Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
Add more filters










Publication year range
1.
Eur J Med Chem ; 259: 115716, 2023 Nov 05.
Article in English | MEDLINE | ID: mdl-37573829

ABSTRACT

New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized as tariquidar and elacridar derivatives and studied as multidrug resistance (MDR) reversers. Their behaviour on the three ABC transporters P-gp, MRP1 and BCRP was investigated. All compounds inhibited the P-gp transport activity in MDCK-MDR1 cells overexpressing P-gp, showing EC50 values even in the low nanomolar range (compounds 15, 22). Oxadiazole derivatives were able to increase the antiproliferative effect of doxorubicin in MDCK-MDR1 and in HT29/DX cells confirming their nature of P-gp modulators, with derivative 15 being the most potent in these assays. Compound 15 also displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP. A computational study suggested a common interaction pattern on P-gp for most of the potent compounds. The bioisosteric substitution of the amide group of lead compounds allowed identifying a new set of potent oxadiazole derivatives that modulate MDR through inhibition of the P-gp efflux activity. If compared to previous amide derivatives, the introduction of the heterocycle rings greatly enhances the activity on P-gp, introduces in two compounds a moderate inhibitory activity on MRP1 and maintains in some cases the effect on BCRP, leading to the unveiling of dual inhibitor 15.


Subject(s)
Antineoplastic Agents , Antineoplastic Agents/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Drug Resistance, Neoplasm , Structure-Activity Relationship , Neoplasm Proteins , Drug Resistance, Multiple , Tetrazoles/pharmacology , Amides/pharmacology
2.
Int J Mol Sci ; 24(13)2023 Jul 06.
Article in English | MEDLINE | ID: mdl-37446333

ABSTRACT

The tandem mass spectrometry (MS/MS) approach employing an ion trap mass analyzer (IT) was evaluated in isomers recognition. The proposed approach consists of sole, simple, and rapid liquid chromatographic separation (HPLC) without requiring resolution between the analytes. Then, the MS/MS properties were optimized to solve the signal assignment using post-processing data elaboration (LEDA). The IT-MS/MS experiment uses the same site, helium as collision gas, and different time steps to modify the applied conditions on the studied ions. Nevertheless, helium cannot ensure the quick energization of the precursor ion due to its small cross-section. Then, different combinations between excitation amplitude (ExA) and excitation time (ExT) were tested to achieve the activation of the fragmentation channels and the formation of the MS/MS spectrum. Usually, the IT-MS/MS acquisition cycle is longer for other multistage instruments, decreasing the frequency of sample data collection and influencing the chromatographic profile. To solve these problems, two time segments were set up, and the elution conditions were optimized with a compromise between peaks distinction and run time reduction. The developed HPLC-MS/MS method was checked and applied to analyze a series of human plasma samples spiked with an equimolar mixture of pair of isomers.


Subject(s)
Helium , Tandem Mass Spectrometry , Humans , Chromatography, High Pressure Liquid , Tandem Mass Spectrometry/methods , Chromatography, Liquid/methods , Algorithms
3.
Molecules ; 28(3)2023 Jan 28.
Article in English | MEDLINE | ID: mdl-36770942

ABSTRACT

Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on the compounds that have been shown or have been designed to interact with nicotinic receptors as allosteric modulators of different subtypes, mainly α7 and α4ß2. Minimal chemical changes can cause a different pharmacological profile, which can then lead to the design of selective modulators. Experimental evidence supports the use of allosteric modulators as therapeutic tools for neurological and non-neurological conditions.


Subject(s)
Receptors, Nicotinic , Receptors, Nicotinic/metabolism , alpha7 Nicotinic Acetylcholine Receptor/chemistry , Allosteric Regulation , Allosteric Site
4.
Molecules ; 29(1)2023 Dec 21.
Article in English | MEDLINE | ID: mdl-38202651

ABSTRACT

The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed.


Subject(s)
Piperazine , United States , United States Food and Drug Administration
5.
Int J Mol Sci ; 25(1)2023 Dec 22.
Article in English | MEDLINE | ID: mdl-38203351

ABSTRACT

Metformin is the most prescribed glucose-lowering drug worldwide; globally, over 100 million patients are prescribed this drug annually. Some different action mechanisms have been proposed for this drug, but, surprisingly, no metabolite of metformin has ever been described. It was considered interesting to investigate the possible reaction of metformin with glucose following the Maillard reaction pattern. The reaction was first performed in in vitro conditions, showing the formation of two adducts that originated by the condensation of the two molecular species with the losses of one or two water molecules. Their structures were investigated by liquid chromatography coupled with mass spectrometry (HPLC-MS), tandem mass spectrometry (MS/MS) and accurate mass measurements (HRMS). The species originated via the reaction of glucose and metformin and were called metformose and dehydrometformose, and some structural hypotheses were conducted. It is worth to emphasize that they were detected in urine samples from a diabetic patient treated with metformin and consequently they must be considered metabolites of the drug, which has never been identified before now. The glucose-related substructure of these compounds could reflect an improved transfer across cell membranes and, consequently, new hypotheses could be made about the biological targets of metformin.


Subject(s)
Metformin , Humans , Tandem Mass Spectrometry , Liquid Chromatography-Mass Spectrometry , Cell Membrane , Glucose
6.
Int J Mol Sci ; 23(21)2022 Oct 28.
Article in English | MEDLINE | ID: mdl-36361928

ABSTRACT

This paper proposes a tandem mass spectrometry (MS/MS) approach in isomer recognition by playing in the "energetic dimension" of the experiment. The chromatographic set up (HPLC) was tuned to minimize the run time, without requiring high efficiency or resolution between the isomers. Then, the MS/MS properties were explored to solve the signal assignment by performing a series of energy resolved experiments in order to optimize the parameters, and by applying an interesting post-processing data elaboration tool (LEDA). The reliability of the new approach was evaluated, determining the accuracy and precision of the quantitative results through analysis of the isomer mixture solutions. Next, the proposed method was applied in a chemical stability study of human plasma samples through the simultaneous addition of a pair of isomers. In the studied case, only one of the isomers suffered of enzymatic hydrolysis; therefore, the influence of the stable isomer on the degradation rate of the other was verified. In order to monitor this process correctly, it must be possible to distinguish each isomer present in the sample, quantify it, and plot its degradation profile. The reported results demonstrated the effectiveness of the LEDA algorithm in separating the isomers, without chromatographic resolution, and monitoring their behavior in human plasma samples.


Subject(s)
Algorithms , Tandem Mass Spectrometry , Humans , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Reproducibility of Results , Isomerism
7.
J Med Chem ; 65(21): 14655-14672, 2022 11 10.
Article in English | MEDLINE | ID: mdl-36269278

ABSTRACT

In a continuing search of dual P-gp and hCA XII inhibitors, we synthesized and studied new N,N-bis(alkanol)amine aryl diester derivatives characterized by the presence of a coumarin group. These hybrids contain both P-gp and hCA XII binding groups to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing both P-gp and hCA XII. Indeed, hCA XII modulates the efflux activity of P-gp and the inhibition of hCA XII reduces the intracellular pH, thereby decreasing the ATPase activity of P-gp. All compounds showed inhibitory activities on P-gp and hCA XII proteins taken individually, and many of them displayed a synergistic effect in HT29/DOX and A549/DOX cells that overexpress both P-gp and hCA XII, being more potent than in K562/DOX cells overexpressing only P-gp. Compounds 5 and 14 were identified as promising chemosensitizer agents for selective inhibition in MDR cancer cells overexpressing both P-gp and hCA XII.


Subject(s)
Carbonic Anhydrases , Neoplasms , Humans , Structure-Activity Relationship , Carbonic Anhydrases/metabolism , Drug Resistance, Multiple , Amines/chemistry , ATP Binding Cassette Transporter, Subfamily B/metabolism , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase IX , Antigens, Neoplasm/metabolism , Molecular Structure , Neoplasms/drug therapy
8.
Curr Top Med Chem ; 22(31): 2535-2569, 2022.
Article in English | MEDLINE | ID: mdl-36284399

ABSTRACT

BACKGROUND: The failure of anticancer chemotherapy is often due to the development of resistance to a variety of anticancer drugs. This phenomenon is called multidrug resistance (MDR) and is related to the overexpression of ABC transporters, such as P-glycoprotein, multidrug resistance- associated protein 1 and breast cancer resistance protein. Over the past few decades, several ABC protein modulators have been discovered and studied as a possible approach to evade MDR and increase the success of anticancer chemotherapy. Nevertheless, the co-administration of pump inhibitors with cytotoxic drugs, which are substrates of the transporters, does not appear to be associated with an improvement in the therapeutic efficacy of antitumor agents. However, more recently discovered MDR reversing agents, such as the two tetrahydroisoquinoline derivatives tariquidar and elacridar, are characterized by high affinity towards the ABC proteins and by reduced negative properties. Consequently, many analogs of these two derivatives have been synthesized, with the aim of optimizing their MDR reversal properties. OBJECTIVE: This review aims to describe the MDR modulators carrying the tetraidroisoquinoline scaffold reported in the literature in the period 2009-2021, highlighting the structural characteristics that confer potency and/or selectivity towards the three ABC transport proteins. RESULTS AND CONCLUSION: Many compounds have been synthesized in the last twelve years showing interesting properties, both in terms of potency and selectivity. Although clear structure-activity relationships can be drawn only by considering strictly related compounds, some of the compounds reviewed could be promising starting points for the design of new ABC protein inhibitors.


Subject(s)
Antineoplastic Agents , Neoplasms , Tetrahydroisoquinolines , Humans , ATP-Binding Cassette Transporters , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Drug Resistance, Neoplasm , Neoplasm Proteins , Drug Resistance, Multiple , Antineoplastic Agents/chemistry , Multidrug Resistance-Associated Proteins , Tetrahydroisoquinolines/pharmacology , Neoplasms/drug therapy
9.
Expert Opin Drug Discov ; 17(9): 969-984, 2022 09.
Article in English | MEDLINE | ID: mdl-35848922

ABSTRACT

INTRODUCTION: Piperazine is a structural element present in drugs belonging to various chemical classes and used for numerous different therapeutic applications; it has been considered a privileged scaffold for drug design. AREAS COVERED: The authors have searched examples of piperazine-containing compounds among drugs recently approved by the FDA and in some research fields (nicotinic receptor modulators, compounds acting against cancer, and bacterial multidrug resistance), looking in particular to the design behind the insertion of this moiety. EXPERT OPINION: Piperazine is widely used due to its peculiar characteristics, such as solubility, basicity, chemical reactivity, and conformational properties. This moiety has represented an important tool to modulate pharmacokinetic and pharmacodynamic properties of drugs.


Subject(s)
Neoplasms , Receptors, Nicotinic , Drug Design , Drug Discovery , Humans , Piperazine/pharmacology
10.
J Pharm Biomed Anal ; 219: 114887, 2022 Sep 20.
Article in English | MEDLINE | ID: mdl-35753165

ABSTRACT

Design and synthesis of new candidate drugs produces a large number of compounds that must be qualified and tested to evaluate their characteristics and potential applications. Therefore, many studies will be scheduled and, consequently, it will be necessary to arrange specific, reliable, fast and relatively cheap analytic methods to support this research. The manuscript proposes a new approach in the HPLC-MS/MS analysis by using a sole chromatographic set up, tuned to minimize the run time, without requiring high efficiency or resolution between the analytes. The chromatographic column was used only to avoid or limit the interference of sample matrix towards the analyte ionization process (matrix-effects). Then, the MS/MS properties were explored to solve the signal assignment, by performing a series of energy resolved experiments to optimize the parameters and applying an interesting post-processing data elaboration tool (LEDA). The reliability of the new approach was evaluated in a chemical stability study in PBS and human plasma samples of a series of isomeric compounds P-glycoprotein/Carbonic Anhydrase (P-gp/CA) hybrid inhibitors. The obtained results demonstrated the effectiveness (reliability 97%-100%) of the LEDA algorithm to recognize and to separate the possible isomers present in the samples. The obtained matrix-effects values (ME 96%-106%) established that the chromatographic set up (short column and fast elution gradient) was proper to avoid the matrix interferences, while recovery values (RE 88%-108%) indicate a suitable sample preparation, despite only a protein precipitation was carried out. The quantitative performances of proposed HPLC-MS/MS methods showed an accuracy ranging between 92% and 108% and a precision lower than 13% that allows to be confident on the determination of new P-gp/CA hybrid inhibitors in the degradation study. Therefore, the general procedure proposed was found adequate to study a series of isomeric compounds without their chromatographic separation but only by applying and developing the MS/MS features.


Subject(s)
Carbonic Anhydrases , Tandem Mass Spectrometry , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Algorithms , Carbonic Anhydrase Inhibitors , Chromatography, High Pressure Liquid/methods , Humans , Reproducibility of Results , Tandem Mass Spectrometry/methods
11.
ChemMedChem ; 17(12): e202200027, 2022 06 20.
Article in English | MEDLINE | ID: mdl-35416421

ABSTRACT

Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC50 values in the nanomolar range (1 d, 1 e, 2 a, 2 c, 2 e). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP.


Subject(s)
Antineoplastic Agents , Quinazolines , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Neoplasm Proteins/metabolism , Quinazolines/pharmacology
12.
Molecules ; 27(2)2022 Jan 15.
Article in English | MEDLINE | ID: mdl-35056859

ABSTRACT

A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.


Subject(s)
Carbonic Anhydrase I/metabolism , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Histamine/chemistry , Histamine/pharmacology , Carbonic Anhydrase I/drug effects , Carbonic Anhydrase II/drug effects , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase V/drug effects , Carbonic Anhydrase V/metabolism , Carbonic Anhydrases/drug effects , Carbonic Anhydrases/metabolism , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Histamine/analogs & derivatives , Histamine/chemical synthesis , Humans , Imidazoles/chemistry , Protein Isoforms/drug effects , Protein Isoforms/metabolism
13.
J Antimicrob Chemother ; 77(2): 413-424, 2022 02 02.
Article in English | MEDLINE | ID: mdl-34747445

ABSTRACT

BACKGROUND: MDR in bacteria is threatening to public health. Overexpression of efflux pumps is an important cause of MDR. The co-administration of antimicrobial drugs and efflux pump inhibitors (EPIs) is a promising approach to address the problem of MDR. OBJECTIVES: To identify new putative EPIs and to characterize their mechanisms of action. METHODS: The effects of four selected piperazine derivatives on resistance-nodulation-cell division (RND) pumps was evaluated in Escherichia coli strains overexpressing or not expressing RND pumps by assays aimed at evaluating antibiotic potentiation, membrane functionality, ethidium bromide accumulation and AcrB expression. The cytotoxicity of selected piperazines towards primary cultures of human dermal fibroblasts was also investigated. RESULTS: Four molecules enhanced levofloxacin activity against strains overexpressing RND efflux pumps (AcrAB-TolC and AcrEF-TolC), but not against RND pump-deficient strains. They had little effects on membrane potential. Molecule 4 decreased, whereas the other three increased, membrane permeability compared with untreated control cells. The four molecules showed differences in the specificity of interaction with RND efflux pumps, by inactivating the transport of one or more antibiotics, and in the levels of ethidium bromide accumulation and of acrB expression inhibition. CONCLUSIONS: Piperazine derivatives are good candidates as inhibitors of RND efflux pumps. They decreased the activity of RND pumps by mixed mechanisms of action. Small structural differences among the molecules can be critical in defining their behaviour.


Subject(s)
Anti-Bacterial Agents , Escherichia coli Proteins , Escherichia coli , Multidrug Resistance-Associated Proteins , Piperazines , Anti-Bacterial Agents/pharmacology , Cell Division , Drug Resistance, Multiple, Bacterial , Escherichia coli/drug effects , Escherichia coli Proteins/metabolism , Humans , Microbial Sensitivity Tests , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Piperazines/pharmacology
14.
Eur J Med Chem ; 228: 114026, 2022 Jan 15.
Article in English | MEDLINE | ID: mdl-34920169

ABSTRACT

Targeting Carbonic Anhydrases (CAs) represents a strategy to treat several diseases, from glaucoma to cancer. To widen the structure-activity relationships (SARs) of our series of piperazines endowed with potent human carbonic anhydrase (hCA) inhibition, a new series of chiral piperazines carrying a (2-hydroxyethyl) group was prepared. The Zn-binding function, the 4-sulfamoylbenzoyl moiety, was connected to one piperazine N-atom, while the other nitrogen was decorated with alkyl substituents. In analogy to the approach used for the synthesis of the previously reported series, the preparation of the new compounds started with (R)- and (S)-aspartic acid. A partial racemization occurred during the synthesis. In order to overcome this problem, other chemical strategies were investigated. The inhibitory activity of the new polar derivatives against four hCAs isoforms I, II, IV and IX using a stopped flow CO2 hydrase assay was determined. Some compounds showed potency in the nanomolar range and a preference for inhibiting hCA IX.


Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Glaucoma/drug therapy , Molecular Dynamics Simulation , Ophthalmic Solutions/pharmacology , Piperazine/pharmacology , Animals , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glaucoma/metabolism , Glaucoma/pathology , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Molecular Structure , Ophthalmic Solutions/chemical synthesis , Ophthalmic Solutions/chemistry , Piperazine/chemical synthesis , Piperazine/chemistry , Rabbits , Structure-Activity Relationship
15.
Future Microbiol ; 15: 987-999, 2020 07.
Article in English | MEDLINE | ID: mdl-32840130

ABSTRACT

Aim: To investigate the action mechanism of 1-benzyl-1,4-diazepane (1-BD) as efflux pump inhibitor (EPI) in Escherichia coli mutants: ΔacrAB or overexpressing AcrAB and AcrEF efflux pumps. Materials & methods: Effect of 1-BD on: antibiotic potentiation, by microdilution method; membrane functionality, by fluorimetric assays; ethidium bromide accumulation, by fluorometric real-time efflux assay; AcrB expression, by quantitative photoactivated localization microscopy. Results: 1-BD decreases the minimal inhibitory concentration of levofloxacin and other antibiotics and increase ethidium bromide accumulation in E. coli overexpressing efflux pumps but not in the ΔacrAB strain. 1-BD increases membranes permeability, without sensibly affecting inner membrane polarity and decreases acrAB transcription. Conclusion: 1-BD acts as an EPI in E. coli with a mixed mechanism, different from that of major reference EPIs.


Subject(s)
Anti-Bacterial Agents/pharmacology , Azepines/pharmacology , Escherichia coli/drug effects , Escherichia coli/metabolism , Drug Resistance, Multiple, Bacterial , Escherichia coli/genetics , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Humans , Levofloxacin/pharmacology , Lipoproteins/genetics , Lipoproteins/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Microbial Sensitivity Tests , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism
16.
J Enzyme Inhib Med Chem ; 35(1): 1003-1010, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32336172

ABSTRACT

The Carbonic Anhydrase (CA, EC 4.2.1.1) activating properties of histamine have been known for a long time. This compound has been extensively modified but only in few instances the imidazole ring has been replaced with other heterocycles. It was envisaged that the imidazoline ring could be a bioisoster of the imidazole moiety. Indeed, we report that clonidine, a 2-aminoimidazoline derivative, was found able to activate several human CA isoforms (hCA I, IV, VA, VII, IX, XII and XIII), with potency in the micromolar range, while it was inactive on hCA II. A series of 2-aminoimidazoline, structurally related to clonidine, was then synthesised and tested on selected hCA isoforms. The compounds were inactive on hCA II while displayed activating properties on hCA I, VA, VII and XIII, with KA values in the micromolar range. Two compounds (10 and 11) showed some preference for the hCA VA or VII isoforms.


Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Clonidine/pharmacology , Imidazoles/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Clonidine/chemistry , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Structure-Activity Relationship
17.
Molecules ; 25(7)2020 Apr 10.
Article in English | MEDLINE | ID: mdl-32290281

ABSTRACT

A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Biological Transport , Carbonic Anhydrase Inhibitors/pharmacology , Doxorubicin/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm/drug effects , Drug Stability , Humans , K562 Cells , Molecular Structure , Structure-Activity Relationship
18.
J Enzyme Inhib Med Chem ; 35(1): 974-992, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32253945

ABSTRACT

Aiming to deepen the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.


Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Esters/pharmacology , Neoplasms/drug therapy , Tetrahydroisoquinolines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Amides/chemical synthesis , Amides/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Esters/chemical synthesis , Esters/chemistry , Humans , Molecular Structure , Neoplasms/metabolism , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/chemistry
19.
Eur J Med Chem ; 182: 111655, 2019 Nov 15.
Article in English | MEDLINE | ID: mdl-31494468

ABSTRACT

Stereo- and regioisomers of a series of N,N-bis(alkanol)amine aryl ester derivatives have been prepared and studied as multidrug resistance (MDR) modulators. The new compounds contain a 2-(methyl)propyl chain combined with a 3-, 5- or 7-methylenes long chain and carry different aromatic ester portions. Thus, these compounds have a methyl group on the 3-methylenes chain and represent branched homologues of previously studied derivatives. The introduction of the methyl group gives origin to a stereogenic center and consequently to (R) and (S) enantiomers. In the pirarubicin uptake assay on K562/DOX cell line these compounds showed good activity and efficacy and in many cases enantioselectivity was observed. Docking studies confirmed the influence of the stereocenter on the interaction in the P-gp pocket. The P-gp interaction mechanism and selectivity towards MRP1 and BCRP were also evaluated on MDCK transfected cells overexpressing the three transporters. Almost all these compounds inhibited both P-gp and BCRP, but only derivatives with specific structural characteristics showed MRP1 activity. Moreover, two compounds, (S)-3 and (R)-7, showed the ability to induce collateral sensitivity (CS) against MDR cells. Therefore, these two CS-promoting agents could be considered interesting leads for the development of selective cytotoxic agents for drug-resistant cells.


Subject(s)
Amines/pharmacology , Antineoplastic Agents/pharmacology , Drug Design , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Esters/pharmacology , Amines/chemical synthesis , Amines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Esters/chemical synthesis , Esters/chemistry , Humans , K562 Cells , Madin Darby Canine Kidney Cells/drug effects , Molecular Docking Simulation , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
20.
Bioorg Chem ; 91: 103130, 2019 10.
Article in English | MEDLINE | ID: mdl-31374520

ABSTRACT

Starting from the molecular simplification of (R) 4-(3,4-dibenzylpiperazine-1-carbonyl)benzenesulfonamide 9a, a compound endowed with selectivity for human Carbonic Anhydrase (hCA) IV, a series of piperazines and 4-aminopiperidines carrying a 4-sulfamoylbenzamide moiety as Zn-binding group have been designed and tested on human isoforms hCA I, II, IV and IX, using a stopped flow CO2 hydrase assay. The aim of the work was to derive structure-activity relationships useful for designing isoform selective compounds. These structural modifications changed the selectivity profile of the analogues from hCA IV to hCA I and II, and improved potency. Several of the new compounds showed subnanomolar activity on hCA II. X-ray crystallography of ligand-hCAII complexes was used to compare the binding modes of the new piperazines and the previously synthesized 2-benzyl-piperazine analogues, explaining the inhibition profiles.


Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Piperazines/pharmacology , Sulfonamides/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/chemistry , Carbonic Anhydrases/metabolism , Catalytic Domain , Crystallography, X-Ray , Humans , Isoenzymes/chemistry , Isoenzymes/metabolism , Molecular Structure , Piperazines/chemical synthesis , Piperazines/metabolism , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...