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1.
Bioorg Med Chem ; 86: 117290, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37137269

RESUMO

Chronic pain, as an unmet medical need, severely impacts the quality of life. The voltage-gated sodium channel NaV1.7 preferentially expressed in sensory neurons of dorsal root ganglia (DRG) serves a promising target for pain therapy. Here, we report the design, synthesis, and evaluation of a series of acyl sulfonamide derivatives targeting Nav1.7 for their antinociceptive activities. Among the derivatives tested, the compound 36c was identified as a selective and potent NaV1.7 inhibitor in vitro and exhibited antinociceptive effects in vivo. The identification of 36c not only provides a new insight into the discovery of selective NaV1.7 inhibitors, but also may hold premise for pain therapy.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7 , Bloqueadores dos Canais de Sódio , Ratos , Animais , Bloqueadores dos Canais de Sódio/farmacologia , Ratos Sprague-Dawley , Qualidade de Vida , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Dor/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico
2.
J Med Chem ; 65(17): 11658-11678, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-36008373

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is a promising target for developing antinociceptive agents. Here, we report the synthesis of N-indazole-4-aryl piperazine carboxamide analogues as TRPV1 modulators. The structure-activity relationship (SAR) reveals that substituting indazole at the 5-/6-position leads to TRPV1 agonism, whereas the 4- and 7-positions of indazole obtain mild antagonism and loss of activity, respectively. The whole-cell clamp patch assay shows that 28 is a potent and selective TRPV1 agonist and it relieves inflammatory and thermal pain by desensitizing the native TRPV1 current in the dorsal root ganglion (DRG) in mice. Additionally, site-directed mutagenesis combined with molecular docking shows an important hydrogen interaction between Arg557 and the indazole of 28. Taken together, our findings provide insight into TRPV1 agonism-antagonism conversion based on the interaction between indazole and Arg557, which provides a strategy to obtain new TRPV1 agonists by structural modification of antagonists. Compound 28 may be used as a lead compound for further optimization.


Assuntos
Indazóis , Canais de Cátion TRPV , Analgésicos/farmacologia , Animais , Capsaicina , Gânglios Espinais , Indazóis/farmacologia , Camundongos , Simulação de Acoplamento Molecular
3.
Talanta ; 249: 123662, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35691129

RESUMO

Non-thermal plasma-based ionization sources have been widely used and shown excellent soft ionization performance in mass spectrometry. Despite their extensive application, the ionization mechanisms of these sources are of great interest for further exploring their full potential. A controlled atmosphere can provide a clean and controllable ionization environment and is beneficial for studying the ionization mechanism. The plasma source itself also has a significant impact on the ionization mechanism of the analyte, and the voltage waveform is one of the key parameters for controlling the plasma source. In this paper, a miniature flexible micro-tube plasma (FµTP) ionization source was sustained using both square and sine-wave voltage. The ionization processes of typical semi-fluorinated n-alkanes (SFAs) were investigated in the controlled atmosphere filled with 80% N2 and 20% O2. The main mass peaks using both square and sine-wave voltages are found to be [M-mH]+ and [M-mH+nO]+ (m = 1, 3; n = 0, 1, 2). However, for the square-wave voltage, the [M-H+O]+ species are the most abundant while [M-H]+ species are dominant for the sine-wave voltage, showing that the plasma generated with sine-wave voltage is somewhat "softer" than the one with square-wave voltage for SFAs. With the assistance of optical spectroscopy, the plasma developments in one discharge cycle for both voltage waveforms were obtained. Only one discharge can be found in each half cycle for square-wave voltage while several for the sine-wave voltage. These would be responsible for the different ionization behaviors in these two cases. This work provides more insight into the ionization mechanism of SFAs and more understanding of plasma-based soft ionization. In addition, the analytical performance was evaluated to be comparable when using these two voltage generators with a big difference in cost, which will benefit the instrumental development.


Assuntos
Alcanos , Atmosfera , Espectrometria de Massas , Plasma , Análise Espectral
4.
Org Biomol Chem ; 19(39): 8597-8606, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34553739

RESUMO

An iron-catalyzed radical cascade cyclization of oxime esters with isocyanides for the synthesis of 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines has been developed. This demonstrates excellent functional group tolerance and broad substrate scope. A diverse range of potentially valuable 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines were obtained in moderate to good yields.

5.
Acta Pharmacol Sin ; 42(8): 1235-1247, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34103689

RESUMO

Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti-nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized. Here, we report the electrophysiological and pharmacodynamic characterization of QLS-81 as a Nav1.7 channel inhibitor with promising anti-nociceptive activity. In whole-cell recordings of HEK293 cells stably expressing Nav1.7, QLS-81 (IC50 at 3.5 ± 1.5 µM) was ten-fold more potent than its parent compound ralfinamide (37.1 ± 2.9 µM) in inhibiting Nav1.7 current. QLS-81 inhibition on Nav1.7 current was use-dependent. Application of QLS-81 (10 µM) caused a hyperpolarizing shift of the fast and slow inactivation of Nav1.7 channel about 7.9 mV and 26.6 mV, respectively, and also slowed down the channel fast and slow inactivation recovery. In dissociated mouse DRG neurons, QLS-81 (10 µM) inhibited native Nav current and suppressed depolarizing current pulse-elicited neuronal firing. Administration of QLS-81 (2, 5, 10 mg· kg-1· d-1, i.p.) in mice for 10 days dose-dependently alleviated spinal nerve injury-induced neuropathic pain and formalin-induced inflammatory pain. In addition, QLS-81 (10 µM) did not significantly affect ECG in guinea pig heart ex vivo; and administration of QLS-81 (10, 20 mg/kg, i.p.) in mice had no significant effect on spontaneous locomotor activity. Taken together, our results demonstrate that QLS-81, as a novel Nav1.7 inhibitor, is efficacious on chronic pain in mice, and it may hold developmental potential for pain therapy.


Assuntos
Analgésicos/uso terapêutico , Fluorbenzenos/uso terapêutico , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neuralgia/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Animais , Formaldeído , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Cobaias , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Neurônios/efeitos dos fármacos , Nervos Espinhais/lesões
6.
J Org Chem ; 85(19): 12284-12293, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32916054

RESUMO

A variety of dihydropyrrole-functionalized phenanthridines were efficiently synthesized by the metal-free, radical cascade cyclization reaction of 2-isocyanobiphenyls with γ,δ-unsaturated oxime esters. The C-N/C-C/C-C bonds were formed via the oil bath method in a one-pot procedure with broad substrate applicability. The radical process was supported by kinetic isotope effect studies and radical inhibition studies.

7.
J Med Chem ; 62(24): 11054-11070, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31738550

RESUMO

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, Ki = 0.47 nM, κ/µ = 682, κ/δ = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1, and E209EL2.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos/farmacologia , Benzilaminas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Descoberta de Drogas , Morfinanos/farmacologia , Dor/tratamento farmacológico , Receptores Opioides kappa/agonistas , Analgésicos/química , Analgésicos Opioides/química , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/química , Benzilaminas/química , Relação Dose-Resposta a Droga , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Morfinanos/química , Dor/metabolismo
8.
Bioorg Med Chem ; 26(14): 4254-4263, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30054192

RESUMO

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7ß-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7ß-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7ß-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7ß-methyl orvinol analogues. Surprisingly, SLL-603, a 7ß-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7ß-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.


Assuntos
Morfinanos/farmacologia , Receptores Opioides kappa/agonistas , Animais , Células CHO , Células Cultivadas , Cricetulus , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Morfinanos/síntese química , Morfinanos/química , Relação Estrutura-Atividade
9.
Org Biomol Chem ; 15(47): 10044-10052, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-29165470

RESUMO

A convenient microwave-assisted protocol for the synthesis of hydroxyl-containing isoquinolines from a metal-free radical cyclization reaction of vinyl isonitriles with alcohols was developed with moderate-to-excellent yields. Vinyl isonitriles are coupled with alkyl radicals through direct catalytic functionalization of the α sp3 C-H bond of alcohols. The methodology demonstrates a broad substrate scope, shows excellent functional group tolerance, is highly atom-economical and highly efficient, thus enabling the preparation of diverse potentially valuable hydroxyl-containing isoquinolines.

10.
Bioorg Med Chem Lett ; 25(5): 1124-8, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25655718

RESUMO

A series of novel 1,2,3-triazole-pyrimidine-urea hybrids were designed, synthesized and evaluated for anticancer activity against four selected cancer cell lines (MGC-803, EC-109, MCF-7 and B16-F10). Majority of the synthesized compounds exhibited moderate to potent activity against all the cancer cell lines assayed. Particularly, compounds 26, 30 and 38 exhibited excellent growth inhibition against B16-F10 with IC50 values of 32nM, 35nM and 42nM, respectively. Flow cytometry analysis demonstrated that compound 26 induced the cellular apoptosis in a concentration-dependent manner.


Assuntos
Antineoplásicos/química , Desenho de Fármacos , Pirimidinas/química , Triazóis/química , Ureia/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia , Ureia/síntese química , Ureia/farmacologia
11.
Eur J Med Chem ; 86: 368-80, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25180925

RESUMO

A series of novel 1,2,3-triazole-pyrimidine hybrids were designed, synthesized and evaluated for their anticancer activity against four selected cancer cell lines (MGC-803, EC-109, MCF-7 and B16-F10). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Compound 17 showed the most excellent anticancer activity with single-digit micromolar IC50 values ranging from 1.42 to 6.52 µM. Further mechanism studies revealed that compound 17 could obviously inhibit the proliferation of EC-109 cancer cells by inducing apoptosis and arresting the cell cycle at G2/M phase.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Pirimidinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-Atividade , Triazóis/química
12.
Eur J Med Chem ; 85: 235-44, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25086915

RESUMO

Trying to develop potent and selective anticancer agents, two series of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives were designed and synthesized. Their antitumor activities were evaluated by MTT method against four selected human cancer cell lines (MGC-803, EC-9706, HeLa and MCF-7). Our results showed that compound 11h exhibited good anticancer activities compared to 5-fluorouracil against the four tested cell lines, with IC50 values ranging from 2.0 to 4.5 µM. Flow cytometry analysis indicated that compound 11h induced the cellular early apoptosis and cell cycle arrest at G2/M phase in EC-9706.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Ftalazinas/química , Ftalazinas/farmacologia , Triazóis/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ftalazinas/síntese química
13.
Bioorg Med Chem Lett ; 24(16): 3877-81, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25001482

RESUMO

A series of pyrimidine-benzimidazol hybrids was synthesized and evaluated for anticancer activity on four human cancer cell lines including MCF-7, MGC-803, EC-9706 and SMMC-7721. Some of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 5a-b and 6a-b showed most effective activity. Compounds 5b and 6b were more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines, with IC50 values ranging from 2.03 to 10.55 µM and 1.06 to 12.89 µM, respectively. Flow cytometry analysis demonstrated that treatment of MGC-803 with 6b led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/química , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 24(12): 2741-3, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24798098

RESUMO

A series of novel 4-substituted-2-{[(1H-benzo[d]imidazol-2-yl)methyl] thio}-6-methylpyrimidine derivatives were designed, synthesized and evaluated for their cytotoxic activities against four human cancer cell lines and inhibitory activities against five type culture strains in vitro. Some of synthetic pyrimidine-benzimidazol combinations showed good inhibitory activities against Stenotrophomonas maltophilia, especially compounds 7b and 7c. Compounds 7a and 7d exhibited enhanced activities against MGC-803 in vitro, when compared to 5-Fu.


Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Benzimidazóis/química , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Combinatória , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/química
15.
Bioorg Med Chem Lett ; 24(4): 1236-8, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24447849

RESUMO

A series of novel 1,2,4-triazolo [3,4-a] phthalazine derivatives were synthesized in five steps from a common precursor, phthalic anhydride. Most of synthesized phthalazine derivatives showed inhibitory activity against Staphylococcus aureus. One of phthalazine derivatives 5l showed inhibitory activity against all tested bacterial and fungal strains.


Assuntos
Antibacterianos/farmacologia , Ftalazinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
16.
Carbohydr Res ; 382: 65-70, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24211367

RESUMO

A series of bicyclic nucleosides containing a triazolyl-carbohydrate moiety were synthesized and their antitumor activity in vitro for human cancer cell lines was also tested. Compound 11 was synthesized efficiently with 3,6-anhydro sugar 7 as raw material, while compound 7 was prepared from 1,2;5,6-di-O-isopropylidene-α-d-glucose. Compounds 12a-e were synthesized by treating compound 11 with alkynes, catalyzed by copper(I). After removal of the acetyl protecting groups, the target compounds 5a-e showed significant inhibitory activity against EC109, PC-3, MGC-803, and HGC-7 cell lines.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Purinas/química , Antineoplásicos/síntese química , Carboidratos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Nucleosídeos/química
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