Joanna Wiśniewska

Acetate platinum(II) compound with 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine that overcomes cisplatin resistance: structural characterization, in vitro cytotoxicity, and kinetic studies

The reaction of silver acetate with cis-[PtI2(dbtp)2], where dbtp = 5,7-ditertbutyl-1,2,4-triazolo-[1,5-a]pyrimidine, yielded cis-[Pt(OOCCH3)2(dbtp)2]·dmf (1). The complex has been analyzed by multinuclear magnetic resonance (1H, 13C, 15N), IR, and Raman. The compound formed two rotamers in CDCl3 and its spatial structures have been optimized using computational calculation. It was found that head-to-tail rotamer (1a) is more stable than its head-to-head counterpart (1b). In vitro antiproliferative activity against four tumor cell lines (A549, T47D, FaDu, and A2780cis) revealed in all cases significant cytotoxicity (IC50 = 0.26–1.80 μM), possessing IC50 values at least fivefold lower than cisplatin, carboplatin, and oxaliplatin (except A2780cis). The remarkable in vitro activity against T47D and A2780cis suggested the ability to overcome cisplatin resistance in these types of tumor cells. In addition, in vitro toxicity was evaluated against BALB/3T3 and has shown that the lipophilic platinum(II) complex (1) inhibits cell proliferation weaker than cisplatin and oxaliplatin. Additionally, cis-[Pt(OOCCH3)2(dbtp)2]·dmf exhibited selective activity, in contrast to cisplatin or oxaliplatin. Graphical abstract

Rational design of dicarboxylato platinum(II) complexes with purine-mimetic ligands as novel anticancer agents

Six novel platinum(II) complexes containing purine-mimetic ligands (5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp), 7-isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp)) and dicarboxylato ligands (glutarato (glut) or cyclobutane-1,1-dicarboxylato (CBDC)) have been prepared and characterized with multinuclear magnetic resonance (1H, 13C, 15N, 195Pt) NMR, infrared (IR) and X-ray crystallography. Spectroscopic data in solid state and in solution unambiguously confirm the square-planar geometry of Pt(II) with two monodentate N3-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine ligands and one O-chelating dicarboxylato ligand. Next, the effect of all the platinum(II) compounds on the viability of normal or cancer cells and their putative mechanisms of action have been investigated. Of the studied platinum(II) complexes, two ([Pt(glut)(dbtp)2] and [Pt(CBDC)(dbtp)2]) overcame the cisplatin resistance in human ovarian tumor cells (A2780cis or OVCAR-3) and arrested the cell cycle at S phase in mice mammary gland cancer cells (4T1), which indicates a mechanism of action different from that of cisplatin. Interestingly, preliminary in vivo toxicity assays revealed that both compounds tested in mice ([Pt(glut)(dbtp)2] 3 and [Pt(CBDC)(dbtp)2] 6) were less toxic in vivo than cisplatin or oxaliplatin. Additionally, compound 6 did not cause myelosuppression and showed over fivefold less accumulation in the liver than its glutarato analog 3.

Kinetics and mechanism of aquation of [Cr(NCS)(edtrp)]-, [Cr(NCS)(R-pdtrp)]-, [Cr(edtrp)(NCSHg)]+ and [Cr(R-pdtrp) (NCSHg)]+ complexes. Unexpected rate retardation in strongly acidic media for NCS- ligand release

Three new complex ions, [Cr(NCS)(R-pdtrp)]-, [Cr(R-pdtrp)(NCSHg)]+ and [Cr(edtrp)(NCSHg)]+, that are derivatives of the trans-equatorial isomers of [Cr(R-pdtrp)(H2O)]0 and [Cr(edtrp)(H2O)]0 (edtrp= ethylenediamine-N,N,N′-tripropionate, R-pdtrp= R-propane-1,2-diamine-N,N,N′-tripropionate) have been obtained and characterized in solution. Rate constants and activation parameters, including, in two cases, volumes of activation, have been determined. Rate retardation for NCS- ligand release has been observed with increasing acidity within the pH 0–2 range. The mechanism of the reactions has been discussed.

Strategies for overcoming tropical disease by ruthenium complexes with purine analog: Application against Leishmania spp. and Trypanosoma cruzi

Tropical diseases currently constitute a major health problem and thus a challenge in the field of drug discovery. The current treatments show serious disadvantages due to cost, toxicity, long therapy duration and resistance, and the use of metal complexes as chemotherapeutic agents against these ailments appears to be a very attractive alternative. Herein, we describe three newly synthesized ruthenium complexes with a bioactive molecule, the purine analogue 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp): cis,fac-[RuCl2(dmso)3(tmtp)] (1), mer-[RuCl3(dmso)(H2O)(tmtp)]·2H2O (2) and fac,cis-[RuCl3(H2O)(tmtp)2] (3). Their structures were characterized using X-ray and spectroscopic methods (IR, NMR or EPR). The stability of the synthesized complexes 1-3 in various buffered solutions (pH=3-7.4) was monitored using conventional and stopped-flow techniques. The in vitro antiproliferative activity of all ruthenium complexes against promastigote forms of Leishmania spp. (L. infantum, L. braziliensis, and L. donovani) and epimastigote forms of Trypanosoma cruzi was investigated. Notably, the results showed that the activity of 1 against L. brasiliensis was more than three-fold higher than that of glucantime, and 1 showed no appreciable toxicity towards J774.2 macrophages. Additionally, 2 displayed even 141-fold lower toxicity against host cells than glucantime, demonstrating significantly higher selectivity than the reference drug. Therefore, 1 and 2 appear to be excellent candidates for further development as potential drugs for the effective treatment of leishmaniasis and Chagas disease. All novel complexes were also shown to be potent inhibitors of Fe-SOD in the studied species, while their effects on human CuZn-SOD were very low.

The oxidative degradation and C–C coupling reaction of dibenzoazepine derivatives by peroxydisulfate ion and sulfate radical in aqueous media

The kinetics of the oxidation of imipramine and opipramol using peroxydisulfate salts in the presence of a large excess of dibenzoazepine derivative (TCA) in acidic sulfate media was studied using UV–vis spectroscopy. The reaction between imipramine and S2O82− proceeds via the formation of two intermediates: a free organic radical and a dimeric dication. Further reaction of the intermediate dimeric dication leads to a positively charged radical dimer as one final product. Simultaneously, two other substituent cleavage degradation processes occur, leading to two dimeric derivatives. The first product, the positively charged radical dimer, and the next main product, a radical dimer without one alkyl substituent, were identified by EPR measurements. The measured kinetic trace is not first order and revealed a sigmoid shape with a characteristic induction time. The rate constants were determined by numerical analysis based on ordinary differential equations (ODEs). The reaction between opipramol and S2O82− proceeds by a two consecutive reaction scheme. The kinetics of the first degradation step were studied independently of the slower degradation reactions. Linear dependences, with zero intercept, of the pseudo-first-order rate constants (kobs) on [TCA] were determined for the first degradation process of opipramol.

Mechanism of the oxidative degradation of dibenzoazepine derivatives via manganese(III) complexes in acidic phosphate media

The oxidative degradation of tricyclic antidepressants (TCA) was studied in the presence of a large excess of the oxidizing agents, manganese(III)-pyrophosphate (P2O74−), phosphate (PO43–), in acidic media. The products were detected and identified using UV–Vis, ESI–MS and IR methods. The reaction between dibenz[b,f]azepines and manganese(III) ions proceeded via two consecutive reactions: first, acridine analogues were formed, and then a dealkylation process resulted in the formation of unsubstituted acridine. The kinetics of the first degradation step of the TCAs was investigated independently of the slower dealkylation step. The pseudo-first order rate constants (kobs) were determined for the first degradation process. The reaction between 10,11-dihydro-5H-dibenz[b,f]azepines and the manganese(III) ion resulted in oxidative dehydrogenation, which proceeded via the formation of two intermediates: a free organic radical and a dimeric dication. Further oxidation of the second intermediate led to a positively charged radical dimer as a single final product. Simultaneously, two other substituent cleavage degradation processes occurred, which led to two dimeric derivatives. The kinetic traces were determined to be zeroth order.

Kinetics and mechanism of the base hydrolysis of cis-eq-[Cr(NCS)(S-pdtra)]−, trans-eq-[Cr(NCS)(edtrp)]− and trans-eq-[Cr(NCS)(R-pdtrp)]− complexes. Strong rate enhancement for NCS− ligand release with an increase of [OH−] only for the trans-equatorial isomers

The [Cr(NCS)(edtrp)]−, [Cr(NCS)(R-pdtrp)]− and [Cr(NCS)(S-pdtra)]− complexes, that are derivatives of the trans-equatorial isomers of [Cr(edtrp)(H2O)]° and [Cr(R-pdtrp)(H2O)]° and the cis-equatorial isomer of [Cr(S-pdtra)-(H2O)]° (edtrp = ethylenediamine-N,N,N′-tripropionate, R-pdtrp = R-propane-1,2-diamine-N,N,N′-tripropionate, S-pdtra = S-propane-1,2-diamine-N,N,N′-triacetate) undergo aquation in alkaline media with a strong dependence of the rate on [OH−] for the trans-equatorial isomers and a very weak dependence for the cis-equatorial isomer. The thiocyanate ligand release follows a stereoretentive course for all reactants. Based on kinetic data the reaction mechanism has been discussed. Rate differences between the isomers are interpreted in terms of an interchange via a conjugate base (I c.b.) mechanism, assuming an equilibrium between the cis-equatorial-CrIII-S-pdtra complexes with penta- and tetradentate coordination of the edta-like ligand.

Dicarboxylato platinum(II) complexes containing dimethyl sulfoxide and triazolopyrimidine as potential anticancer agents: synthesis, structural and biological studies in solution

Four dicarboxylato platinum(II) complexes of the general formula [Pt(R(COO)2)(dmso)(N-donor)], where: R(COO)2 – cyclobutane-1,1-dicarboxylato or malonato, dmso – dimethyl sulfoxide and N-donor – 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) or 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp), have been synthesized and structurally characterized using multinuclear magnetic resonance (1H, 13C, 15N, and 195Pt) techniques. The NMR parameters unambiguously confirmed the square-planar geometry of Pt(II) in solution with monodentate N(3)-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine, monodentate and S-bonded dimethyl sulfoxide and O,O-chelating dicarboxylate ions. The obtained platinum(II) complexes exhibit (i) higher susceptibility to hydrolysis and (ii) lower toxicity and affinity to glutathione in comparison with cisplatin and carboplatin. Additionally, it is noted that two lipophilic platinum(II) complexes: (3) [Pt(mal)(dmso)(dptp)] and (4) [Pt(CBDC)(dmso)(dptp)] display the most gratifying in vitro antiproliferative activity. Above and beyond, these promising coordination compounds exhibit definitely lower toxicity towards normal cells and anticancer activity comparable to that of cisplatin.