Discovery of membrane permeability, pharmacokinetics properties and mechanism of action for analogs of ethylenediamine-n,n′-di-2-(3-cyclohexyl)propionic acid and 1,3-propandiamine-n,n′-di-2-(3-cyclohexyl)propionic acid with antiproliferative activity using in vitro and in silico methods

In previously in vitro studies on different cell lines and in vivo on melanoma and 4T1 murine breast cancer and metastasis it was shown antiproliferative activity for ester derivatives of (S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoic acid, and (S,S)-1,3-propanediamine-N,N′-di-2-(3-cyclohexyl)propanoic acid. The aim of this study was to predict membrane permeability by parallel artificial membrane permeability assay (PAMPA), molecular mechanism of action, metabolites and absorption, distribution, metabolism, toxicity—ADMET properties for observed substances using in vitro and in silico methods. Obtained results of PAMPA show the best membrane permeability of ethyl esters analogs (DE-EDCP and DE-PDCP) and refer to the hypothesis that the retention in cell membrane is important for cytotoxic activity of investigated substances. Prediction of main metabolic pathways was performed by the Metabolizer software and it was obtained that the major metabolic reactions were the hydrolyses of ester and subsequently intramolecular cyclization. Toxicity of investigated substances and their potential metabolites are lower than toxicity of observed official cytotoxic drugs. Based on the results obtained by the Molecular docking, it can be assumed that the antiproliferative effects of the investigated substances were realized through the multiple mechanisms by potential metabolites: acids, lactam carboxylate and lactam alkyl esters, while the esters are probably a prodrug substance with favorable properties to provide sufficient bioavailability at the target of action. Based on obtained results it can be proposed there to be investigated the existence of the metabolites: lactam carboxylate and lactam alkyl esters in biological materials

Discovery of membrane permeability, pharmacokinetics properties and mechanism of action for analogs of ethylenediamine-n,n′-di-2-(3-cyclohexyl)propionic acid and 1,3-propandiamine-n,n′-di-2-(3-cyclohexyl)propionic acid with antiproliferative activity using In Vitro and In Silico Methods

In previously in vitro studies on different cell lines and in vivo on melanoma and 4T1 murine breast cancer and metastasis it was shown antiproliferative activity for ester derivatives of (S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoic acid, and (S,S)-1,3-propanediamine-N,N′-di-2-(3-cyclohexyl)propanoic acid. The aim of this study was to predict membrane permeability by parallel artificial membrane permeability assay (PAMPA), molecular mechanism of action, metabolites and absorption, distribution, metabolism, toxicity—ADMET properties for observed substances using in vitro and in silico methods. Obtained results of PAMPA show the best membrane permeability of ethyl esters analogs (DE-EDCP and DE-PDCP) and refer to the hypothesis that the retention in cell membrane is important for cytotoxic activity of investigated substances. Prediction of main metabolic pathways was performed by the Metabolizer software and it was obtained that the major metabolic reactions were the hydrolyses of ester and subsequently intramolecular cyclization. Toxicity of investigated substances and their potential metabolites are lower than toxicity of observed official cytotoxic drugs. Based on the results obtained by the Molecular docking, it can be assumed that the antiproliferative effects of the investigated substances were realized through the multiple mechanisms by potential metabolites: acids, lactam carboxylate and lactam alkyl esters, while the esters are probably a prodrug substance with favorable properties to provide sufficient bioavailability at the target of action. Based on obtained results it can be proposed there to be investigated the existence of the metabolites: lactam carboxylate and lactam alkyl esters in biological materials

Tetravalent Metal Ion Guests in Polyoxopalladate Chemistry: Synthesis and Anticancer Activity of [MO8Pd12(PO4)8]12- (M=SnIV, PbIV)

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Synthesis, characterization and antitumor activity of polymeric copper(II) complexes with thiosemicarbazones of 3-methyl-5-oxo-1-phenyl-3-pyrazolin-4-carboxaldehyde and 5-oxo-3-phenyl-3-pyrazolin-4-carboxaldehyde

New polymeric copper(II) complexes with two tridentate ONS thiosemicarbazone ligands containing substituted pyrazolone moiety were synthesized and characterized by means of spectroscopic, electrochemical and crystallographic techniques. While both ligands exist as different tautomers in the solid state and DMSO-d(6) solution, Cu(II) ion coordinates the ligands from the same tautomeric form with square-pyramidal geometry around each Cu atom. In the crystal structures, the copper(II) complex cation forms polymeric chains {[Cu(L)Cl+]}(n) with a bridging chlorine atom. One of the complexes was found to have a significantly higher cytotoxic potential in comparison with cisplatin in inhibition of several cell lines (HL60, REH, C6, L929 and B16). The results obtained on the basis of flow cytometry indicated that apoptosis could be possible mechanism of cell death

Prehabilitation in patients undergoing colorectal surgery fails to confer reduction in overall morbidity : results of a single-center, single-blinded, randomized controlled trial

Objective: Patients undergoing major surgery are prone to a functional decline due to the impairment of muscle, cardiorespiratory and neurological function as a response to surgical stress. Currently, there are solely weak recommendations in the ERAS protocol regarding the role of preoperative physical activity and prehabilitation in patients undergoing colorectal surgery. Studies in heterogenous cohorts showed contradictory results regarding the impact of prehabilitation on the reduction of postoperative complications. This randomized controlled trial assesses the impact of prehabilitation on postoperative complications in patients undergoing colorectal surgery within an ERAS protocol. Methods: Between July 2016 and June 2019, a single-center, single-blinded , randomized controlled trial designed to test whether physiotherapeutic prehabilitation vs. normal physical activities prior to colorectal surgery may decrease morbidity within a stringent ERAS protocol was carried out. The primary endpoint was postoperative complications assessed by Comprehensive Complications Index (CCI®). Primary and secondary endpoints for both groups were analyzed and compared. Results: A total of 107 patients (54 in the pERACS and 53 in the control cohort) were included in the study and randomized. Dropout rate was 4.5% (n = 5). Mean age (SD) in the control cohort was 65 (29–86) and 66 (24–90) years in pERACS cohort. The pERACS cohort contained more female patients (40% vs. 55%, p = 0.123) and a higher percentage of colorectal adenocarcinoma (32% vs. 23%, p = 0.384) although not significant. Almost all patients underwent minimally invasive surgery in both cohorts (96% vs 98%, p = 1.000). There was no between-cohort difference in the primary outcome measure 30-day Comprehensive Complications Index (15 [0 – 49] vs. 18 [0 – 43], p = 0.059). Secondary outcome as complications assessed according to Clavien-Dindo, length of hospital stay, reoperation rate and mortality showed no difference between both cohorts. Conclusion: Routine physiotherapeutic prehabilitation cannot be recommended for patients undergoing colorectal surgery within an ERAS protocol (Grade A recommendation). To eliminate other confounders like geographical difference or difference in surgical technique, further multicenter RCTs are needed