Synthesis, characterization and cytotoxity of Pd(II), Pt(II) and Pt(IV) complexes with R2edda-type esters

U ovom radu su opisane sinteze, karakterizacija i antiproliferativna aktivnost liganada u obliku hidrohloridnih soli, estara etilendiamin-N,N’-di-3-propanske kiseline (H2eddp), (S,S)-etilendiamin-N,N’-di-2-propanske kiseline ((S,S)-H2eddip) i (S,S)-etilendiamin-N,N’-di-2-(4-metil)-pentanske kiseline ((S,S)-H2eddl), kao i odgovarajućih kompleksa sa platinom(IV), platinom(II) i paladijumom(II). Sintetisano je osam novih estara, a to su izopropil i izobutil estri svih navedenih kiselina, a sa (S,S)-H2eddip dobijeni su i ciklopentil i cikloheksil estri. Ova jedinjenja su dobijena refluktovanjem suspenzije kiseline u odgovarajućem apsolutnom alkoholu kome je prethodno ukapan tionil-hlorid. Svi estri su dobijeni u obliku dihidrohlorida: [(S,S)-H2iPr2eddip]Cl2, [(S,S)-H2iBu2eddip]Cl2, [(S,S)-H2cPe2eddip]Cl2, [(S,S)-H2Cy2eddip]Cl2, [H2iPr2eddp]Cl2, [H2iBu2eddp]Cl2, [(S,S)-H2iPr2eddl]Cl2 i [(S,S)-H2iBu2eddl]Cl2. Estri su okarakterisani elementalnom analizom, infracrvenom i NMR spektroskopijom, a [(S,S)-H2iPr2eddip]Cl2, [(S,S)-H2cPe2eddip]Cl2 i [(S,S)-H2iBu2eddl]Cl2 urađena je i rendgenostrukturna analiza. U pokušaju sinteze ciklopentil estra (S,S)-etilendiamin-N,N'-di-2-(3-metil)-butanske kiseline (S,S)-H2eddv, dobijeni su neočekivani monokristali sastava [(S,S)-H4eddv]Br0,17Cl1,83.4C5H9OH. Kompleksi platine(IV) dobijeni su u reakciji natrijum- ili kalijum-heksahloroplatinata(IV) sa navedenim estrima. Sintetisano je pet novih kompleksa platine(IV): [PtCl4{(S,S)-iPr2eddip}], [PtCl4{(S,S)-iBu2eddip}], [PtCl4{(S,S)-cPe2eddip}], [PtCl4(iPr2eddp)] i [PtCl4(iBu2eddp)]. Ovi kompleksi su okarakterisani elementalnom analizom, infracrvenom i NMR spektroskopijom. Kristalna struktura određena je kompleksima [PtCl4{(S,S)-iPr2eddip}] i [PtCl4{(S,S)-cPe2eddip}]. Kompleksi platine(II) dobijeni su u reakciji kalijum-tetrahloroplatinata(II) sa estrima. Sintetisano je tri nova kompleksa platine(II): [PtCl2{(S,S)-iPr2eddip}], [PtCl2{(S,S)-iBu2eddip}] i [PtCl2{(S,S)-cPe2eddip}]. Ovi kompleksi su okarakterisani elementalnom analizom, infracrvenom i NMR spektroskopijom. Sedam novih kompleksa paladijuma(II): [PdCl2{(S,S)-iPr2eddip}], [PdCl{(S,S)-iPreddip}], [PdCl2{(S,S)-iBu2eddip}], [PdCl2{(S,S)-cPe2eddip}], [PdCl2{(S,S)-Cy2eddip}], [PdCl2{(S,S)-iPr2eddl}] i [PdCl2{(S,S)-iBu2eddl}] dobijeno je u reakciji kalijum-tetrahloropaladata(II) sa estrima. Ovi kompleksi su okarakterisani elementalnom analizom, infracrvenom i NMR spektroskopijom...This work describes synthesis, characterization and antiproliferative activity of ligands precursors, esters of ethylenediamine-N,N’-di-3-propanoic acid (H2eddp), (S,S)-ethylenediamine-N,N’-di-2-propanoic acid ((S,S)-H2eddip) and (S,S)-ethylenediamine-N,N’-di-2-(4-methyl)-pentanoic acid ((S,S)-H2eddl), as well as their complexes with platinum(IV), platinum(II) and palladium(II). Eight novel esters are synthesized, isopropyl and isobutyl esters of the mentioned acids, and cyclopentyl and cyclohexyl esters of (S,S)-H2eddip. Thionyl-chloride was intoduced into a flask containing absolute alcohol. The corresponding acid is added forming a suspension which was reflucted. All of the esters were obtained as dihydrochlorides: [(S,S)-H2iPr2eddip]Cl2, [(S,S)-H2iBu2eddip]Cl2, [(S,S)-H2cPe2eddip]Cl2, [(S,S)-H2Cy2eddip]Cl2, [H2iPr2eddp]Cl2, [H2iBu2eddp]Cl2, [(S,S)-H2iPr2eddl]Cl2, [(S,S)-H2iBu2eddl]Cl2. Esters were characterized by elemental analysis, IR and NMR spectroscopy. Crystal structures of [(S,S)-H2iPr2eddip]Cl2, [(S,S)-H2cPe2eddip]Cl2 and [(S,S)-H2iBu2eddl]Cl2 are solved by X-ray analyses. While trying to synthesize the cyclopentyl ester of (S,S)-ethylenediamine-N,N'-di-2-(3-methyl)-butanoic acid (S,S)-H2eddv, unexpected crystals suitable for X-ray analysis were obtained and determined - [(S,S)-H4eddv]Br0.17Cl1.83.4C5H9OH. Complexes of platinum(IV) are synthesized in a reaction of potassium-hexachloroplatinate(IV) with esters. Five novel platinum(IV) complexes are obtained: [PtCl4{(S,S)-iPr2eddip}], [PtCl4{(S,S)-iBu2eddip}], [PtCl4{(S,S)-cPe2eddip}], [PtCl4(iPr2eddp)] and [PtCl4(iBu2eddip)]. These complexes are characterized by elemental analysis, IR and NMR spectroscopy..

(S,S)-N,N '-Bis(1-carboxy-2-methylpropyl)ethylenediammonium dihalide cyclopentanol tetrasolvate (halide = bromide/chloride similar or equal to 1:12)

In the crystal structure of the title compound, C(12)H(26)N(2)O(4)(2+)center dot-2(Br(0.085)Cl(0.915))(-)center dot 4C(5)H(9)OH, the complete cation is generated by crystallographic twofold symmetry. Contamination of the chloride counter-anion with bromide occured during the preparation, due to the use of 1,2-dibromoethane. One of the solvent molecules is disordered, with occupancies 0.53 (3): 0.47 (3). The crystal packing is stabilized by an infinite two dimensional center dot center dot center dot X center dot center dot center dot H-N-H center dot center dot center dot X center dot center dot center dot hydrogen-bonding network (X: Br(-)/Cl(-) similar or equal to 1:12). In addition, O-H center dot center dot center dot X and O-H center dot center dot center dot O hydrogen bonds involving solvent molecules are observed

Kompleksi paladijuma(II) sa ligandima R2edda tipa, deo III - diizobutil-(s,s)-2,2'-(1,2,-etandiildiimino)-di(4-metilpentanoat)-dihidrohlorid i njegov kompleks sa paladijumom(II) - sinteza i karakterizacija

A new R(2)edda-type ester, diisobutyl (SS)-2,2'-(1,2-ethane-diyldiimino)di(4-methylpentanoate) dihydrochloride, [(S,S)-H(2)iBu(2)eddl]Cl-2, 1, and its palladium(II) complex, dichloro(diisobutyl (SS)-2,2'-(1,2-ethanediyldiimino)di(4-methylpentanoate))palladium(II), [PdCl2{(S,S)-iBu(2)eddl}], 2, were synthesized and characterized by elemental analysis, as well as IR and NMR spectroscopy. It was found that complex 2 was obtained as mixture of two diastereoisomers, observed in NMR spectra. The crystal structure of compound I was determined by X-ray diffraction studies and is described. The isolated crystals consisted of one dicationic species [(SS)-H(2)iBu(2)eddl](2+) and two Cl-. The crystal system was tetragonal with the space group P4(2). Hydrogen bonds significant for the manner of packing are N-H1N center dot center dot center dot Cl, 3.049(3) angstrom, 159(3)degrees and N-H2N center dot center dot center dot Cl, 3.100(3) angstrom, 164(3)degrees. An infinite chain was formed building a one layer structure, usual for these types of compounds. The C-2 symmetry axis of the compound passes through the Cl-Cl-i bond vector and lies perpendicular to the plane N2Cl2.Novi estar R2edda-tipa diizobutil-(S,S)-2,2'-(1,2-etandiildiimino)-di(4-metilpen-tanoat)-dihidrohlorid [(S,S)-H2iBu2eddl]Cl2,1, i njegov kompleks paladijuma(II), dihlorodiizobutil-(S,S)-2,2'-(1,2-etandiildiimino)-di(4-metilpentanoat)-paladijum(II) [PdCl2{(S,S)-iBu2eddl}], 2, sintetisani su i okarakterisani uz pomoć elementalne analize, IR i NMR spektroskopije. Nađeno je da je kompleks 2 dobijen kao smeša dva dijastereoizomera, što je primećeno u NMR spektrima. Kristalna struktura 1 je rešena i opisana. Izolovani kristali se sastoje iz jedne dikatjonske vrste [(S,S)-H2iBu2eddl]2+ i dva Cl-. Kristalni sistem je tetragonalan sa prostornim grupom P42. Značajne vodonične veze za način pakovanja su N-H1N•••Cl, 3,049(3) Å, 159(3)°i N-H2N...Cl, 3,100(3) Å, 164(3)°. Time se formira beskonačan lanac i jednoslojna struktura, koji su uobičajeni za ove tipove struktura. Osa simetrije C2 jedinjenja prolazi kroz C1-C1i vektor veze i leži normalno na N2Cl2 ravan. PR Projekat Ministarstva nauke Republike Srbije, br. 142010

Supplementary data for article: Pantelic, N.; Stanojkovic, T. P.; Zmejkovski, B. B.; Sabo, T. J.; Kaluerovic, G. N. In Vitro Anticancer Activity of Gold(III) Complexes with Some Esters of (S, S)-Ethylenediamine-N, N G2-Di-2-Propanoic Acid. European Journal of Medicinal Chemistry 2015, 90, 766–774. https://doi.org/10.1016/j.ejmech.2014.12.019

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2014.12.019]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1651

Design and In Vitro Biological Evaluation of a Novel Organotin(IV) Complex with 1-(4-Carboxyphenyl)-3-ethyl-3-methylpyrrolidine-2,5-dione

A novel triphenyltin(IV) compound with 1-(4-carboxyphenyl)-3-ethyl-3-methylpyrrolidine-2,5-dione was synthesized and characterized by IR, NMR spectroscopy, mass spectrometry, and elemental analysis. In vitro anticancer activity of ligand precursor and synthesized organotin(IV) compound was determined against tumor cell lines: human adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human breast cancer (MDA-MB-453), using microculture tetrazolium test (MTT) assay. The results indicate that complex exhibited very high antiproliferative activity against all tested cell lines with IC50 values in the range of 0.22 to 0.53 mu M. The highest activity organotin(IV) compound expressed against the HeLa cells (IC50=0.22 +/- 0.04 mu M). The ligand precursor did not show anticancer activity (IC50>200 mu M). Furthermore, fluorescence microscopy analysis of HeLa cells reveal that organotin(IV) complex induced apoptosis as a mode of cell death, which is consistent with the increase of cells in the sub-G1 phase

Supplementary data for article: Pantelic, N.; Stanojkovic, T. P.; Zmejkovski, B. B.; Sabo, T. J.; Kaluerovic, G. N. In Vitro Anticancer Activity of Gold(III) Complexes with Some Esters of (S, S)-Ethylenediamine-N, N G2-Di-2-Propanoic Acid. European Journal of Medicinal Chemistry 2015, 90, 766–774. https://doi.org/10.1016/j.ejmech.2014.12.019

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2014.12.019]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1651

(18-Crown-6)potassium(I) Trichlorido[28-acetyl-3-(tris-(hydroxylmethyl)amino-ethane)betulinic ester-κN]platinum(II): Synthesis and In Vitro Antitumor Activity

Synthesis of platinum(II) conjugate with acetylated betulinic acid tris(hydroxymethyl)aminomethane ester (BATRIS) is presented (BATRISPt). HR-ESI-MS and multinuclear NMR spectroscopy, as well as elemental analysis were used for characterization of BATRISPt. Cytotoxicity (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet (CV), and sulforhodamine B (SRB) assays) of BA, BATRIS, BATRISPt, and cisplatin were assessed on seven different tumor cell lines: melanoma B16, colon HCT116 and DLD-1, adenocarcinoma HeLa, breast MCF-7, and anaplastic thyroid tumor 8505C and SW1736; as well as normal MRC-5 fibroblasts. Furthermore, the effect of the mentioned compounds on the apoptosis (Annexin V/PI assay) and autophagy induction (acridine orange (AO) assay) as well as caspase 3, 8, and 9 activation were investigated on the selected B16 melanoma cell line. BATRISPt showed lower activity than BA, BATRIS, or cisplatin. All tested compounds triggered apoptosis in B16 cells. Induction of autophagy was observed in B16 cells exposed only to BATRIS. On the other hand, new conjugate activates caspases 8 and 9 in B16 cells with higher impact than BATRIS or cisplatin alone

Supplementary data for article: Pantelić, N. Đ.; Zmejkovski, B. B.; Trifunović-Macedoljan, J.; Savić, A.; Stanković, D.; Damjanović, A.; Juranic, Z.; Kaluđerović, G. N.; Sabo, T. Gold(III) Complexes with Esters of Cyclohexyl-Functionalized Ethylenediamine-N,N ’-Diacetate. Journal of Inorganic Biochemistry 2013, 128, 146–153. https://doi.org/10.1016/j.jinorgbio.2013.08.002

Supplementary material for: [https://doi.org/10.1016/j.jinorgbio.2013.08.002]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1422

Supplementary data for article: Pantelić, N.; Zmejkovski, B. B.; Kolundžija, B.; Crnogorac, M. Đ.; Vujić, J. M.; Dojčinović, B.; Trifunović, S. R.; Stanojković, T. P.; Sabo, T. J.; Kaluđerović, G. N. In Vitro Antitumor Activity, Metal Uptake and Reactivity with Ascorbic Acid and BSA of Some Gold(III) Complexes with N,N′-Ethylenediamine Bidentate Ester Ligands. Journal of Inorganic Biochemistry 2017, 172, 55–66. https://doi.org/10.1016/j.jinorgbio.2017.04.001

Supplementary material for: [https://doi.org/10.1016/j.jinorgbio.2017.04.001]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2478]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3070

Synthesis, Characterization, and Cytotoxicity of a Novel Gold(III) Complex with O,O-Diethyl Ester of Ethylenediamine-N,N-Di-2-(4-Methyl)Pentanoic Acid

A novel gold(III) complex, [AuCl2{(S,S)-Et(2)eddl}]PF6, ((S,S)-Et(2)eddl = O,O-diethyl ester of ethylenediamine-N,N-di-2-(4-methyl)pentanoic acid) was synthesized and characterized by IR, 1D (H-1 and C-13), and 2D (H,H-COSY and H,H-NOESY) NMR spectroscopy, mass spectrometry, and elemental analysis. Density functional theory calculations confirmed that (R,R)-N,N diastereoisomer was energetically the most stable isomer. In vitro antitumor action of ligand precursor [(S,S)-H(2)Et(2)eddl]Cl-2 and corresponding gold(III) complex was determined against tumor cell lines: human adenocarcinoma (HeLa), human colon carcinoma (LS174), human breast cancer (MCF7), non-small cell lung carcinoma cell line (A549), and non-cancerous cell line human embryonic lung fibroblast (MRC-5) using microculture tetrazolium test (MTT) assay. The results indicate that both ligand precursor and gold(III) complex have showed very good to moderate cytotoxic activity against all tested malignant cell lines. The highest activity was expressed by [AuCl2{(S,S)-Et(2)eddl}]PF6 against the LS174 cells, with IC50 value of 7.4 +/- 1.2 mu M