Synthesis and in vitro antitumoral activity of novel O,O′-di-2-alkyl-(S,S)-ethylenediamine-N,N′-di-2-propanoate ligands and corresponding platinum(II/IV) complexes (original) (raw)
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European Journal of Medicinal Chemistry, 2011
Platinum(II) complexes (1e4) with bidentate N,N 0 -ligands, O,O 0 -dialkyl esters (alkyl ¼ ethyl, n-propyl, nbutyl and n-pentyl), of (S,S)-ethylenediamine-N,N 0 -di-2-(4-methyl)pentanoic acid were synthesized and characterized by IR, 1 H NMR and 13 C NMR spectroscopy and elemental analysis. DFT calculations were performed for the complexes and it was found that only one diastereoisomer could be formed. Cytotoxic activity of complexes 1e4 was determined against chronic lymphocytic leukemia cells (CLL) and compared to the activity of ligand precursors L1$2HCleL4$2HCl and corresponding palladium(II) complexes, [PdCl 2 L] (L ¼ L1eL4). The complexes were found to exhibit significantly higher antitumor activities than cisplatin on CLL cells. Cytotoxic effect of platinum(II) complexes on CLL cells was higher compared to corresponding palladium(II) complexes. In addition the mode of cell death induced by platinum(II) complexes was determined.
Chemical biology & drug design, 2017
This study presents the synthesis, characterization, and antitumor action of five new Pt(II) halogenido, chlorido, and iodido complexes with edda type of ligands. (S,S)-Ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid dihydrochloride and its methyl, ethyl, and n-propyl esters were prepared according to the previously reported procedure. All investigated complexes were characterized by IR, ESI-MS ((1) H, (13) C, and HMBC) NMR spectroscopy, and elemental analysis. Their cytotoxic action was investigated in four human tumor cell lines: promyelocytic (HL-60) and lymphocytic (REH) leukemia, glioma (U251), and lung carcinoma (H460). Cell viability was assessed by acid phosphatase and LDH assay, while oxidative stress and cell death parameters were analyzed by flow cytometry. The results showed that novel Pt(II) complexes exhibited antitumor action superior to precursor ligands, with iodido complexes being more efficient than corresponding chlorido complexes. Human promyelocytic ...
Archiv der Pharmazie, 2002
Enantiomerically pure 1,2-diamino-1-(4-fluorophenyl)propanes were synthesized by stereospecific and stereoselective procedures by use of the (1R,2S)-and (1S,2R)-2-amino-1-(4-fluorophenyl)propanols (12 a) as intermediates. The enantiomeric purity was determined by 1 H NMR spectroscopy after conversion of the propanolamines and the diamines with (1R)-myrtenal into mono-and diimines. For the coordination to platinum the diamines were reacted with K 2 PtCl 4. The resulting dichloroplatinum(II) complexes 4F-Ph/Me-PtCl 2 were tested for antiproliferative activity on the MCF-7 breast cancer cell line. (SS)-and (RR)-4F-Ph/Me-PtCl 2 produced the strongest inhibitory effect. Both complexes showed cytocidal effects, (SS)-4F-Ph/Me-PtCl 2 even in a concentration of 1 µM. The (1S,2R)-and (1R,2S)configurated complexes were far less active (SS > RR > RS = SR) and comparable in this respect with the standard cisplatin.
Dual Antitumor and Antiangiogenic Activity of Organoplatinum(II) Complexes
Journal of Medicinal Chemistry, 2015
A library of over 20 cycloplatinated compounds of the type [Pt(dmba-R)LCl] (dmba-R = C,N-dimethylbenzylamine-like ligand; R being MeO, Me, H, Br, F, CF 3 , and NO 2 substituents in the R 5 or R 4 position of the phenyl ring; L = DMSO and P(C 6 H 4 CF 3 -p) 3 ) has been prepared. All compounds are active in both human ovarian carcinoma A2780 cells and cisplatin-resistant A2780cisR cells, with most of the DMSO platinum complexes exhibiting IC 50 values in the submicromolar range in the A2780 cell line. Interestingly, DMSO platinum complexes show low cytotoxicity in the nontumorigenic kidney cell line BGM and therefore high selectivity factors SF. In addition, some of the DMSO platinum complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926. These are the first platinum(II) complexes reported to inhibit angiogenesis at a close concentration to their IC 50 in A2780 cells, turning them into dual cytotoxic and antiangiogenic compounds.
Antitumor activity of isomeric 1,2-diaminocyclohexane platinum(IV) complexes
Journal of Cancer Research and Clinical Oncology, 1994
Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. DACH can exist as the trans-1R,2R, trans-lS,2S or cis isomer, and we have examined whether specific isomers coordinated to a platinum(IV) center can modulate antitumor activities in murine tumor models in vivo. Ten isomeric series of DACH-Pt([V) complexes were synthesized, each series containing a different combination of axial and equatorial ligands and varying only by the isomeric form of the DACH ligand. Among the ten series, seven clearly indicated superiority of the (R,R)-DACH-Pt(IV) complex against leukemia L1210/0 cells, while in three the R,R and S,S configurations gave similar efficacies which were better than that of the corresponding cis analog. In three out of the ten series, the antitumor activities of the S,S and cis complexes were similar, in six the cis analogs were the least effective, and in the remaining one the cis analog was superior to &S. One series of complexes with axial chloro ligands and an equatorial 1,1-cyclobutanedicarboxylato group, which had produced the efficacy ranking R,R>cis>S,S in the L1210/0 model, gave S,S>R,R>cis against cisplatin-resistant L1210/DDP cells, R,R=S,S>cis against B16 melanoma cells, and R,R=S,S=cis against M5076 reticulosarcoma cells. The results demonstrate that profound variation can occur in antitumor activities among isomeric forms of the DACH-Pt(IV) complex. However, the
Synthesis and antitumor activity of 1,2-diaminocyclohexane platinum(IV) complexes
Journal of Inorganic Biochemistry, 1994
The synthesis, characterization, and antitumor activity of a series of platinum(IV) complexes of the type DACH-Pt'"(X),Y (where DACH = truns-dl, or buns-1-1,2-diaminocyclohexane, X = OH or Cl, and Y = oxalato, malonato, methylmalonato, tartronato, ketomalonato, l,l-cyclopropanedicarboxylato, or l,l-cyclobutanedicarbor@ato, are described. These complexes have been characterized by elemental analysis, HPLC, and infrared and '95Pt NMR spectroscopic techniques. The complexes had good in vitro cytotoxic activity (IC,, = 0.14-7.6 pg/ml) and were highly active in vivo against leukemia L1210 cells (%T/C = 152-> 600, cisplatin = 218). In addition, excellent in vivo antitumor activities against B16 melanoma (%T/C = 309), M.5076 reticulosarcoma (100% cures) and cisplatin-resistant Ll%lO/DDP (%T/C = 217) cell lines were also exhibited by an analog selected for further evaluation.
Journal of Inorganic Biochemistry, 2003
Synthesis, characterization, cytotoxic activity and crystal structures of tri-and di-organotin(IV) complexes constructed from the b-{[(E)-1-(2hydroxyaryl)alkylidene]amino}propionate and b-{[(2Z)-(3-hydroxy-1methyl-2-butenylidene)]amino}propionate skeletons Abstract Reactions of potassium b-{[(E)-1-(2-hydroxyaryl)alkylidene]amino}propionates (L 1 HK-L 3 HK) and potassium b-{[(2Z)-(3-hydroxy-1-methyl-2-butenylidene)]amino}propionate (L 4 HK) with R These complexes have been characterized by 1 H, 13 C, 119 Sn NMR, ESI-MS, IR and 119m Sn Mö ssbauer spectroscopic techniques in combination with elemental analyses. The crystal structures of 1, 4, 5 and 6 were determined. In the solid state, compound 1 is a one-dimensional polymer built from SnPh 3 moieties bridged by single carboxylate ligands, but two alternating modes of bridging are present along the polymeric chain. Compound 4 is also a one-dimensional polymer built from SnBu 3 moieties bridged by the two carboxylate O-atoms of a single ligand, but only one mode of bridging is present. Di-n-butyltin compounds 5 and 6 are centrosymmetric tetranuclear bis(dicarboxylatotetrabutyldistannoxane) complexes containing a planar Sn 4 O 2 core in which two l 3 -oxo O-atoms connect an Sn 2 O 2 ring to two exocyclic Sn-atoms. The four carboxylate ligands display two different modes of coordination where both modes involve bridging of two Sn-atoms. The solution structures were predicted by 119 Sn NMR spectroscopy. The in vitro cytotoxic activity of compound 5 against WIDR, M19 MEL, A498, IGROV, H226, MCF7 and EVSA-T human tumor cell lines is reported.