Cyclopalladated Benzophenone Imines: Synthesis, Antitumor Activity, Cell Accumulation, DNA Interaction, and Cathepsin B Inhibition

Abstract

The synthesis of the endo five-membered cyclo-ortho-palladated benzophenone imines [Pd{C6H4(Ph)CNR}]2(μ-X)2 [1 (X = OAc), 2 (X = Cl), a (R = phenyl), b (R = 1-naphthyl), c (R = benzyl), d (R = α-methylbenzyl)], and trans-N,P-[Pd{C6H4(Ph)CNR}X(PPh3)] [3 (X = OAc), 4 (X = Cl), a (R = phenyl), b (R = 1-naphthyl), c (R = benzyl), d (R = α-methylbenzyl)] and the X-ray molecular structure of 1a, 1c, 1d, 4a, 4b, and 4c are reported. The antitumor activity, DNA interaction, and cathepsin B inhibition of palladium compounds a–d were studied and compared with those previously reported for palladium compounds e with R = H and compound 4f analogous to 4e but with a platinum(II) center. The IC50 values against a panel of human cancer cell lines allowed the establishment of a qualitative relationship between their structure and antitumor activity. Compounds 3e, 4e, and 4f were the most active ones in relation to their in vitro anticancer activity. Compounds 3e and 4e were about 4 times more active than cisplatin against the MDA-MB-231 and MCF-7 breast human cancer lines, and compound 4f was about 4 times more active than cisplatin against the cisplatin-resistant HCT-116 colon human cancer cell line. In addition, compound 3e was 3 times less cytotoxic than cisplatin toward the quiescent HUVEC cells. Accumulation of palladium compounds e and b in the MDA-MB-231 cell line was considerably greater than that of cisplatin in the same cell line, but palladium compounds b were noncytotoxic. Some of these complexes altered the DNA tertiary structure in a similar way to cisplatin but at higher concentration, and most cytotoxic ones did not present a high efficiency as cathepsin B inhibitors.

Planar Chiral Ferrocene Cyclopalladated Derivatives Induce Caspase-Dependent Apoptosis and Antimetastasis in Cancer Cells

“…In this investigation, only the supercoiled closed circular (ccc) form in PET21a plasmid DNA was studied. As shown in Figure , cisplatin altered the electrophoretic mobility of PET21a at low concentrations (2.5–5 μM) and fragmented the DNA at slightly higher concentrations (10–25 μM), which was in accordance with previous reports . In contrast, dimeric cyclopalladated compounds showed no interaction with PET21a plasmid DNA, even at a high concentration (200 μM).…”

“…Plasmid DNA PET21a (Novagen, Madison, WI) was obtained using PureYieldTM Plasmid Maxiperp System as described by the manufacturer (Promega, Beijing, China). Interaction of drugs with PET21a plasmid DNA was analyzed by agarose gel electrophoresis following a modification of the method previously described . Plasmid DNA aliquots (40 μg/mL) were incubated in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.5) with different concentrations of test compounds ranging from 0 to 200 μM at 37 °C for 24 h. Final DMSO concentration in the reactions was always lower than 1%.…”

“…Platinum-based antitumor drugs, such as cisplatin, carboplatin, and oxaliplatin, are used extensively as cancer therapeutics. However, the observed side effects and inefficiency against cisplatin-resistant tumors have severely limited the clinical application of those compounds. , Recently, cyclopalladated compounds have attracted attention as potential agents with excellent antitumor activity. , Structure–activity relationship studies indicated that the activity of cyclopalladated compounds was highly related to the N-group, , the C–N cycle , and the ligands of palladium . The anticancer mechanism of cyclopalladated compounds is still unclear.…”

Synthesis, characterization and molecular docking of new C,N‐palladacycles containing pyridinium‐derived ligands: DNA and BSA interaction studies and evaluation as anti‐tumor agents

“…This refers to higher biological activity of primary amine metallacycles than secondary amines due to the possibility of being involved in hydrogen bonds through the NH 2 group . Although the IC 50 values of complexes against MCF‐7 cells are close to or higher than cisplatin, they are comparable with other similar palladium complexes …”

Síntese, Caracterização E Avaliação Da Atividade Citotóxica De Compostos Ciclopaladados Contendo Como Ligantes Benzaldeidoxima Ortometalada E Etilenotiouréia

“…Além disso, os íons metálicos apresentam números de coordenação, preferências estereoquímicas e reatividade que dependem da sua carga, tamanho e estrutura eletrônica, tornando-os uma plataforma única para o planejamento de novos fármacos com conceitos muito diferentes daqueles usados para moléculas orgânicas. 5,6 Atualmente, fármacos como a cisplatina, carboplatina e oxaliplatina são utilizados em cerca de 50 a 70% dos tratamentos de tumores, 7 contudo, a baixa seletividade unida à resistência adquirida pelo organismo a essas drogas e aos efeitos colaterais que elas causam motivam o desenvolvimento de novos compostos mais eficazes e menos tóxicos. 8,9 Nesse contexto, os complexos de paládio(II) representam uma alternativa promissora pelas semelhanças entre os íons Pd(II) e Pt (II).…”