Novel platinum(II) complexes of long chain aliphatic diamine ligands with oxalato as the leaving group: comparative cytotoxic activity relative to chloride precursors

Abstract

Os complexos de platina são importantes no desenvolvimento de drogas anticancerígenas. Sua citotoxicidade pode ser afetada pelos ligantes abandonadores, devido ao mecanismo da reação de hidrólise que ocorre antes da ligação do complexo ao DNA. Os grupos não-abandonadores, como as diaminas lipofílicas, também podem afetar a velocidade de entrada do composto na célula. Neste trabalho é descrita a síntese de novos complexos de platina(II) contendo ligantes oxalato e derivados de etilenodiamina N-substituída por uma cadeia carbônica longa de tamanho variável. Os produtos foram caracterizados por análise elementar, espectroscopia de absorção na região do infravermelho e ressonância magnética nuclear de 1 H, 13 C e 195 Pt. A atividade biológica dos complexos foi investigada em linhagens de células tumorais (A 549 , B16-F1, B16-F10, MDA-MB-231) e não-tumorais (BHK-21 e CHO). O tamanho da cadeia carbônica afetou a citotoxicidade e os complexos com oxalato mostraram-se menos citotóxicos do que os análogos com cloretos.Platinum complexes play an important role in the development of anticancer drugs. Their cytotoxicity can be influenced by the nature of the leaving ligands, due to the hydrolysis reaction that occurs prior to the binding of the platinum complex to DNA. Also, non-leaving groups such as lipophilic diamines may affect cellular uptake. In this work, we describe the synthesis of platinum(II) complexes having oxalato and long chain aliphatic N-alkyl ethylenediamines as ligands. The products were characterized by elemental analyses, infrared spectroscopy and 1 H, 13 C and 195 Pt NMR spectroscopy. Biological activity was assessed against tumor cell lines (A 549 , B16-F1, B16-F10, MDA-MB-231) and non-tumor cell lines (BHK-21 and CHO). The length of the carbon chain affects the cytotoxicity and the oxalato complexes were less cytotoxic than the respective chloride-containing analogues.

Dual drug-loaded biofunctionalized amphiphilic chitosan nanoparticles: Enhanced synergy between cisplatin and demethoxycurcumin against multidrug-resistant stem-like lung cancer cells

“…Additional evidence for the formation of a chemical bond between CDDP and CHC through replacement of chlorine with oxygen was provided by 195 Pt NMR, where chemical shifts of 2101 ppm and 1849 ppm were recorded for CDDP and CHC/CDDP, respectively(Fig. 2), in agreement with literature[23,24]. Combined the results prove that CDDP formed bonds with the carboxylic acid oxygen of CHC through replacement of chlorine.…”

“…The solutions were divided into 1.5 mL Eppendorf tubes, 3 for each time point.The tubes were gently shaken at 37 o C in an orbital shaker incubator. At predetermined times(4,8,12,24, 42 and 48 h) the released (free) drugs were separated from nanoparticles loaded with drugs by centrifugation. For DMC samples were centrifuged at 1000 rpm for 2 min and the pellet consisting of the precipitated released DMC was analyzed.…”

Synthesis, Characterization and in Vitro Antitumor Activity of Platinum(II) Oxalato Complexes Involving 7-Azaindole Derivatives as Coligands

“…, carboxylates) ligands is one of the crucial challenge of modern bioinorganic chemistry [11,12,13], although those involved in clinically used drugs are still substantial part of this research, as exemplified by the NH 3 carrier ligands involved in original platinum-based drug cisplatin, as well as in currently studied picoplatin [14]. As for the biologically effective platinum oxalato complexes, it is quite interesting that although these complexes can be considered, thanks to clinically used anticancer drug oxaliplatin [15], as biologically perspective group of compounds [16], not many papers dealing with such compounds in connection with their biological effect have been reported in last five years [17,18,19,20,21,22,23,24]. Our research group reported the platinum(II) oxalato complexes involving variously substituted N 6-benzyladenine derivatives [17,18,19], whose the most effective representatives showed IC 50 (HOS) = 3.6 µM ([Pt(ox)(L 1 )]; L 1 =2-chloro- N 6-(2-methoxybenzyl)-9-isopropyladenine) and IC 50 (MCF7) = 3.6 µM ([Pt(ox)(L 2 )]; L 2 =2-chloro- N 6-(2,4-dimethoxybenzyl)-9-isopropyladenine).…”

“…The work of Silva et al dealt with the [Pt(ox)(L 3 )] (L 3 symbolizes a long-chain aliphatic diamine) and their cytotoxic effect against A549, B16-F1, B16-F10 and MDA-MB-231 cancer cells and BHK-21 and CHO non-cancer cells. The obtained results proved four reported oxalato complexes as less active against the named cancer cells (IC 50 (A549) = 12.6–60.6 µM, IC 50 (B16-F1) = 14.5–21.9 µM, IC 50 (B16-F10) = 16.6–38.0 µM, IC 50 (MDA-MB-231) = 16.6–25.1 µM) as compared with cisplatin (IC 50 (A549) = 2.7 µM, IC 50 (B16-F1) = 3.5 µM, IC 50 (B16-F10) = 4.2 µM, IC 50 (MDA-MB-231) = 1.4 µM) [21]. Other platinum(II) oxalato complexes involved 1,2-diaminocyclohexane with variously monoalkyl-substituted nitrogen atom (L 4 ) [22].…”