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1.
Int J Mol Sci ; 24(20)2023 Oct 13.
Article in English | MEDLINE | ID: mdl-37894841

ABSTRACT

This work presents the results of research on obtaining chitosan (CS) films containing on their surface ciprofloxacin (CIP). A unique structure was obtained that not only gives new properties to the films, but also changes the way of coverage and structure of the surface. The spectroscopic test showed that in the process of application of CIP on the surface of CS film, CIP was converted from its crystalline form to an amorphic one, hence improving its bioavailability. This improved its scope of microbiological effect. The research was carried out on the reduction of CIP concentration during the process of CIP adhesion to the surface of chitosan films. The antibacterial activity of the CS films with and without the drug was evaluated in relation to Escherichia coli and Staphylococcus aureus, as well as Candida albicans and Penicillium expansum. Changes in the morphology and roughness of membrane surfaces after the antibacterial molecule adhesion process were tested with atomic force microscopy (AFM) and scanning electron microscopy (SEM). Structural analysis of CS and its modifications were confirmed with Fourier-transform spectroscopy in the infrared by an attenuated total reflectance of IR radiation (FTIR-ATR) and solid-state nuclear magnetic resonance (NMR).


Subject(s)
Chitosan , Chitosan/chemistry , Ciprofloxacin/pharmacology , Ciprofloxacin/chemistry , Spectroscopy, Fourier Transform Infrared , Anti-Bacterial Agents/chemistry , Magnetic Resonance Spectroscopy
2.
Int J Mol Sci ; 24(18)2023 Sep 05.
Article in English | MEDLINE | ID: mdl-37761977

ABSTRACT

Among the various substances that interfere with the microtubule formation process, isothiocyanates (ITCs) are the group of compounds for which the binding mode and mechanism of action have not yet been explained. To better understand the structure-activity relationship of tubulin-isothiocyanate interactions, we designed and synthesized a series of sixteen known and novel, structurally diverse ITCs, including amino acid ester-derived isothiocyanates, bis-isothiocyanates, analogs of benzyl isothiocyanate, and phosphorus analogs of sulforaphane. All synthesized compounds and selected natural isothiocyanates (BITC, PEITC, AITC, and SFN) were tested in vitro to evaluate their antiproliferative activity, tubulin polymerization inhibition potential, and influence on cell cycle progression. The antiproliferative activity of most of the newly tested compounds exceeded the action of natural isothiocyanates, with four structures being more potent as tubulin polymerization inhibitors than BITC. As a confirmation of anti-tubulin activity, the correlation between polymerization inhibition and cell cycle arrest in the G2/M phase was observed for the most active compounds. In light of the biological results indicating significant differences in the impact of structurally diverse isothiocyanate on tubulin polymerization, in silico analysis was conducted to analyze the possible mode of isothiocyanate-tubulin binding and to show how it can influence the polymerization reaction.

3.
Int J Mol Sci ; 23(15)2022 Aug 03.
Article in English | MEDLINE | ID: mdl-35955773

ABSTRACT

One of the main treatment modalities for non-small-cell lung cancer (NSCLC) is cisplatin-based chemotherapy. However, the acquisition of cisplatin resistance remains a major problem. Existing chemotherapy regimens are often ineffective against cancer cells expressing aldehyde dehydrogenase (ALDH). As such, there is an urgent need for therapies targeting ALDH-positive cancer cells. The present study compares the anticancer properties of 36 structurally diverse isothiocyanates (ITCs) against NSCLC cells with the ALDH inhibitor disulfiram (DSF). Their potential affinity to ALDH isoforms and ABC proteins was assessed using AutoDockTools, allowing for selection of three compounds presenting the strongest affinity to all tested proteins. The selected ITCs had no impact on NSCLC cell viability (at tested concentrations), but significantly decreased the cisplatin tolerance of cisplatin-resistant variant of A549 (A549CisR) and advanced (stage 4) NSCLC cell line H1581. Furthermore, long-term supplementation with ITC 1-(isothiocyanatomethyl)-4-phenylbenzene reverses the EMT phenotype and migratory potential of A549CisR to the level presented by parental A549 cells, increasing E-Cadherin expression, followed by decreased expression of ABCC1 and ALDH3A1. Our data indicates that the ALDH inhibitors DSF and ITCs are potential adjuvants of cisplatin chemotherapy.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Aldehyde Dehydrogenase/metabolism , Antineoplastic Agents/therapeutic use , Benzene/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cisplatin/therapeutic use , Disulfiram/pharmacology , Disulfiram/therapeutic use , Drug Resistance, Neoplasm , Enzyme Inhibitors/pharmacology , Humans , Isothiocyanates/therapeutic use , Lung Neoplasms/metabolism , Neoplastic Stem Cells/metabolism
4.
Molecules ; 27(7)2022 Mar 31.
Article in English | MEDLINE | ID: mdl-35408669

ABSTRACT

Eight dipeptides containing antifibrinolytic agents (tranexamic acid, aminocaproic acid, 4-(aminomethyl)benzoic acid, and glycine-natural amino acids) were synthesized in a three-step process with good or very good yields. DMT/NMM/TsO- (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate) was used as a coupling reagent. Hemolysis tests were used to study the effects of the dipeptides on blood components. Blood plasma clotting tests were used to examine their effects on thrombin time (TT), prothrombin time (PT), and the activated partial thromboplastin time (aPTT). The level of hemolysis did not exceed 1%. In clotting tests, TT, PT, and aPTT did not differentiate any of the compounds. The prothrombin times for all amides 1-8 were similar. The obtained results in the presence of amides 1-4 and 8 were slightly lower than for the other compounds and the positive control, and they were similar to the results obtained for TA. In the case of amide 3, a significantly decreased aPTT was observed. The aPTTs observed for plasma treated with amide 3 and TA were comparable. In the case of amide 6 and 8, TT values significantly lower than for the other compounds were found. The clot formation and fibrinolysis (CFF) assay was used to assess the influence of the dipeptides on the blood plasma coagulation cascade and the fibrinolytic efficiency of the blood plasma. In the clot formation and fibrinolysis assay, amides 5 and 7 were among the most active compounds. The cytotoxicity and genotoxicity of the synthesized dipeptides were evaluated on the monocyte/macrophage peripheral blood cell line. The dipeptides did not cause hemolysis at any concentrations. They exhibited no significant cytotoxic effect on SC cells and did not induce significant DNA damage.


Subject(s)
Hemostatics , Amides/pharmacology , Dipeptides/pharmacology , Hemolysis , Hemostasis , Humans , Partial Thromboplastin Time , Prothrombin Time
5.
Molecules ; 27(5)2022 Mar 07.
Article in English | MEDLINE | ID: mdl-35268851

ABSTRACT

For decades, various plants have been studied as sources of biologically active compounds. Compounds with anticancer and antimicrobial properties are the most frequently desired. Cruciferous plants, including Brussels sprouts, broccoli, and wasabi, have a special role in the research studies. Studies have shown that consumption of these plants reduce the risk of lung, breast, and prostate cancers. The high chemopreventive and anticancer potential of cruciferous plants results from the presence of a large amount of glucosinolates, which, under the influence of myrosinase, undergo an enzymatic transformation to biologically active isothiocyanates (ITCs). Natural isothiocyanates, such as benzyl isothiocyanate, phenethyl isothiocyanate, or the best-tested sulforaphane, possess anticancer activity at all stages of the carcinogenesis process, show antibacterial activity, and are used in organic synthesis. Methods of synthesis of sulforaphane, as well as its natural or synthetic bifunctional analogues with sulfinyl, sulfanyl, sulfonyl, phosphonate, phosphinate, phosphine oxide, carbonyl, ester, carboxamide, ether, or additional isothiocyanate functional groups, and with the unbranched alkyl chain containing 2-6 carbon atoms, are discussed in this review. The biological activity of these compounds are also reported. In the first section, glucosinolates, isothiocyanates, and mercapturic acids (their metabolites) are briefly characterized. Additionally, the most studied anticancer and antibacterial mechanisms of ITC actions are discussed.


Subject(s)
Isothiocyanates , Sulfoxides
6.
Cells ; 10(11)2021 11 18.
Article in English | MEDLINE | ID: mdl-34831440

ABSTRACT

Isothiocyanates (ITCs) show strong activity against numerous human tumors. Five structurally diverse ITCs were tested in vivo using the zebrafish embryos 6 and 48 h post-fertilization (hpf). The survival rate, hatching time, and gross morphological changes were assessed 24, 48, and 72 h after treatment with all compounds in various doses (1-10 µM). As a result, we selected a phosphonate analog of sulforaphane (P-ITC; 1-3 µM) as a non-toxic treatment for zebrafish embryos, both 6 and 48 hpf. Furthermore, the in vivo anti-cancerogenic studies with selected 3 µM P-ITC were performed using a set of cell lines derived from the brain (U87), cervical (HeLa), and breast (MDA-MB-231) tumors. For the experiment, cells were labeled using red fluorescence dye Dil (1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindocarbocyanine, 10 µg/mL) and injected into the hindbrain ventricle, yolk sac region and Cuvier duct of zebrafish embryos. The tumor size measurement after 48 h of treatment demonstrated the significant inhibition of cancer cell growth in all tested cases by P-ITC compared to the non-treated controls. Our studies provided evidence for P-ITC anti-cancerogenic properties with versatile activity against different cancer types. Additionally, P-ITC demonstrated the safety of use in the living organism at various stages of embryogenesis.


Subject(s)
Antineoplastic Agents/pharmacology , Isothiocyanates/pharmacology , Organophosphonates/pharmacology , Sulfoxides/pharmacology , Xenograft Model Antitumor Assays , Zebrafish/physiology , Animals , Cell Line, Tumor , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/metabolism , Humans , Isothiocyanates/chemical synthesis , Isothiocyanates/chemistry , Microwaves , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Signal Transduction/drug effects , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Zebrafish/embryology
7.
Molecules ; 26(9)2021 May 06.
Article in English | MEDLINE | ID: mdl-34066597

ABSTRACT

Thirty-three alkyl and aryl isothiocyanates, as well as isothiocyanate derivatives from esters of coded amino acids and from esters of unnatural amino acids (6-aminocaproic, 4-(aminomethyl)benzoic, and tranexamic acids), were synthesized with satisfactory or very good yields (25-97%). Synthesis was performed in a "one-pot", two-step procedure, in the presence of organic base (Et3N, DBU or NMM), and carbon disulfide via dithiocarbamates, with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TsO-) as a desulfurization reagent. For the synthesis of aliphatic and aromatic isothiocyanates, reactions were carried out in a microwave reactor, and selected alkyl isothiocyanates were also synthesized in aqueous medium with high yields (72-96%). Isothiocyanate derivatives of L- and D-amino acid methyl esters were synthesized, under conditions without microwave radiation assistance, with low racemization (er 99 > 1), and their absolute configuration was confirmed by circular dichroism. Isothiocyanate derivatives of natural and unnatural amino acids were evaluated for antibacterial activity on E. coli and S. aureus bacterial strains, where the most active was ITC 9e.


Subject(s)
Chemistry, Organic/methods , Isothiocyanates/chemical synthesis , Morpholines/chemistry , Toluene/chemistry , Triazines/chemistry , Amines/chemistry , Anti-Bacterial Agents/chemistry , Chemistry Techniques, Synthetic , Chromatography , Circular Dichroism , Escherichia coli/drug effects , Indicators and Reagents , Isothiocyanates/analysis , Isothiocyanates/chemistry , Magnetic Resonance Spectroscopy , Microwaves , Solvents , Staphylococcus aureus/drug effects , Sulfur/chemistry , Temperature
8.
Chem Biodivers ; 18(4): e2100034, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33687147

ABSTRACT

Amylin aggregation is one of the factors in the development of diabetes mellitus, which is classified as a civilization disease. The aim of this research was to find whether non-aggregating fragments 1-7, 8-12, 13-17 and 28-32 of amylin would inhibit the aggregation of the amyloidogenic cores 18-22, 23-27, 33-37 of hormone. In the study of the inhibitory potential of non-aggregating amylin fragments, a set of independent methods were used to study aggregation properties (spectroscopic and fluorescence studies with the use of indicators, microscopic studies, circular dichroism studies) and the method of prediction of aggregation properties. The performed research allowed to select the cyclic fragment (1-7) H-KCNTATC-OH with disulfide bond as an inhibitor capable of inhibiting the aggregation of all amyloidogenic cores 18-22, 23-27, 33-37 of the hormone. Additionally, it was found that this peptide inhibits insulin hot spot aggregation, which may indicate its universal utility in inhibiting the process of aggregation of hormones regulating carbohydrate metabolism directly related to the development of diabetes. Research on the possibility of the extensive use of the cyclic fragment (1-7) of H-KCNTATC-OH as a peptide inhibitor of the polypeptide/protein aggregation process is ongoing.


Subject(s)
Hormones/metabolism , Islet Amyloid Polypeptide/pharmacology , Peptide Fragments/pharmacology , Humans , Islet Amyloid Polypeptide/chemistry , Peptide Fragments/chemistry , Protein Aggregates/drug effects
9.
Life Sci ; 219: 264-271, 2019 Feb 15.
Article in English | MEDLINE | ID: mdl-30658100

ABSTRACT

Thirty-four novel, diaryl ω-(isothiocyanato)alkylphosphonates with chlorine atom and methoxy, dimethoxy, methylsulfanyl, or methoxycarbonyl groups at ortho, meta, or para positions of the phenyl ring, and with an unbranched alkyl chain (n = 2-6) were designed and synthesized in a one-pot reaction in 11-76% yields. All isothiocyanates thus generated were evaluated for the first time for antibacterial activity on Pseudomonas aeruginosa and Staphylococcus aureus bacterial strains, and had satisfactory antibacterial activity in most cases. The highest activity, similar to that of reference gentamicin activity against S. aureus, was seen in compounds 9 and 13 (1.5 ±â€¯0.1 and 2.5 ±â€¯0.2 µM, respectively), whereas for P. aeruginosa more than half of tested compounds proved to be more effective than gentamicin. Additionally, selected isothiocyanates (9, 13, 18, and 23) were transformed in 52-73% yields into mercapturic acids 42-45, which also exhibited satisfactory antibacterial effect against S. aureus strain.


Subject(s)
Acetylcysteine/analogs & derivatives , Isothiocyanates/pharmacology , Organophosphonates/pharmacology , Acetylcysteine/pharmacology , Anti-Bacterial Agents , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 28(15): 2611-2615, 2018 08 15.
Article in English | MEDLINE | ID: mdl-29945793

ABSTRACT

A series of phosphonates, phosphinates and phosphine oxides isothiocyanate-derived mercapturic acids were synthesized. A temperature dependence dynamic proton decoupled 31P NMR studies indicated that in most cases the compounds were obtained as a mixture of rotamers. Moreover, biologically relevant reversibility of mercapturic acids synthesis from the parental isothiocyanates was confirmed. All compounds were evaluated ashighly active antiproliferative agents in vitro in human colon cancer cell lines (LoVo and its doxorubicin-resistant subline LoVo/DX). The cell cycle progression and caspase-3 activity analyses revealed compounds moderate activity as apoptosis inducers and their poor influence on cell cycle progression in the LoVo cells. Our results confirm that isothiocyanate-derived mercapturic acids present a reasonable alternative for the parental compounds, and can replace them in the future studies on isothiocyanates potential as anticancer agents.


Subject(s)
Acetylcysteine/therapeutic use , Antineoplastic Agents/therapeutic use , Isothiocyanates/chemistry , Neoplasms, Experimental/drug therapy , Phosphorus/chemistry , Acetylcysteine/pharmacology , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Humans , Isothiocyanates/therapeutic use , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry , Neoplasms, Experimental/pathology , Spectrophotometry, Infrared
11.
ChemMedChem ; 13(1): 105-115, 2018 01 08.
Article in English | MEDLINE | ID: mdl-29171934

ABSTRACT

A series of 21 novel, structurally diverse ω-(isothiocyanato)alkylphosphinates and phosphine oxides (ITCs) were designed and synthesized in moderate to good yields. The synthesized compounds were evaluated for in vitro antiproliferative activity using LoVo and LoVo/DX cancer cell lines. The biological activity of the synthesized compounds was higher than that of natural isothiocyanates such as benzyl isothiocyanate or sulforaphane. The antiproliferative activity of selected ITCs was also tested on selected cancer cell lines: A549, MESSA and MESSA/DX-5, HL60 and HL60MX2, BALB/3T3, and 4T1. These compounds were assessed for their mechanism of action as inducers of cell-cycle arrest and apoptosis. Ethyl (6-isothiocyanatohexyl)(phenyl)phosphinate (71) was tested in vivo on the 4T1 cell line and demonstrated moderate antitumor activity, similar to that benzyl isothiocyanate and cyclophosphamide.


Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Design , Phosphines/chemistry , Phosphinic Acids/chemistry , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Isothiocyanates/chemistry , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred BALB C , Neoplasms/drug therapy , Neoplasms/pathology , Oxides/chemistry , Phosphines/pharmacology , Phosphines/therapeutic use , Phosphinic Acids/pharmacology , Phosphinic Acids/therapeutic use , Structure-Activity Relationship
12.
Eur J Med Chem ; 132: 63-80, 2017 May 26.
Article in English | MEDLINE | ID: mdl-28342398

ABSTRACT

A library of over forty, novel, structurally diverse phosphonate analogs of sulforaphane (P-ITCs) were designed, synthesized and fully characterized. All compounds were evaluated for antiproliferative activity in vitro on Lovo and LoVo/DX colon cancer cell lines. All compounds exhibited high antiproliferative activity, comparable or higher to the activity of naturally occurring benzyl isothiocyanate and sulforaphane. Assessment of the mechanisms of action of selected compounds revealed their potential as inducers of G2/M cell cycle arrest and apoptosis. Further antiproliferative studies for selected compounds with the use of a set of selected cell lines derived from colon, lung, mammary gland and uterus as well as normal murine fibroblasts were performed. In vivo studies of the analyzed phosphonate analogs of sulforaphane showed lower activity in comparison with those of benzyl isothiocyanate. Our studies demonstrated that newly synthesized P-ITCs can be used for as a starting point for the synthesis of novel isothiocyanates with higher anticancer activity in the future.


Subject(s)
Antineoplastic Agents/chemical synthesis , Isothiocyanates/chemical synthesis , Organophosphonates/chemistry , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Isothiocyanates/pharmacology , Mice , Organophosphonates/pharmacology , Sulfoxides
13.
Org Biomol Chem ; 13(24): 6844-56, 2015 Jun 28.
Article in English | MEDLINE | ID: mdl-26018626

ABSTRACT

Fourteen novel prodrug-like analogs of two highly ionic phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase were synthesized and preliminary assessment of their chemical and enzymatic stability was evaluated in buffers (pH 6.5 and 7.4) and rat intestinal homogenate (pH 6.5). Both acidic groups in phosphonocarboxylates were subject to modification. Phosphonic acid was protected either as bis(acyloxyalkyl) ester or phosphonodiamidate derived from amino acids. The carboxylic acid group was either left unchanged or was studied as ethyl ester. The compounds exhibited favorable stability in physiologically relevant pH (t1/2 above 18 h), while in intestinal homogenate they showed a large variety of half-lives (from 5 minutes to over 150 hours). LC MS studies have shown that the main product of decomposition under studied conditions resulted from cleavage of one of the ester (for acyloxyalkyl analogs) or amide (for phosphonodiamidate) bonds with phosphorus.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Carboxylic Acids/chemical synthesis , Enzyme Inhibitors/chemistry , Organophosphonates/chemical synthesis , Prodrugs/chemical synthesis , Animals , Carboxylic Acids/chemistry , Carboxylic Acids/metabolism , Drug Stability , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Intestinal Mucosa/metabolism , Organophosphonates/chemistry , Organophosphonates/metabolism , Prodrugs/chemistry , Prodrugs/metabolism , Rats
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