Highly Cytotoxic Palladium(II) Pincer Complexes Based on Picolinylamides Functionalized with Amino Acids Bearing Ancillary S-Donor Groups

Abstract

The reactions of picolinyl and 4-chloropicolinyl chlorides with methyl esters of S-methyl-l-cysteine, l- and d-methionine, and l-histidine afforded a series of functionalized carboxamides, which readily formed pincer-type complexes upon interaction with PdCl(NCPh) in solution under mild conditions. The direct cyclopalladation of the ligands derived was also accomplished in the solid phase, in particular, mechanochemically, although it was complicated by the partial deactivation of the starting amides. The resulting complexes with 5,5- and 5,6-membered fused metallocycles were fully characterized by IR and NMR spectroscopy, including variable-temperature and 2D-NMR studies. In the case of some cysteine- and methionine-based derivatives, the realization of κ-N,N,S-coordination was supported by X-ray diffraction. The cytotoxic effects of these complexes were examined on HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 as a representative of normal cells. The comparative studies allowed us to determine that the presence of the sulfide ancillary donor group is crucial for cytotoxic activity of this type of Pd(II) complexes. The main structure-activity relationships and the most promising palladocycles were outlined. The additional studies by gel electrophoresis revealed that 4-chloropicolinyl derivatives, despite the nature of an amino acid, can bind with DNA and inhibit topoisomerase I activity.

Design of pincer complexes based on (methylsulfanyl)acetic/propionic acid amides with ancillary S‐ and N‐donors as potential catalysts and cytotoxic agents

“…Furthermore, it was found that the substituent at the sulfur atom only slightly affects the cytotoxicity of this type of metal complex (Table S2 in supporting information). As was expected from our previous study, none of the pyridine‐containing sulfoxide derivatives (complexes 7o – 10o ) appeared to be cytotoxic at a concentration as high as 100 μM. At the same time, their counterparts bearing the quinoline and diphenylthiophosphoryl donor groups exhibited moderate efficiencies, although the values of IC 50 were higher than those for the corresponding sulfide derivatives (entries 7 versus 5 and 8 versus 6).…”

“…In recent years, our research group has extended a range of pincer‐type palladocycles based on functionalized carboxamides with several series of complexes (see, for example, Scheme ) [3c,d,4c,7a,8,9]. Some of them demonstrated pronounced cytotoxic effects against human colon (HCT116), breast (MCF7) and prostate (PC3) cancer cells (compounds XII and XIII );[7a,8] others exhibited moderate to high catalytic activity in Suzuki cross‐coupling (compounds XIV – XVI ) . The performed investigations allowed us to outline preliminary tendencies in the structure–activity relationships.…”

Pd-pincer complexes containing six-membered rings that are more active allylation catalysts than five-membered ring analogues

“…This high activity of catalysts derived from L8 led us to investigate it further. The catalysis with L8 and Table2, entries[10][11][12][13][14][15]. These results demonstrated the greater activity of the Pd-TFA catalysts than the Pd-Cl catalysts: at 60 °C, after 2 h and at 1.25 mol% catalyst loading, full conversion was observed with Pd-TFA catalysts whilst only 48% conversion was observed with the Pd-Cl catalyst (Table2, entry 12).…”

Synthesis, Characterization and Anticancer Studies of Rh(I), Rh(III), Pd(II) and Pt(II) Complexes Bearing A Dithiooxamide Ligand

“…In fact, following the success of cisplatin, a large number of other platinum‐based drugs have been synthesized and evaluated . Also, due to the similarity of Pd(II) to Pt(II) analogs in structure and coordination chemistry, promising biological properties as well as chemotherapeutic potential with different mechanism cause that Pd(II) complexes take attention in this field . Furthermore, in the field of non‐platinum compounds exhibiting antitumor properties, arene Ru(II) and Rh(III) complexes with an ancillary chloride ligand are promising, showing activity against cisplatin‐resistant tumors .…”