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Butyl phenyl-H-phosphinate that is not available commercially was prepared from phenyl-H-phosphinic acid by three methods: by alkylating esterification (i), by microwave-assisted direct esterification (ii), and unexpectedly, by thermal esterification (iii). Considering the green aspects, selectivity and scalability, the thermal variation seemed to be optimal. However, there was need for prolonged heating. The butyl phenyl-H-phosphinate, along with the ethyl analogue, was utilized in the synthesis of alkyl (α-alkylamino-arylmethyl-)phenyl phosphinates in the aza-Pudovik reaction with imines obtained from primary amines and substituted benzaldehydes. The aminophosphinates were obtained as diastereomeric mixtures in 65–92% yields. The aza-Pudovik approach was more efficient than the Kabachnik–Fields condensation. Interestingly, one aminophosphinate, the butyl (α-butylamino-benzyl-)phenylphosphinate, was of significant cytotoxic activity on the PANC-1 pancreas cell line. Another derivative, ethyl (α-benzylamino-benzyl-)phenylphosphinate, revealed a selective toxic activity on U266 myeloma cells.

A series of α-hydroxy-alkylphosphonates and α-hydroxy-alkylphosphine oxides were synthesized by the Pudovik reaction of acetaldehyde and acetone with dialkyl phosphites or diarylphosphine oxides. The additions were performed in three different ways: in liquid phase using triethylamine as the catalyst (1), on the surface of Al2O3/KF solid catalyst (2), or by a MW-assisted Na2CO3-catalyzed procedure (3). In most of the cases, our methods were more efficient and more robust than those applied in the literature. Two of the α-hydroxy-alkylphosphonates were subjected to single-crystal X-ray analysis, suggesting a dimeric and a chain supramolecular buildup in their respective crystals. Four α-hydroxy-alkylphosphonates and one α-hydroxy-ethylphosphine oxide were reacted with different acid chlorides to afford ten α-acyloxyphosphonates. Diethyl α-hydroxy-ethylphosphonate was transformed to the methanesulfonyloxy derivative that was useful in the Michaelis–Arbuzov reaction with triethyl phosphite and ethyl diphenylphosphinite to afford tetraethyl ethylidenebisphosphonate and diethyl α-(diphenylphosphinoyl)-ethylphosphonate, respectively. The α-hydroxyphosphonates and α-hydroxyphosphine oxides prepared were subjected to bioactivity studies, and the compounds tested exhibited limited cytotoxic effects on U266 cells with modest reductions in viability at a concentration of 100 μM.

Background: Methylenebisphosphonic derivatives including hydroxy-methylenebisphosphonic species may be of potential biological activity, and a part of them is used in the treatment of bone diseases. Methods: Methylenebisphosphonates may be obtained by the Michaelis–Arbuzov reaction of suitably α-substituted methylphosphonates and trialkyl phosphites or phosphinous esters, while the hydroxy-methylene variations are prepared by the Pudovik reaction of α-oxophosphonates and different >P(O)H reagents, such as diethyl phosphite and diarylphosphine oxides. Results: After converting α-hydroxy-benzylphosphonates and -phosphine oxides to the α-halogeno- and α-sulfonyloxy derivatives, they were utilized in the Michaelis–Arbuzov reaction with trialkyl phosphites and ethyl diphenylphosphinite to afford the corresponding bisphosphonate, bis(phosphine oxide) and phosphonate–phosphine oxide derivatives. The Pudovik approach led to α-hydroxy-methylenebisphosphonic species and to their rearranged products. A part of the derivatives revealed a significant cytotoxic effect on pancreatic adenocarcinoma or multiple myeloma cells. Conclusions: The new families of compounds synthesized by our novel approaches may be of practical importance due to the significant cytotoxic activity on the cell cultures investigated. Compounds lacking hydroxy groups showed anti-myeloma activity or limited effect on pancreatic cancer (PANC-1) cells unless substituted with para-trifluoromethyl group. Hydroxy-containing bisphosphonates and their rearranged derivatives demonstrated varying effects depending on structural modifications. While myeloma (U266) cells indicated greater sensitivity overall, the most significant reductions in cell viability were observed in PANC-1 cancer cells, raising potential therapeutic applications of bisphosphonates beyond myeloma-associated bone disease, particularly for malignancies like pancreatic ductal adenocarcinoma.

Abstract Background Oxidative stress is an important factor in the pathomechanism of atherosclerosis. Advanced oxidation protein products (AOPPs) are considered markers of oxidative stress. Thickening of the carotid intima-media layers indicates subclinical atherosclerosis and can be detected by carotid ultrasound. Objective Our aim was to examine the association between carotid intima-media thickness (CIMT) and the level of AOPPs. Methods Carotid duplex scans and measurements of AOPPs were performed on 476 participants of a cardiovascular population study. The presence of conventional cardiovascular risk factors was investigated with a questionnaire, physical examination, and laboratory tests. Results There was a positive correlation between maximum CIMT and the level of AOPPs only in the male population (r = 0.219, p = 0.033). Multivariate analysis has revealed that the association between AOPPs and mean or maximum CIMT was independent of cardiovascular risk factors (OR = 1.458, p = 0.004, and OR = 2.038, p

Abstract Stem cell-based therapies raise hope for cell replacement and provide opportunity for cardiac regenerative medicine and tumor therapy. Extracellular vesicles are a membrane-enclosed intercellular delivery system with the potential to improve the therapeutic efficacy of the treatment of a variety of disorders. As the incidence of breast cancer continues to rise, radiotherapy has emerged as a leading treatment modality. Radiotherapy also increases the risk of coronary heart disease and cardiac mortality. In a chest-irradiated mouse model of cardiac injury, we investigated the effects of local irradiation. We found an increased lethality after 16 Gy irradiation. Importantly, radio-detoxified LPS (RD-LPS) treatment prolonged the survival significantly. By flow cytometry, we demonstrated that upon administration of RD-LPS, the number of bone marrow-derived endothelial progenitor cells increased in the bone marrow and, in particular, in the circulation. Furthermore, mass spectrometry analysis showed that RD-LPS altered the proteomic composition of bone marrow cell-derived small extracellular vesicles (sEVs). RD-LPS treatment increased interferon-induced transmembrane protein-3 (IFITM3) expression markedly both in bone marrow cells and in bone marrow cell-derived small extracellular vesicles. This is the first study to demonstrate that radio-detoxified LPS treatment induces an increase of circulating endothelial progenitor cells (EPCs) in parallel with a reduced radiotherapy-related mortality. While the total number of bone marrow-derived extracellular vesicles was significantly increased 24 h after treatment in the RD-LPS groups, the number of endothelial progenitor cells was reduced in animals injected with GW4896 (a chemical inhibitor of exosome biogenesis) as compared with controls. In contrast to these in vivo results, in vitro experiments did not support the effect of sEVs on EPCs. Our data raise the intriguing possibility that IFITM3 may serve as a marker of the radio-detoxified LPS treatment.

Tamoxifen is a long-known anti-tumor drug, which is the gold standard therapy in estrogen receptor (ER) positive breast cancer patients. According to previous studies, the conjugation of the original tamoxifen molecule with different functional groups can significantly improve its antitumor effect. The purpose of this research was to uncover the molecular mechanisms behind the cytotoxicity of different ferrocene-linked tamoxifen derivates. Tamoxifen and its ferrocene-linked derivatives, T5 and T15 were tested in PANC1, MCF7, and MDA-MB-231 cells, where the incorporation of the ferrocene group improved the cytotoxicity on all cell lines. PANC1, MCF7, and MDA-MB-231 express ERα and GPER1 (G-protein coupled ER 1). However, ERβ is only expressed by MCF7 and MDA-MB-231 cells. Tamoxifen is a known agonist of GPER1, a receptor that can promote tumor progression. Analysis of the protein expression profile showed that while being cytotoxic, tamoxifen elevated the levels of different tumor growth-promoting factors (e.g., Bcl-XL, Survivin, EGFR, Cathepsins, chemokines). On the other hand, the ferrocene-linked derivates were able to lower these proteins. Further analysis showed that the ferrocene-linked derivatives significantly elevated the cellular oxidative stress compared to tamoxifen treatment. In conclusion, we were able to find two molecules possessing better cytotoxicity compared to their unmodified parent molecule while also being able to counter the negative effects of the presence of the GPER1 through the ER-independent mechanism of oxidative stress induction.

Combination antitumor treatments are essential parts of modern tumor therapy as—compared to monotherapies—(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of bortezomib (BOZ) in A2058 melanoma cells. Unfortunately, dose-related side effects are common during BOZ therapy, which could be prevented by reducing the dose of BOZ. This study aimed to characterize synergistic combinations of BOZ with a TRAIL (TNF-related apoptosis-inducing ligand) -inducing compound (TIC10), where the doses can be cut down but the efficacy is preserved. Endpoint cell viability assays were performed on A2058 cells, and synergism of BOZ and TIC10 was observed after 72 h. Synergism was further validated in a real-time impedimetric assay, and our results showed that BOZ-treated melanoma cells survived the treatment, an effect not registered in the co-treatments. Treatment with the combinations resulted in increased apoptosis, which was not accompanied by enhanced LDH release. Nevertheless, the expression of death receptor 5 (DR5) was increased on the cell surface without transcriptional regulation. In summary, our findings support the theory that the application of BOZ and TIC10 in combination could provide higher efficacy in vitro.

Use of a Pictet-Spengler reaction of tryptamine and l-tryptophan methyl ester and subsequent reduction of the nitro group followed by further cyclocondensation with aryl aldehydes and formyl–substituted carboxylic acids, including ferrocene-based components, furnished a series of diastereomeric 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo[2′,3′:3,4]pyrido[1-c]-quinazolines and 5,5b,17,18-tetrahydroindolo[2′,3′:3,4]pyrido[1,2-c]isoindolo[2,1-a]quinazolin-11-(15bH)-ones with the elements of central-, planar and conformational chirality. The relative configuration and the conformations of the novel polycyclic indole derivatives were determined by 1H- and 13C-NMR methods supplemented by comparative DFT analysis of the possible diastereomers. The structure of one of the pentacyclic methyl esters with defined absolute configuration “S” was also confirmed by single crystal X-ray diffraction measurement. Accounting for the characteristic substituent-dependent diastereoselective formation of the products multistep mechanisms were proposed on the basis of the results of DFT modeling. Preliminary in vitro cytotoxic assays of the products revealed moderate-to-significant antiproliferative effects against PANC-1-, COLO-205-, A-2058 and EBC-1 cell lines that proved to be highly dependent on the stereostructure and on the substitution pattern of the pending aryl substituent.

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.

Inspired by the well-established clinical evidence about the interplay between apoptotic TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) mechanism and reactive oxygen species (ROS)-mediated oxidative stress, a set of novel ONC201 hybrids containing the impiridone core and one or two differently positioned ferrocenylalkyl groups were synthesised in our present work. These two types of residues have been implicated in the aforementioned mechanisms associated with cytotoxic activity. A straightforward, primary amine-based synthetic approach was used allowing the introduction of a variety of N-substituents into the two opposite regions of the heterocyclic skeleton. Reference model compounds with benzyl and halogenated benzyl groups were also synthesised and tested. The in vitro assays of the novel impiridones on five malignant cell lines disclosed characteristic structure-activity relationship (SAR) featuring significant substituent-dependent activity and cell-selectivity. A possible contribution of ROS-mechanism to the cytotoxicity of the novel metallocenes was suggested by density functional theory (DFT)studies on simplified models. Accordingly, unlike the mono-ferrocenylalkyl-substituted products, the compounds containing two ferrocenylalkyl substituents in the opposite regions of the impiridone core display a much more pronounced long-term cytotoxic effect against A-2058 cell line than do the organic impiridones including ONC201 and ONC212. Furthermore, the prepared bis-metallocene derivatives also present substantial activity against COLO-205- and EBC-1 cell lines.