Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 25
Filter
Add more filters










Publication year range
1.
Eur J Med Chem ; 260: 115730, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37633202

ABSTRACT

The development of drugs for the treatment of advanced prostate cancer (PCA) remains a challenging task. In this study we have designed, synthesized and tested twenty-nine novel HDAC inhibitors based on three different zinc binding groups (trifluoromethyloxadiazole, hydroxamic acid, and 2-mercaptoacetamide). These warheads were conveniently tethered to variously substituted phenyl linkers and decorated with differently substituted pyrrolo-pyrimidine and purine cap groups. Remarkably, most of the compounds showed nanomolar inhibitory activity against HDAC6. To provide structural insights into the Structure-Activity Relationships (SAR) of the investigated compounds, docking of representative inhibitors and molecular dynamics of HDAC6-inhibitor complexes were performed. Compounds of the trifluoromethyloxadiazole and hydroxamic acid series exhibited promising anti-proliferative activities, HDAC6 targeting in PCA cells, and in vitro tumor selectivity. Representative compounds of the two series were tested for solubility, cell permeability and metabolic stability, demonstrating favorable in vitro drug-like properties. The more interesting compounds were subjected to migration assays, which revealed that compound 13 and, to a lesser extent, compound 15 inhibited the invasive behaviour of androgen-sensitive and -insensitive advanced prostate cancer cells. Compound 13 was profiled against all HDACs and found to inhibit all members of class II HDACs (except for HDAC10) and to be selective with respect to class I and class IV HDACs. Overall, compound 13 combines potent inhibitory activity and class II selectivity with favorable drug-like properties, an excellent anti-proliferative activity and marked anti-migration properties on PCA cells, making it an excellent lead candidate for further optimization.


Subject(s)
Histone Deacetylase Inhibitors , Prostatic Neoplasms , Male , Humans , Histone Deacetylase Inhibitors/pharmacology , Prostatic Neoplasms/drug therapy , Purines , Pyrimidines/pharmacology , Hydroxamic Acids , Histone Deacetylases
2.
Int J Mol Sci ; 24(11)2023 Jun 02.
Article in English | MEDLINE | ID: mdl-37298633

ABSTRACT

The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer.


Subject(s)
Melanoma , Receptors, sigma , Humans , Apoptosis , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Signal Transduction , Receptors, sigma/genetics , Endoplasmic Reticulum Stress , Transcription Factor CHOP/metabolism , Activating Transcription Factor 4/metabolism , eIF-2 Kinase/metabolism
3.
Molecules ; 28(11)2023 Jun 04.
Article in English | MEDLINE | ID: mdl-37299020

ABSTRACT

Tau is a protein characterized by large structural portions displaying extended conformational changes. Unfortunately, the accumulation of this protein into toxic aggregates in neuronal cells leads to a number of severe pathologies, collectively named tauopathies. In the last decade, significant research advancements were achieved, including a better understanding of Tau structures and their implication in different tauopathies. Interestingly, Tau is characterized by a high structural variability depending on the type of disease, the crystallization conditions, and the formation of pathologic aggregates obtained from in vitro versus ex vivo samples. In this review, we reported an up-to-date and comprehensive overview of Tau structures reported in the Protein Data Bank, with a special focus on discussing the connections between structural features, different tauopathies, different crystallization conditions, and the use of in vitro or ex vivo samples. The information reported in this article highlights very interesting links between all these aspects, which we believe may be of particular relevance for a more informed structure-based design of compounds able to modulate Tau aggregation.


Subject(s)
Alzheimer Disease , Tauopathies , Humans , tau Proteins/metabolism , Tauopathies/metabolism , Molecular Conformation , Neurons/metabolism , Alzheimer Disease/metabolism
4.
Eur J Med Chem ; 249: 115163, 2023 Mar 05.
Article in English | MEDLINE | ID: mdl-36716640

ABSTRACT

Sigma-1 receptor (S1R) has been considered a promising therapeutic target for several neurodegenerative diseases and S1R agonists have shown neuroprotective activity against glutamate excitotoxicity and oxidative stress. Starting from a previously identified low nanomolar S1R agonist, in this work we prepared and tested novel benzylpiperidine/benzylpiperazine-based compounds designed by applying a ring opening strategy. Among them, 4-benzyl-1-(2-phenoxyethyl)piperidine 6b (S1R Ki = 0.93 nM) and 4-benzyl-1-(3-phenoxypropyl)piperidine 8b (S1R Ki = 1.1 nM) emerged as high affinity S1R ligands and showed selectivity over S2R and N-methyl-d-aspartate receptor (NMDAR). Candidate compounds behaved as potent S1R agonists being able to enhance the neurite outgrowth induced by nerve growth factor (NGF) in PC12 cell lines. In SH-SY5Y neuroblastoma cell lines they exhibited a neuroprotective effect against rotenone- and NMDA-mediated toxic insults. The neuroprotective activity of 6b and 8b was reverted by co-treatment with an S1R antagonist, PB212. Compounds 6b and 8b were tested for cytotoxicity in-vitro against three human cancer cell lines (A549, LoVo and Panc-1) and in-vivo zebrafish model, resulting in a good efficacy/safety profile, comparable or superior to the reference drug memantine. Overall, these results encourage further preclinical investigations of 6b and 8b on in-vivo models of neurodegenerative diseases.


Subject(s)
Neuroblastoma , Neurodegenerative Diseases , Neuroprotective Agents , Receptors, sigma , Animals , Humans , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , N-Methylaspartate/pharmacology , N-Methylaspartate/metabolism , Zebrafish/metabolism , Neuroblastoma/drug therapy , Oxidative Stress , Neurodegenerative Diseases/drug therapy , Piperidines/therapeutic use
5.
J Enzyme Inhib Med Chem ; 36(1): 2080-2086, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34583596

ABSTRACT

Histone deacetylase 6 (HDAC6) is an established drug target for cancer treatment. Inhibitors of HDAC6 based on a hydroxamic acid zinc binding group (ZBG) are often associated with undesirable side effects. Herein, we describe the identification of HDAC6 inhibitors based on a completely new 3-hydroxy-isoxazole ZBG. A series of derivatives decorated with different aromatic or heteroaromatic linkers, and various cap groups were synthesised and biologically tested. In vitro tests demonstrated that some compounds are able to inhibit HDAC6 with good potency, the best candidate reaching an IC50 of 700 nM. Such good potency obtained with a completely new ZBG make these compounds particularly attractive. The effect of the most active inhibitors on the acetylation levels of histone H3 and α- tubulin and their anti-proliferative activity of DU145 cells were also investigated. Docking studies were performed to evaluate the binding mode of these new derivatives and discuss structure-activity relationships.


Subject(s)
Coordination Complexes/pharmacology , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Zinc/pharmacology , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Zinc/chemistry
6.
Bioorg Chem ; 106: 104462, 2021 01.
Article in English | MEDLINE | ID: mdl-33213894

ABSTRACT

Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.


Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Acetylation/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 1/metabolism , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/metabolism , Histones/metabolism , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/metabolism , MCF-7 Cells , Molecular Docking Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship
7.
ACS Chem Neurosci ; 11(24): 4111-4127, 2020 12 16.
Article in English | MEDLINE | ID: mdl-33263393

ABSTRACT

Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the µ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.


Subject(s)
Pharmaceutical Preparations , Receptor, Serotonin, 5-HT1A , Analgesics, Opioid/pharmacology , Animals , Mice , Molecular Docking Simulation , Pain
8.
ACS Med Chem Lett ; 11(5): 1028-1034, 2020 May 14.
Article in English | MEDLINE | ID: mdl-32435421

ABSTRACT

Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders. A series of novel SRs ligands were designed by combining key pharmacophoric amines (i.e., benzylpiperidine or benzylpiperazine) with new 1,3-dithiolane-based heterocycles and their bioisosters. The new compounds exhibited a low nanomolar affinity for sigma-1 and sigma-2 receptors. Five selected compounds were evaluated for their neuroprotective capacity on SH-SY5Y neuroblastoma cell line. They were able to counteract the neurotoxicity induced by rotenone, oligomycin and NMDA. Competition studies with PB212, a S1R antagonist, confirmed the involvement of S1R in neuroprotection from the oxidative stress induced by rotenone. Electrophysiological experiments performed on cortical neurons in culture highlighted the compounds ability to reduce NMDA-evoked currents, suggesting a negative allosteric modulator activity toward the NMDA receptor. Altogether these results qualify our novel dithiolane derivatives as potential agents for fighting neurodegeneration.

9.
Pharmacol Rep ; 72(2): 427-434, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32002826

ABSTRACT

BACKGROUND: In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). METHODS: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. RESULTS: All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a µM-nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. CONCLUSIONS: In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2.


Subject(s)
Dioxanes/pharmacology , Drug Discovery , Receptor, Serotonin, 5-HT1A/metabolism , Spiro Compounds/pharmacology , Animals , Binding, Competitive , CHO Cells , Cricetulus , Dioxanes/chemistry , Dioxanes/metabolism , Humans , Ligands , Molecular Structure , Protein Binding , Radioligand Assay , Receptor, Serotonin, 5-HT1A/genetics , Receptors, Adrenergic, alpha-2/genetics , Receptors, Adrenergic, alpha-2/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Structure-Activity Relationship
10.
Eur J Med Chem ; 176: 310-325, 2019 Aug 15.
Article in English | MEDLINE | ID: mdl-31112892

ABSTRACT

A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.


Subject(s)
Analgesics/therapeutic use , Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Dioxanes/therapeutic use , Neuroprotective Agents/therapeutic use , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Analgesics/chemical synthesis , Analgesics/pharmacokinetics , Analgesics/toxicity , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/toxicity , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/toxicity , Brain/metabolism , Dioxanes/chemical synthesis , Dioxanes/pharmacokinetics , Dioxanes/toxicity , Male , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/toxicity , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/pharmacokinetics , Serotonin 5-HT1 Receptor Agonists/toxicity , Stereoisomerism , Structure-Activity Relationship
11.
Future Med Chem ; 10(18): 2137-2154, 2018 Sep 01.
Article in English | MEDLINE | ID: mdl-30043643

ABSTRACT

AIM: Targeting 5-HT1A receptor (5-HT1AR) as a strategy for CNS disorders and pain control. METHODOLOGY: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α1-adrenoceptors and 5-HT1AR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds. RESULTS & CONCLUSION: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1AR agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A/α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.


Subject(s)
Central Nervous System Diseases/drug therapy , Dioxolanes/chemistry , Dioxolanes/pharmacology , Neuralgia/drug therapy , Neuroprotective Agents/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Central Nervous System Diseases/metabolism , Dioxolanes/chemical synthesis , Dose-Response Relationship, Drug , Humans , Molecular Structure , Neuralgia/metabolism , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Serotonin Receptor Agonists/chemistry , Structure-Activity Relationship
12.
ChemMedChem ; 12(22): 1893-1905, 2017 11 22.
Article in English | MEDLINE | ID: mdl-28940806

ABSTRACT

A new series of spirocyclic σ receptor (σR) ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ1 R; three compounds were shown to be σ1 R agonists, while another proved to be the only σ1 R antagonist. Only one of the σ1 R agonists (BS148) also exhibited σ2 R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines without affecting normal human melanocytes. The antiproliferative activity of this compound suggested an σ2 R agonist profile. Further, preliminary investigations indicated that the mechanism of metastatic malignant melanoma cell death induced by BS148 is due, at least in part, to apoptosis.


Subject(s)
Analgesics, Opioid/pharmacology , Antineoplastic Agents/pharmacology , Melanoma/drug therapy , Piperidines/pharmacology , Receptors, sigma/agonists , Spiro Compounds/pharmacology , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Ligands , Male , Melanoma/pathology , Mice , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship
13.
J Enzyme Inhib Med Chem ; 32(1): 214-230, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28114832

ABSTRACT

The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands. [Formula: see text].


Subject(s)
Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Antagonists/chemistry , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Dose-Response Relationship, Drug , Humans , Ligands , Models, Molecular , Molecular Structure , Quantitative Structure-Activity Relationship , Structure-Activity Relationship
14.
Eur J Med Chem ; 125: 435-452, 2017 Jan 05.
Article in English | MEDLINE | ID: mdl-27689727

ABSTRACT

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A/α1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.


Subject(s)
Alkanes/chemistry , Alkanes/therapeutic use , Analgesics/chemistry , Analgesics/therapeutic use , Pain/drug therapy , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Alkanes/pharmacokinetics , Alkanes/pharmacology , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Blood-Brain Barrier/metabolism , Formaldehyde , Humans , Male , Mice , Models, Molecular , Pain/chemically induced , Pain Measurement , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacokinetics , Serotonin 5-HT1 Receptor Agonists/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship
15.
Arch Pharm Res ; 40(5): 537-549, 2017 May.
Article in English | MEDLINE | ID: mdl-27615010

ABSTRACT

Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and ß anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.


Subject(s)
Anti-HIV Agents/pharmacology , Antineoplastic Agents/pharmacology , Dioxolanes/pharmacology , HIV-1/drug effects , Purine Nucleosides/pharmacology , Pyrimidine Nucleosides/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Crystallography, X-Ray , Dioxolanes/chemical synthesis , Dioxolanes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Purine Nucleosides/chemical synthesis , Purine Nucleosides/chemistry , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/chemistry , Structure-Activity Relationship
16.
Chem Biol Drug Des ; 86(4): 447-58, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25546401

ABSTRACT

Several spiroxatrine derivatives were synthesized and evaluated as potential NOP receptor ligands. Structural modifications of the 1,4-benzodioxane moiety of spiroxatrine have been the focus of this research project. The structure-activity relationships that emerged indicate that the presence of an H-bond donor group (hydroxyl group) is more favorable for NOP activity when it is positioned α with respect to the CH2 linked to the 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one portion. Moreover, cis diastereoisomers of the hydroxyl derivatives4 and 22 show a moderately higher degree of stereoselectivity than trans isomers. In particular, the spiropiperidine derivative cis-4 has submicromolar agonistic activity, and it will be the reference compound for the design and synthesis of new NOP agonists.


Subject(s)
Aza Compounds , Receptors, Opioid/agonists , Spiro Compounds , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Humans , Ligands , Molecular Structure , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship , Nociceptin Receptor
17.
Eur J Med Chem ; 87: 248-66, 2014 Nov 24.
Article in English | MEDLINE | ID: mdl-25261823

ABSTRACT

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α1 or 5-HT1AR ligands.


Subject(s)
Alkanes/chemistry , Alkanes/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Spiro Compounds/chemistry , Humans , Ligands , Molecular Docking Simulation , Protein Conformation , Receptor, Serotonin, 5-HT1A/chemistry , Receptors, Adrenergic, alpha-1/chemistry , Structure-Activity Relationship
18.
Med Chem ; 8(5): 769-78, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22741790

ABSTRACT

A series of 1,3-oxathiolane-based nucleoside analogs 5-methyl substituted was synthesized and tested as potential antiviral agents. Structural characterization and C2-C4 / C2-C5 relative stereochemistry assignments were performed by NMR experiments. All tested isomers were found to be inactive and cytotoxic.


Subject(s)
Antiviral Agents/chemical synthesis , HIV-1/drug effects , Nucleosides/chemical synthesis , Thiophenes/chemical synthesis , Antiviral Agents/toxicity , Cell Line , Cell Survival/drug effects , HIV-1/growth & development , Humans , Magnetic Resonance Spectroscopy , Nucleosides/toxicity , Stereoisomerism , Structure-Activity Relationship , Thiophenes/toxicity
19.
Eur J Med Chem ; 45(9): 3740-51, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20605276

ABSTRACT

A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha(1)-adrenoceptor subtypes and 5-HT(1A) receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective alpha(1a(A))/alpha(1d(D))-adrenoceptor subtype antagonist, over alpha(1b(B)) subtype and 5-HT(1A) receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha(1)/5-HT(1A) selectivity is observed, mainly due to the increase in 5-HT(1A) affinity. In functional experiments lactam derivatives seems to favour 5-HT(1A) receptor antagonism (pKb = 7.20-7.80) and alpha(1B)-adrenoceptor antagonist selectivity (alpha(1B)/alpha(1A) and alpha(1B)/alpha(1D) of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective alpha(1D)-adrenoceptor antagonist (pKb = 8.1 and alpha(1D)/alpha(1A) and alpha(1D)/alpha(1B) selectivity ratios of 16 and 11 respectively) whereas at 5-HT(1A) receptor it is a potent partial agonist (pD2 = 7.98, E(max) = 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT(1A)/agonist and 5HT(1A)/antagonist interaction.


Subject(s)
Dioxolanes/chemistry , Dioxolanes/metabolism , Imides/chemistry , Lactams/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Adrenergic alpha-1 Receptor Agonists/chemical synthesis , Adrenergic alpha-1 Receptor Agonists/chemistry , Adrenergic alpha-1 Receptor Agonists/metabolism , Adrenergic alpha-1 Receptor Agonists/pharmacology , Adrenergic alpha-1 Receptor Antagonists/chemical synthesis , Adrenergic alpha-1 Receptor Antagonists/chemistry , Adrenergic alpha-1 Receptor Antagonists/metabolism , Adrenergic alpha-1 Receptor Antagonists/pharmacology , Animals , Dioxolanes/chemical synthesis , Dioxolanes/pharmacology , Humans , Ligands , Male , Models, Molecular , Protein Binding , Protein Conformation , Rats , Receptor, Serotonin, 5-HT1A/chemistry , Receptors, Adrenergic, alpha-1/chemistry , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT1 Receptor Antagonists/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists/chemistry , Serotonin 5-HT1 Receptor Antagonists/metabolism , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Stereoisomerism , Structure-Activity Relationship , Substrate Specificity
20.
Bioorg Med Chem Lett ; 20(6): 2017-20, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-20185311

ABSTRACT

Starting from compounds previously identified as alpha(1)-adrenoceptor antagonists that were also found to bind to the 5-HT(1A) receptor, in an attempt to separate the two activities, a new series of 5-HT(1A) receptor agonists was identified and shown to have high potency and/or high selectivity. Of these, compound 13, which combines high selectivity (5-HT(1A)/alpha(1)=151) and good agonist potency (pD(2)=7.82; E(max)=76), was found to be the most interesting.


Subject(s)
Serotonin 5-HT1 Receptor Agonists , Drug Discovery
SELECTION OF CITATIONS
SEARCH DETAIL
...