Unsymmetrical Pd(II) Pincer Complexes with Benzothiazole and Thiocarbamate Flanking Units: Expedient Solvent-Free Synthesis and Anticancer Potential.

Driven by the growing threat of cancer, many research efforts are directed at developing new chemotherapeutic agents, where the central role is played by transition metal complexes. The proper ligand design serves as a key factor to unlock the anticancer potential of a particular metal center. Following a recent trend, we have prepared unsymmetrical pincer ligands that combine benzothiazole and thiocarbamate donor groups. These compounds are shown to readily undergo direct cyclopalladation, affording the target S,C,N-type Pd(II) pincer complexes both in solution and in the absence of a solvent. The solid-phase strategy provided the complexes in an efficient and ecologically friendly manner. The resulting palladacycles are fully characterized using nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy and, in one case, by single-crystal X-ray diffraction (XRD). The solvent-free reactions are additionally analyzed by powder XRD. The pincer complexes exhibit remarkable cytotoxicity against several solid and blood cancer cell lines, including human colorectal carcinoma (HCT116), breast cancer (MCF7), prostate adenocarcinoma (PC3), chronic myelogenous leukemia (K562), multiple plasmacytoma (AMO1), and acute lymphoblastic leukemia (H9), with the dimethylamino-substituted derivative being particularly effective. The latter also induced an appreciable level of apoptosis in both parental and doxorubicin-resistant cells K562 and K562/iS9, vindicating the high anticancer potential of this type of palladacycles.

(Aminoalkyl)diphenylphosphine sulfides: synthesis and application as building blocks in the design of multidentate ligands for cytotoxic Pd(II) complexes.

Amino-functionalized phosphoryl compounds are among the most useful molecular scaffolds in medicinal chemistry, while the potential of their thiophosphorylated analogs, especially those having an alkylamino moiety, is still uncovered. This is mainly due to the lack of convenient synthetic routes to these organophosphorus derivatives. To address this issue, we have suggested the facile approaches to α-(aminomethyl)- and substituted/unsubstituted α-(aminobenzyl)diphenylphosphine sulfides based on either the sequential transformations of (hydroxymethyl)diphenylphosphine sulfide, with the Staudinger reaction of an azide derivative as the key stage, or the addition of Ph2P(S)H to hydrobenzamides followed by the acid hydrolysis. The compounds obtained were reacted with picolinyl chloride to yield functionalized amides which readily underwent direct cyclopalladation, resulting in new representatives of non-classical N-metalated Pd(II) pincer complexes. The latter exhibit promising cytotoxic activity against several human cancer cell lines and apoptosis inducing ability along with the remarkable cytotoxic effects on doxorubicin-resistant cell sublines.

Modulation of the Cytotoxic Properties of Pd(II) Complexes Based on Functionalized Carboxamides Featuring Labile Phosphoryl Coordination Sites.

Platinum-based drugs are commonly recognized as a keystone in modern cancer chemotherapy. However, intrinsic and acquired resistance as well as serious side effects often caused by the traditional Pt(II) anticancer agents prompt a continuous search for more selective and efficient alternatives. Today, significant attention is paid to the compounds of other transition metals, in particular those of palladium. Recently, our research group has suggested functionalized carboxamides as a useful platform for the creation of cytotoxic Pd(II) pincer complexes. In this work, a robust picolinyl- or quinoline-carboxamide core was combined with a phosphoryl ancillary donor group to achieve hemilabile coordination capable of providing the required level of thermodynamic stability and kinetic lability of the ensuing Pd(II) complexes. Several cyclopalladated derivatives featuring either a bi- or tridentate pincer-type coordination mode of the deprotonated phosphoryl-functionalized amides were selectively synthesized and fully characterized using IR and NMR spectroscopy as well as X-ray crystallography. The preliminary evaluation of the anticancer potential of the resulting palladocycles revealed a strong dependence of their cytotoxic properties on the binding mode of the deprotonated amide ligands and demonstrated certain advantages of the pincer-type ligation.

Pincer-dipeptide and pseudodipeptide conjugates: Synthesis and bioactivity studies.

Following a recent trend on the application of different pincer scaffolds for the development of new metal-based antitumor agents, in this work, dipeptides and dipeptide surrogates based on picolinyl- and 4-chloropicolinylamides with S-donor amino acid residues (cysteine, homocysteine, or methionine) bearing glycinate, alaninate, or phosphonate moieties either at the C-terminus or in the S-donor side arm have been designed as nonclassical pincer ligands with central amide units and shown to smoothly undergo site-selective direct cyclopalladation under mild conditions, affording the target Pd(II) pincer complexes in good to high yields. The realization of S,N,N-coordination through the sulfur atom of the thioether group and nitrogen atoms of the pyridine and deprotonated amide units was unambiguously confirmed using different NMR techniques (1H, 13C, 31P, and 2D NMR methods, including 1H15N HMBC) and IR spectroscopy; the structure of one representative was elucidated by X-ray crystallography. The resulting pincer-(pseudo)dipeptide conjugates were screened for cytotoxicity against several cancer cell lines and noncancerous human embryonic kidney cells and at least some of them provided an appreciable level of activity comparable to that of cisplatin. The S-modified homocysteine-based derivatives exhibited also significant antiproliferative effects against doxorubicin-resistant transformed breast cells HBL100/Dox, implying the possibility of overcoming drug resistance. The complexes can induced apoptosis but did not affect mitochondria. The comparative DNA/protein binding studies of one of the most active pincer-(pseudo)dipeptide conjugates with the monoamino acid-based prototype revealed certain advantages of the former and gave further insights into the potential of this type of palladium-based antitumor agents.

Mechanochemistry for the synthesis of non-classical N-metalated palladium(II) pincer complexes.

The peculiarities of cyclopalladation of a series of non-classical pincer-type ligands based on monothiooxalyl amides bearing ancillary N- or S-donor groups in the amide units have been scrutinized both under conditions of conventional solution-based synthesis and in the absence of a solvent according to a solid-phase methodology including mechanochemical activation. Grinding the functionalized monothiooxamides with PdCl2(NCPh)2 in a mortar or vibration ball mill is shown to serve as an efficient and green alternative to the synthesis of these complex metal-organic systems in solution that can offer such advantages as the absence of any auxiliary and significant rate and yield enhancement, especially for the challenging ligands. The realization of S,N,N- or S,N,S-monoanionic tridentate coordination in the resulting pincer complexes has been confirmed by multinuclear NMR (including 2D NMR) and IR spectroscopy and, in some cases, X-ray diffraction. The course and outcome of the solid-phase reactions have been studied by a combination of different spectroscopic methods as well as SEM/EDS analysis. The preliminary evaluation of cytotoxic activity against several human cancer cell lines has revealed the high potency of some of the cyclopalladated derivatives obtained, rendering further development of solvent-free synthetic routes to this type of complexes very urgent.

Palladium(II) Pincer Complexes of Functionalized Amides with S-Modified Cysteine and Homocysteine Residues: Cytotoxic Activity and Different Aspects of Their Biological Effect on Living Cells.

In the search for potential new metal-based antitumor agents, two series of nonclassical palladium(II) pincer complexes based on functionalized amides with S-modified cysteine and homocysteine residues have been prepared and fully characterized by 1D and 2D NMR (1H, 13C, COSY, HMQC or HSQC, 1H-13C, and 1H-15N HMBC) and IR spectroscopy and, in some cases, X-ray diffraction. Most of the resulting complexes exhibit a high level of cytotoxic activity against several human cancer cell lines, including colon (HCT116), breast (MCF7), and prostate (PC3) cancers. Some of the compounds under consideration are also efficient in both native and doxorubicin-resistant transformed breast cells HBL100, suggesting the prospects for the creation of therapeutic agents based on the related compounds that would be able to overcome drug resistance. An analysis of different aspects of their biological effects on living cells has revealed a remarkable ability of the S-modified derivatives to induce cell apoptosis and efficient cellular uptake of their fluorescein-conjugated counterpart, confirming the high anticancer potential of Pd(II) pincer complexes derived from functionalized amides with S-donor amino acid pendant arms.

Direct arylation of C60Cl6 and C70Cl8 with carboxylic acids: a synthetic avenue to water-soluble fullerene derivatives with promising antiviral activity.

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.

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

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 PdCl2(NCPh)2 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 κ3-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.

Photoresponsive dendron-like metallocomplexes of the crown-containing styryl derivatives of 2,2'-bipyridine.

We studied 15-crown-5 ether mono- and bis(styryl) derivatives of 2,2'-bipyridine ( and ) as a scaffold to construct photoresponsive complexes possessing metallodendrimer structure. The synthesis and optical properties of one dimensional (1D) Ca(2+)-containing and octahedral 3D Zn(2+)-containing complexes with crowned styryl derivatives of 2,2'-bipyridine are described. Bimetallic Ca(2+), Zn(2+)-containing complexes of and possess well-defined structures and particular optical characteristics. The effective size of the complexes was estimated by diffusion-ordered NMR spectroscopy (DOSY) by measuring translation diffusion coefficients. The NMR data on the compositions of the formed complexes are in full agreement with those obtained by an optical method. The properties of the zinc polypyridyl complexes are modified by intermolecular interactions between the crown ether center and the metal ions, so they are potentially useful in the preparation of chemical sensors.

Hybrid photoactive fullerene derivative-ruboxyl nanostructures for photodynamic therapy.

Here we report the investigation of photophysical properties and photodynamic action of two novel water soluble hybrid molecular structures based on [60]fullerene dyads bearing covalently attached residues of anthracycline antibiotic "ruboxyl". Molecular structures of the designed compounds were confirmed by IR and UV-VIS absorption spectroscopy, electrospray mass spectrometry (compound 5), and (1)H and (13)C NMR spectroscopy. Dynamic light scattering, steady-state and kinetic fluorimetry and UV-VIS absorption spectroscopy techniques were used to study the behavior of the synthesized hybrid molecular structures in aqueous solutions. Photodynamic activity of the compounds was evaluated by monitoring the O2(-) generation under visible light irradiation using the NBT test. It has been shown that the anthracycline chromophore (ruboxyl moiety possesses no photodynamic activity) behaves as an efficient photosensitizer for the fullerene core operating via the energy and/or the electron transfer pathways. The presented approach opens up wide opportunities for the design of various fullerene-based donor-acceptor systems with enhanced photodynamic properties potentially suitable for biomedicinal applications.

Polyphenylenepyridyl dendrimers as stabilizing and controlling agents for CdS nanoparticle formation.

Semiconductor nanoparticles (NPs) are being actively explored for applications in medical diagnostics and therapy and numerous electronic devices including solar cells. In this paper we demonstrate the influence of the third generation rigid polyphenylenepyridyl dendrimers (PPPDs) of a different architecture on the formation of well-defined CdS NPs. A high temperature approach to the synthesis of novel CdS/PPPD nanocomposites is feasible due to the high thermal stability of PPPDs. The PPPD architecture affects the CdS NP formation: larger NPs are obtained in the presence of dendrimers with 1,3,5-triphenylbenzene cores compared to those with tetrakis(4-ethynylphen-1-yl)methane cores. The reaction conditions such as concentrations of PPPDs and NP precursors and the temperature regime also influence the CdS NP sizes. For the first time, we elucidated a mechanism of CdS NP formation in a non-coordinating solvent through the CdO redispersion in the presence of PPPDs. Interesting optical properties of these CdS/PPPD nanocomposites make them promising candidates for imaging applications.

Synthesis of alpha-amino acids via asymmetric phase transfer-catalyzed alkylation of achiral nickel(II) complexes of glycine-derived Schiff bases.

Achiral, diamagnetic Ni(II) complexes 1 and 3 have been synthesized from Ni(II) salts and the Schiff bases, generated from glycine and PBP (7) and PBA (11), respectively, in MeONa/MeOH solutions. The requisite carbonyl-derivatizing agents pyridine-2-carboxylic acid(2-benzoyl-phenyl)-amide 7 (PBP) and pyridine-2-carboxylic acid(2-formyl-phenyl)-amide 11 (PBA) were readily prepared from picolinic acid and o-aminobenzophenone or picolinic acid and methyl o-anthranilate, respectively. The structure of 1 was established by X-ray crystallography. Complexes 1 and 3 were found to undergo C-alkylation with alkyl halides under PTC conditions in the presence of beta-naphthol or benzyltriethylammonium bromide as catalysts to give mono- and bis-alkylated products, respectively. Decomposition of the complexes with aqueous HCl under mild conditions gave the required amino acids, and PBP and PBA were recovered. Alkylation of 1 with highly reactive alkyl halides, carried out under the PTC conditions in the presence of 10% mol of (S)- or (R)-2-hydroxy-2'-amino-1,1'-binaphthyl 31a (NOBIN) and/or its N-acyl derivatives and by (S)- or (R)-2-hydroxy-8'-amino-1,1'-binaphthyl 32a (iso-NOBIN) and its N-acyl derivatives, respectively, gave rise to alpha-amino acids with high enantioselectivities (90-98.5% ee) in good-to-excellent chemical yields at room temperature within several minutes. An unusually large positive nonlinear effect was observed in these reactions. The Michael addition of acrylic derivatives 37 to 1 was conducted under similar conditions with up to 96% ee. The (1)H NMR and IR spectra of a mixture of the sodium salt of NOBIN and 1 indicated formation of a complex between the two components. Implications of the association and self-association of NOBIN for the observed sense of asymmetric induction and nonlinear effects are discussed.