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1.
J Med Chem ; 62(3): 1274-1290, 2019 02 14.
Article in English | MEDLINE | ID: mdl-30633509

ABSTRACT

The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3',4',5'-trimethoxyanilino)thieno[3,2- d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3',4',5'-trimethoxyanilino)-6-( p-tolyl)thieno[3,2- d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 µM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.


Subject(s)
Drug Design , ErbB Receptors/antagonists & inhibitors , Microtubules/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/metabolism , Drug Evaluation, Preclinical , Enzyme Activation , HeLa Cells , Humans , Membrane Potential, Mitochondrial/drug effects , Poly(ADP-ribose) Polymerases/metabolism , Polymerization , Reactive Oxygen Species/metabolism , Tubulin/metabolism , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
2.
Bioorg Chem ; 80: 361-374, 2018 10.
Article in English | MEDLINE | ID: mdl-29986184

ABSTRACT

Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3',4',5'-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC50 < 1 µM) against selected cancer cells. Among them, several molecules preferentially inhibited the proliferation of leukemic cell lines, showing IC50 values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC50 value of 0.66 µM, half that obtained in simultaneous experiments with CA-4 (IC50 = 1.3 µM).


Subject(s)
Drug Design , Triazoles/chemistry , Tubulin Modulators/chemical synthesis , Tubulin/metabolism , Apoptosis/drug effects , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Colchicine/chemistry , Colchicine/metabolism , Drug Screening Assays, Antitumor , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , Molecular Dynamics Simulation , Protein Binding , Protein Structure, Tertiary , Structure-Activity Relationship , Thermodynamics , Triazoles/metabolism , Triazoles/pharmacology , Tubulin/chemistry , Tubulin Modulators/metabolism , Tubulin Modulators/pharmacology
3.
J Enzyme Inhib Med Chem ; 33(1): 727-742, 2018 Dec.
Article in English | MEDLINE | ID: mdl-29620429

ABSTRACT

The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. To investigate the influence of the position of the pyridine nitrogen on biological activity, two different series of α-bromoacryloylamido indolyl pyridinyl propenones 3a-h and 4a-d were designed and synthesized by a pharmacophore hybridization approach and evaluated for their antiproliferative activity against a panel of six human cancer cell lines. These hybrid molecules were prepared to combine the α-bromoacryloyl moiety with two series of indole-inspired chalcone analogues, possessing an indole derivative and a 3- or 4-pyridine ring, respectively, linked on either side of 2-propen-1-one system. The structure-activity relationship was also investigated by the insertion of alkyl or benzyl moieties at the N-1 position of the indole nucleus. We found that most of the newly synthesized displayed high antiproliferative activity against U-937, MOLT-3, K-562, and NALM-6 leukaemia cell lines, with one-digit to double-digit nanomolar IC50 values. The antiproliferative activities of 3-pyridinyl derivatives 3f-h revealed that N-benzyl indole analogues generally exhibited lower activity compared to N-H or N-alkyl derivatives 3a-b and 3c-e, respectively. Moreover, cellular mechanism studies elucidated that compound 4a induced apoptosis along with a decrease of mitochondrial membrane potential and activated caspase-3 in a concentration-dependent manner.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Indoles/pharmacology , Pyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Chalcone/analogs & derivatives , Chalcone/chemical synthesis , Chalcone/chemistry , Chalcone/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
4.
J Med Chem ; 61(3): 1340-1354, 2018 02 08.
Article in English | MEDLINE | ID: mdl-29309142

ABSTRACT

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol, which is implicated in many physiological processes. Beyond the possible utilization of MAGL inhibitors as anti-inflammatory, antinociceptive, and anticancer agents, their application has encountered obstacles due to the unwanted effects caused by the irreversible inhibition of this enzyme. The possible application of reversible MAGL inhibitors has only recently been explored, mainly due to the deficiency of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of reversible MAGL inhibitors. Among them, compound 26 showed to be a potent MAGL inhibitor (IC50 = 0.51 µM, Ki = 412 nM) with a good selectivity versus fatty acid amide hydrolase (FAAH), α/ß-hydrolase domain-containing 6 (ABHD6), and 12 (ABHD12). Interestingly, this compound also possesses antiproliferative activities against two different cancer cell lines and relieves the neuropathic hypersensitivity induced in vivo by oxaliplatin.


Subject(s)
Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Monoacylglycerol Lipases/antagonists & inhibitors , Pyrazoles/chemistry , Pyrazoles/pharmacology , Analgesics/chemistry , Analgesics/metabolism , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Male , Mice , Molecular Docking Simulation , Monoacylglycerol Lipases/chemistry , Monoacylglycerol Lipases/metabolism , Neuralgia/drug therapy , Protein Conformation , Pyrazoles/metabolism , Pyrazoles/therapeutic use , Substrate Specificity
5.
Eur J Med Chem ; 143: 683-698, 2018 Jan 01.
Article in English | MEDLINE | ID: mdl-29220790

ABSTRACT

Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC50 values ranging from 0.13 to 0.84 µM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC50 value of 140 nM, inhibited tubulin polymerization with an IC50 value of 1.2 µM, similar to that of CA-4 (IC50: 1.1 µM), and induced apoptosis in HeLa cells.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Microtubules/drug effects , Thiophenes/pharmacology , Tubulin Modulators/pharmacology , Tubulin/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Membrane Potential, Mitochondrial/drug effects , Mice , Models, Molecular , Molecular Structure , Polymerization/drug effects , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry
6.
Med Res Rev ; 38(4): 1031-1072, 2018 07.
Article in English | MEDLINE | ID: mdl-28682469

ABSTRACT

The A3 adenosine receptor (A3 AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A3 AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A3 AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A3 AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A3 AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A3 AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A3 AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A3 AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.


Subject(s)
Adenosine A3 Receptor Agonists/pharmacology , Arthritis, Rheumatoid/drug therapy , Carcinoma, Hepatocellular/drug therapy , Inflammation/drug therapy , Liver Neoplasms/drug therapy , Psoriasis/drug therapy , Receptor, Adenosine A3/metabolism , Allosteric Site , Animals , Clinical Trials as Topic , Crystallography, X-Ray , Humans , Immune System , Mice , Molecular Dynamics Simulation , Rats , Structure-Activity Relationship
7.
Sci Rep ; 7: 46356, 2017 04 13.
Article in English | MEDLINE | ID: mdl-28406191

ABSTRACT

Antimitotic agents that interfere with microtubule formation are one of the major classes of cytotoxic drugs for cancer treatment. Multiple 2-methyl-4-(3',4',5'-trimethoxyphenyl)-5-substituted oxazoles and their related 4-substituted-5-(3',4',5'-trimethoxyphenyl) regioisomeric derivatives designed as cis-constrained combretastatin A-4 (CA-4) analogues were synthesized and evaluated for their antiproliferative activity in vitro against a panel of cancer cell lines and, for selected highly active compounds, interaction with tubulin, cell cycle effects and in vivo potency. Both these series of compounds were characterized by the presence of a common 3',4',5'-trimethoxyphenyl ring at either the C-4 or C-5 position of the 2-methyloxazole ring. Compounds 4g and 4i, bearing a m-fluoro-p-methoxyphenyl or p-ethoxyphenyl moiety at the 5-position of 2-methyloxazole nucleus, respectively, exhibited the greatest antiproliferative activity, with IC50 values of 0.35-4.6 nM (4g) and 0.5-20.2 nM (4i), which are similar to those obtained with CA-4. These compounds bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. Furthermore, 4i strongly induced apoptosis that follows the mitochondrial pathway. In vivo, 4i in a mouse syngeneic model demonstrated high antitumor activity which significantly reduced the tumor mass at doses ten times lower than that required for CA-4P, suggesting that 4i warrants further evaluation as a potential anticancer drug.


Subject(s)
Oxazoles/chemical synthesis , Oxazoles/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Animals , Apoptosis/drug effects , Cell Cycle/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , DNA Damage/drug effects , Humans , Mice , Mitochondria/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Poly(ADP-ribose) Polymerases/metabolism , Protein Multimerization , Signal Transduction , Tubulin/chemistry , Tubulin/metabolism , Xenograft Model Antitumor Assays
8.
Eur J Med Chem ; 134: 258-270, 2017 Jul 07.
Article in English | MEDLINE | ID: mdl-28419928

ABSTRACT

The 2-oxindole nucleus is the central core to develop new anticancer agents and its substitution at the 3-position can effect antitumor activity. Utilizing a pharmacophore hybridization approach, a novel series of antiproliferative agents was obtained by the modification of the structure of 3-substituted-2-oxindole pharmacophore by the attachment of the α-bromoacryloyl moiety, acting as a Michael acceptor, at the 5-position of 2-oxindole framework. The impact of the substituent at the 3-position of 2-oxindole core on the potency and selectivity against a panel of seven different cancer cell lines was examined. We found that these hybrid molecules displayed potent antiproliferative activity against a panel of four cancer cell lines, with one-to double digit nanomolar 50% inhibitory concentrations (IC50). A distinctive selective antiproliferative activity was obtained towards CCRF-CEM and RS4; 11 leukemic cell lines. In order to study the possible mechanism of action, we observed that the two most active compounds namely 3(E) and 6(Z) strongly induce apoptosis that follow the mitochondrial pathway. Interestingly a decrease of intracellular reduced glutathione content (GSH) and reactive oxygen species (ROS) production was detected in treated cells compared with controls suggesting that these effects may be involved in their mechanism of action.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Indoles/chemistry , Indoles/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Glutathione/metabolism , Humans , Indoles/chemical synthesis , Membrane Potential, Mitochondrial/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Oxindoles , Reactive Oxygen Species/metabolism , Structure-Activity Relationship
9.
Med Res Rev ; 37(4): 936-983, 2017 07.
Article in English | MEDLINE | ID: mdl-27976413

ABSTRACT

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.


Subject(s)
Capsaicin/analogs & derivatives , TRPV Cation Channels/chemistry , TRPV Cation Channels/pharmacology , Animals , Capsaicin/chemistry , Capsaicin/pharmacology , Chemistry, Pharmaceutical , Humans , Structure-Activity Relationship , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/metabolism
10.
Sci Rep ; 6: 26602, 2016 05 24.
Article in English | MEDLINE | ID: mdl-27216165

ABSTRACT

A novel series of tubulin polymerization inhibitors, based on the 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3'-chloro-4'-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HL-60 Cells , HT29 Cells , HeLa Cells , Humans , Jurkat Cells , MCF-7 Cells , Mice , Models, Molecular , Molecular Structure , Neoplasms/metabolism , Stilbenes/chemistry , Tubulin Modulators/chemistry , Xenograft Model Antitumor Assays
11.
Eur J Med Chem ; 113: 11-27, 2016 May 04.
Article in English | MEDLINE | ID: mdl-26922225

ABSTRACT

CB2 cannabinoid receptor ligands are known to be therapeutically important for the treatment of numerous diseases. Recently, we have identified the heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives as highly potent and selective CB2 receptor ligands, showing that the pharmakodynamics of the new compounds was controlled by the nature of the heterocycle core. In this paper we describe the synthesis and biological evaluation of 7-oxo-4-pentyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide derivatives that led to the identification of novel CB2 receptor inverse agonists. Cyclic AMP experiments on CB2 receptors expressed in CHO cells revealed that introduction of structural modifications at position 2 of triazolopyrimidine template changes the functional activity from partial to inverse agonism. The molecular docking analysis of the novel structures is reported.


Subject(s)
Pyrimidines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Triazoles/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
12.
J Med Chem ; 58(13): 5355-60, 2015 Jul 09.
Article in English | MEDLINE | ID: mdl-26046697

ABSTRACT

In this paper we describe an extension SAR study of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A3AR antagonist. Our initial aim was to replace the phenylcarbamoyl moiety at the 5 position of PTP nucleus with a thiourea functionality to evaluate the contribution of new structural modification against the A3AR. The synthesized 12-25 were not characterized by the predicted side chain but by a 1,3-disubstituted guanidine and are shown to be interesting A3AR antagonists.


Subject(s)
Drug Design , Purinergic P1 Receptor Antagonists/chemistry , Purinergic P1 Receptor Antagonists/pharmacology , Pyrazoles/chemistry , Pyrimidines/chemistry , Receptor, Adenosine A3/chemistry , Animals , Binding, Competitive , CHO Cells , Cricetulus , Cyclic AMP/metabolism , Humans , Models, Molecular , Molecular Structure , Radioligand Assay , Structure-Activity Relationship
13.
Eur J Med Chem ; 97: 289-305, 2015 Jun 05.
Article in English | MEDLINE | ID: mdl-26002335

ABSTRACT

Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrazoles/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship
14.
J Med Chem ; 58(7): 3253-67, 2015 Apr 09.
Article in English | MEDLINE | ID: mdl-25780876

ABSTRACT

Stimulation of A2A adenosine receptors (AR) promotes anti-inflammatory responses in animal models of allergic rhinitis, asthma, chronic obstructive pulmonary disease, and rheumatic diseases. Herein we describe the results of a research program aimed at identifying potent and selective agonists of the A2AAR as potential anti-inflammatory agents. The recent crystallographic analysis of A2AAR agonists and antagonists in complex with the receptor provided key information on the structural determinants leading to receptor activation or blocking. In light of this, we designed a new series of 2-((4-aryl(alkyl)piperazin-1-yl)alkylamino)-5'-N-ethylcarboxamidoadenosines with high A2AAR affinity, activation potency and selectivity obtained by merging distinctive structural elements of known agonists and antagonists of the investigated target. Docking-based SAR optimization allowed us to identify compound 42 as one of the most potent and selective A2A agonist discovered so far (Ki hA2AAR = 4.8 nM, EC50 hA2AAR = 4.9 nM, Ki hA1AR > 10 000 nM, Ki hA3AR = 1487 nM, EC50 hA2BAR > 10 000 nM).


Subject(s)
Adenosine A2 Receptor Agonists/chemistry , Adenosine A2 Receptor Agonists/pharmacology , Receptor, Adenosine A2A/chemistry , Adenosine A2 Receptor Agonists/chemical synthesis , Adenosine A2 Receptor Agonists/metabolism , Adenosine-5'-(N-ethylcarboxamide)/chemistry , Animals , CHO Cells/drug effects , Chemistry Techniques, Synthetic , Cricetulus , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical/methods , Humans , Molecular Docking Simulation , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/metabolism , Structure-Activity Relationship
15.
Med Chem ; 11(4): 342-53, 2015.
Article in English | MEDLINE | ID: mdl-25494808

ABSTRACT

A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay. Docking studies into bacterial topoisomerase II (DNA Gyrase), topoisomerase IIα and topoisomerase IIß binding sites in the DNA binding interface were performed.


Subject(s)
Antineoplastic Agents/chemical synthesis , DNA-Binding Proteins/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridones/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , DNA/antagonists & inhibitors , DNA/chemistry , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Etoposide/pharmacology , Humans , Molecular Docking Simulation , Pyrazoles/pharmacology , Pyridones/pharmacology , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacology
16.
J Med Chem ; 57(18): 7673-86, 2014 Sep 25.
Article in English | MEDLINE | ID: mdl-25181013

ABSTRACT

A Sonogashira coupling strategy was employed to synthesize a new series of allosteric modulators for the A1 adenosine receptor based on the 2-amino-3-(p-chlorobenzoyl)-4-substituted thiophene skeleton, with a two-carbon (rigid or flexible) linker between the 5-position of the thiophene ring and a (hetero)aryl or alkyl moiety. Among the compounds characterized by the presence of a common phenylacetylene moiety at the 5-position of the thiophene ring, the neopentyl substitution at the 4-position supported a strong activity. In the series of 4-neopentyl derivatives, the presence of an acetylene spacer at the 5-position of the thiophene is optimal for activity, whereas reduction of the acetylene to an ethyl moiety decreased activity, both in functional and binding assays. Derivatives 4e, 4g-h, 4j, 4l, and 4m were the most promising compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor, with 4e as the best compound of the series. The latter compound also retarded the dissociation of another radiolabeled agonist, [(3)H]NECA, from the receptor.


Subject(s)
Adenosine A1 Receptor Agonists/chemical synthesis , Adenosine A1 Receptor Agonists/pharmacology , Receptor, Adenosine A1/chemistry , Receptor, Adenosine A1/metabolism , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Adenosine A1 Receptor Agonists/chemistry , Allosteric Regulation/drug effects , Animals , CHO Cells , Chemistry Techniques, Synthetic , Cricetinae , Cricetulus , Humans , Kinetics , Thiophenes/chemistry
17.
Bioorg Med Chem ; 22(1): 148-66, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24332652

ABSTRACT

2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor.


Subject(s)
Receptor, Adenosine A1/metabolism , Thiophenes/chemical synthesis , Thiophenes/metabolism , Allosteric Regulation , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Structure-Activity Relationship , Thiophenes/chemistry
18.
J Med Chem ; 56(11): 4482-96, 2013 Jun 13.
Article in English | MEDLINE | ID: mdl-23697626

ABSTRACT

We recently described the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidines as CB2 receptor partial agonists, showing that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. We describe herein the design and synthesis of the 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxamides, structural isomers of our previously reported pyrazolo[3,4-b]pyridines. All of the new compounds showed high affinity and selectivity for the CB2 receptor in the nanomolar range. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series shows stimulatory effects on forskolin-induced cAMP production acting as inverse agonists.


Subject(s)
Amides/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Receptor, Cannabinoid, CB2/metabolism , Amides/chemistry , Amides/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Drug Inverse Agonism , Humans , Male , Models, Molecular , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Structure-Activity Relationship
19.
J Med Chem ; 56(3): 1098-112, 2013 Feb 14.
Article in English | MEDLINE | ID: mdl-23350768

ABSTRACT

Recent developments indicate that CB(2) receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB(2) receptor. Very recently, we have identified the oxazinoquinoline carboxamides as a novel class of CB(2) receptor full agonists. In this paper we describe the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives. Some of the reported compounds showed high affinity and potency at the CB(2) receptor while showing only modest affinity for the centrally expressed CB(1) cannabinoid receptor. Moreover, we found that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series show dose-dependent effects on the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists, and inverse agonists.


Subject(s)
Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Animals , Drug Design , Humans , Magnetic Resonance Spectroscopy , Male , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
20.
J Med Chem ; 55(14): 6608-23, 2012 Jul 26.
Article in English | MEDLINE | ID: mdl-22738271

ABSTRACT

Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB(2) receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20, hCB(2)K(i) = 2.5 nM, SI = 166; 21, hCB(2)K(i) = 0.81 nM, SI = 383; 38, hCB(2)K(i) = 15.8 nM, SI > 633; 56, hCB(2)K(i) = 8.12 nM, SI > 1231; (R)-58, hCB(2)K(i) = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated, and it was found that the (R)-enantiomers exhibited greater affinity at the CB(2) receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB(2) receptor.


Subject(s)
Quinolines/metabolism , Quinolines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Quinolines/chemical synthesis , Quinolines/chemistry , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Substrate Specificity
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