray ionization (ESI). The samples were dissolved in MeOH. In the spectra we could detect the molecular ions and some decomposition fragments. Thermoanalytical measurements (TG-DTG-DTA) Thermal measurements were performed with a 951 TG and 910 DSC calorimeter (DuPont Instruments), in Ar or N2 at a heating rate of 10 Kmin  (sample mass 4–10 mg).  In the case of [Pt(diethyl-glyoxH)2(amine)2] complexes the first decomposition steps are belonging to the leaving amine groups up to 300 °C. Subsequently the decomposition of  24th International Symposium on Analytical and Environmental Problems 29 glyoxime groups begins, which is accompanied by a big exothermic peak. This behavior can be explained with the presence of oxygen in the molecule as shown, for example, in Figure 1. The general decomposition mechanism is the following: [Pt(diethyl-glyoxH)2(amine)2]  [Pt(diethyl-glyoxH)2(amine)]  [Pt(diethyl-glyoxH)2]   [Pt(diethyl-glyoxH)]  PtO  Figure 1. Thermal decomposition of [Pt(diethyl-glyoxH)2(imidazole)2]  NMR spectroscopic study The NMR spectra (1H and 13C NMR) were recorded in DMSO-d6 in 5mm tubes at RT on a Bruker DRX 500 spectrometer at 500 MHz, using TMS as internal reference. In the 1H NMR spectra the aliphatic protons appear at 1.1–2.8 ppm in all complexes, the aromatic protons appear between 7.7–8.3 ppm. In the 13C NMR spectra the aliphatic carbons appear at 10–20 ppm, and the double bonded carbons appear at 158 ppm. Powder X-ray diffraction measurements Powder XRD measurements were carried out on PANalytical X’pert Pro MPD X-ray diffractometer. The crystal structure of the complexes was studied with this method. As being new compounds their diffractograms are not deposited in the Cambridge database. UV–VIS spectroscopy The electronic spectra were recorded with Jasco V-670 Spectrophotometer in 10% EtOH/water solutions containing substrate in 10–4 mol/l concentration. For a few complexes the characteristic wavelengths are the followings: [Pt(diethyl-glyoxH)2] – 271 nm, 320 nm, 470 nm; [Pt(diethyl-glyoxH)2(2-amino-pyrimidine)2] – 198 nm, 286 nm. Using Britton-Robinson buffer solutions the electronic spectra were also recorded as a function of pH, and then the acidity constants were calculated with the formula below: Ka = 10-pKa, pKa = pH + lgAAAAminmax , where A is the absorbance. The obtained values are listed in Table 3.  24th International Symposium on Analytical and Environmental Problems 30  Table 3. The acidity constants for selected complexes. Compound  pH A Amax Amin pKa Ka [Pt(diethyl-glyoxH)2] 448 10.48 0.020123 0.0282773 0.0143296 10.63068 2.34·10-11 323 10.48 0.108823 0.112591 0.0803457 9.604606 2.49·10-10 273 9.71 0.31477 0.339324 0.285667 9.638467 2.3·10-10 [Pt(diEt-glyoxH)2 (2-am.-pyrimid.)2] 268 10.48 0.458324 0.475482 0.290584 9.48983 3.24·10-10 195 11.31 2.51446 2.63318 2.31618 11.08724 8.18·10-12  Biological study The antimicrobial effects of complexes were studied for Gram-negative and Gram-positive (especially B. Subtilis) germs. The observation was made with the disk method. Filtering paper disks were impregnated with a concentrate probe solution, and sterilized (with UV-radiation or in autoclave), then putted on the germ substrate. After a 24 hour-incubation we investigated whether the studied compound blocked the growth of the germ substrate. When there was no growth of germ substrate around the disks, the case was called as inhibition zone. The Gram staining [5] is an empirical solution for dividing the germs into two parts (Gram-negative and Gram-positive) in accordance with the physical and chemical properties of the cell-wall. The results are included in Table 4. The complexes were dissolved in DMSO in 2 mmol/l concentration.  The results are included in table 4. The complexes were solved in DMSO, and the concentration was 2 mmol/l.  Table 4. The inhibition zone dimension as a function of the quantity of complexes. Compound 5 μl 10 μl 20 μl 30 μl [Pt(diethyl-glyoxH)2(imidazole)2] - 9 mm 12,7 mm 16,33 mm [Pt(diethyl-glyoxH)2(3-hydroxy-aniline)2] - 7,83 mm 13,66 mm 14,66 mm  Conclusion In this work new platinum complexes were synthesized and their physico-chemical properties were studied. Decomposition mechanism was determined with the thermoanalytical method. The antibacterial effect of compounds was investigated, and in the future we propose to study their anti-tumor effect, too.  Acknowledgement The authors wish to express their thankfulness to the “Domus Hungarica Foundation” of Hungary for the several fellowships provided to Csaba Várhelyi jr.  References [1]  T. Lazarević, A. Rilak, European Journal of Medicinal Chemistry 142 (2017) 1 [2]  N.J. Wheate, S. Walker, Dalton Transactions 39 (2010) 8097 [3]  M.J. Cleare, J.D. Hoeschele, Bioinorganic Chemistry 2 (1973) 187 [4]  P. Ruiz-Sanchez, J. Biol. Inorg. Chem. 16 (2011) 33 [5]  T.J. Beveridge, Biotech. Histochem. 76(3) (2001) 111    

Synthesis of novel Pt complexes with α-glyoximes, schiff bases and their physical-chemical and biological study

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Synthesis of novel Pt complexes with α-glyoximes, schiff bases and their physical-chemical and biological study

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