Analysis of two cycloplatinated compounds derived from N-(4-methoxyphenyl)-.alpha.-benzoylbenzylidenamine. Comparison of the activity of these compounds with other isostructural cyclopalladated compounds

Navarro‐Ranninger, Carmen; López‐Solera, Isabel; Jm, Pérez de la Cruz; Rodríguez, Judit; Jl, García-Ruano; Raithby, Paul R.; Masaguer,; Alonso, Carlos

doi:10.1021/jm00076a006

Cited by 94 publications

(54 citation statements)

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“…They are much more stable and less toxic than other derivatives of palladium (II) (18) and were able to inhibit cathepsin B (3). One of these compounds, called complex 7a, showed specific in vitro and in vivo activities against tumor cells, with no significant toxicity in animals, even at high doses (20).…”

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confidence: 99%

In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

Matsuo

Silva

Torrecilhas

et al. 2010

Antimicrob Agents Chemother

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Chagas' disease, a neglected tropical infection, affects about 18 million people, and 100 million are at risk. The only drug available, benznidazole, is effective in the acute form and in the early chronic form, but its efficacy and tolerance are inversely related to the age of the patients. Side effects are frequent in elderly patients. The search for new drugs is thus warranted. In the present study we evaluated the in vitro and in vivo effect of a cyclopalladated compound (7a) against Trypanosoma cruzi, the agent of Chagas' disease. The 7a compound inhibits trypomastigote cell invasion, decreases intracellular amastigote proliferation, and is very effective as a trypanocidal drug in vivo, even at very low dosages. It was 340-fold more cytotoxic to parasites than to mammalian cells and was more effective than benznidazole in all in vitro and in vivo experiments. The 7a cyclopalladate complex exerts an apoptosis-like death in T. cruzi trypomastigote forms and causes mitochondrion disruption seen by electron microscopy.

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confidence: 99%

In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

Matsuo

Silva

Torrecilhas

et al. 2010

Antimicrob Agents Chemother

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“…Based on the results described above, in the present paper, we investigated the interactions of cathepsin B with some palladacycles derived from the reaction of 2-Bromo-3,4,5-trimethoxybenzaldehyde 1 with [Pd 2 (dba) 3 ].dba (Pd(dba) 2 ; dba = dibenzylideneacetone), in the presence of N-donor ligands, such as N,N,N',N'-tetramethyl-ethane-1,2-diamine (TMEDA), (2,2'-bipyridine (bpy), (4,4'-dimethyl-2,2'-bipyridine (dmbpy) and 1,10-phenanthrroline (Phen). We concluded that the antitumor activity of the palladacycles compounds presented here can be attributed, at least in part, to the inhibitory properties of these complexes on the cysteine-protease activity, such as cathepsin B. Palladacycles are one of the most popular classes of organo palladium derivatives, which are widely applied in organic synthesis [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39], organometallic catalysis [40][41][42][43][44], and new molecular materials [24]. Among them, the most investigated cyclic Pd-complexes are five-or six-membered rings fused with an aromatic ring, and the metallated carbon is usually an aromatic sp2 carbon [35][36][37][38][39].…”

Section: Introductionmentioning

confidence: 79%

“…N-, S-,O-, P-, Se-donor) [2][3][4]. Palladacycles are described in the literature as promising antitumor agents [5][6][7][8][9][10][11][12][13][14][15][16], but have yet to make sufficient progress to clinical trials for evaluation as drugs [17].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Palladacycles Inhibitors of the Cathepsin B Activity and Antitumoral Agents

Elgazwy

Shehata²,

Zaki³

et al. 2013

Med chem (Los Angeles)

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The reaction of 2-bromo-3,4,5-trimethoxybenzaldehyde 1 with Pd(dba) 2 ; dba=dibenzylideneacetone) in the presence of a stoichiometric amount of nitrogen donor ligands, such as N,N,N',, 2,2'-bipyridine (bpy) 4,4'-dimethyl-2,2'-bipyridine (dmbpy) and an 1,10-phenanthroline (Phen), should be added to with equimolar ratio in degassed acetone under nitrogen to give mononuclear σ-aryl palladium (II) complexes cis-[2-Pd{C 6 H(CHO)-6-(OMe) 3 -3,4,5}BrL 2 ] 3a-d, where L 2 =TMEDA (3a); L 2 =bpy (3b); L 2 =dmbpy (3c); L 2 =Phen (3d) in good yields 48-65%. The reaction of the synthesized five-membered C,N-palladacycle cis-[2-Pd{C 6 H(CHO)-6-(OMe) 3 -3,4,5} BrL 2 ] 3a-d, where L 2 =TMEDA (3a); L=bpy (3b); L 2 =dmbpy (3c); L 2 =Phen (3d), with an1-naphthylisocyanates (C 10 H 7 -NCO) and an 1-naphthylisothiocyanates (C 10 H 7 -NCS), leads to the formation of novel palladacycle 4a-d and 5a-d, which was characterized in solution by 1 H NMR spectroscopy. The solid products were characterized by satisfactory elemental analysis and spectra studies. All the resulting complexes 3a-d, 4a-d and 5a-d were tested in vitro against a number of cell lines. For example, it inhibited K562 leukaemia cells with an IC 50 value in the range of (3.00 -4.3) µM (1 h exposure) and displayed cathepsin B inhibitory action with an IC 50 value in the range of (0.045-0.055 µM). .

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“…Already the same authors mentioned that the cyclopalladated complexes are "much more stable and less toxic than other derivatives of palladium(II) 53 and were able to inhibit cathepsin B (CpB)". 54 Other authors [55][56][57] reported that cathepsin B and L are involved in the growth of Leishmania and their virulence in vitro and in vivo.…”

Section: Resultsmentioning

confidence: 99%

Antiprotozoal Activity of the Cyclopalladated Complexes AgainstLeishmania amazonensisandTrypanosoma cruzi

Velásquez¹,

Souza²,

Passalacqua³

et al. 2015

Journal of the Brazilian Chemical Society

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The present study describes the antiprotozoal activities of four cyclopalladated compounds, [Pd(dmba)(μ-Cl)] 2 , [Pd(dmba)(NCO)(isn)], [Pd(dmba)(N 3 )(isn)] and [Pd(dmba)(μ-NCO)] 2 , (dmba: N,N'-dimethylbenzylamine and isn: isonicotinamide), against the diseases leishmaniasis (Leishmania amazonensis and Leishmania infantum), Chagas disease (Trypanosoma cruzi) and human African trypanosomiasis (Trypanosoma brucei). [Pd(dmba)(μ-NCO)] 2 exhibited good leishmanicidal and trypanocidal activities against L. amazonensis and T. cruzi intracellular amastigote forms, with a 50% inhibitory concentration (IC 50 ) value of less than 9 μM and selectivity indexes of 14.47 and 28.42, respectively. Stability essays were conducted in phosphate buffer saline (PBS) pH 7.0 and showed that [Pd(dmba)(μ-NCO)] 2 is the most stable molecule. These findings indicate that this compound presented higher selectivity for these parasites than the other tested compounds. The data presented here suggest that this compound should be considered in the development of new and more potent drugs for the treatment of leishmaniasis and Chagas disease. 7 Pentavalent antimonial drugs are the most frequently prescribed treatments for leishmaniasis. 8 The main adverse effects that occur in systemic administration of these antimonials are arthralgias, myalgias, anorexia, and nausea, and other serious side effects include pancreatitis, liver-enzyme abnormalities, cardiac malfunctions and severe renal toxic effects. Other drugs, such as amphotericin B, pentamidine and miltefosine, are second choice drugs but they also produce side effects that can endanger the patient's life. KeywordsTrypanosoma cruzi is the causative agent of Chagas disease, which is present mainly in Latin America but also in North America. [10][11][12] Nifurtimox and benznidazole are the only drugs available to treat patients in the acute phase of the disease.13,14 However, these drugs are not Velásquez et al. 1033 Vol. 27, No. 6, 2016 effective against the chronic phase of the disease, and they present multiple side effects, from dermatitis to bone marrow depression. 15 HAT is caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. 16Treatment of the hemolymphatic stage of HAT relies on suramin and pentamidine. In the meningoencephalitis stage, melarsoprol, a highly toxic arsenic-based drug that is effective against both T. b. gambiense and T. b. rhodesiense is used. Eflornithine is useful only against T. b. gambiense. An eflornithine/nifurtimox combined therapy has been used, but this also causes several side effects.17 In summary, the conventional drugs that have been employed to treat these diseases are antiquated, have high toxicity and are ineffective due to drug resistance. Therefore, is critical to develop new drugs for the treatment of these trypanosomiases.The use of transition metal-based drugs is increasing significantly in the therapy of cancer and tropical diseases; in fact, many organometallic compounds have been designed to specifically bind to a well-d...

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Analysis of two cycloplatinated compounds derived from N-(4-methoxyphenyl)-.alpha.-benzoylbenzylidenamine. Comparison of the activity of these compounds with other isostructural cyclopalladated compounds

Cited by 94 publications

References 8 publications

In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

Synthesis of Novel Palladacycles Inhibitors of the Cathepsin B Activity and Antitumoral Agents

Antiprotozoal Activity of the Cyclopalladated Complexes AgainstLeishmania amazonensisandTrypanosoma cruzi

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