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1.
Bioorg Chem ; 141: 106845, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37797453

RESUMO

Blapspirooxindoles A-C (1-3), three novel spirooxindole alkaloids with a unique spiro[chromane-4,3'-indoline]-2,2'-dione motif, blapcumaranons A and B (4 and 5), two new 2-cumaranon derivatives, blapoxindoles A-J (6-15), ten new oxindole alkaloid derivatives, along with one known compound (16), were isolated from the whole bodies of Blaps japanensis. Their structures including absolute configurations were determined by using spectroscopic, X-ray crystallographic, and computational methods. Compounds 1-11 and 13 exist as racemic mixtures in nature, and their (-)- and (+)-antipodes were separated by chiral HPLC. Biological evaluations of these compounds were determined with multiple assays including anti-tumor, anti-inflammatory, and renal protection activities in vitro. Several compounds displayed effective activity in one or more assays.


Assuntos
Alcaloides , Antineoplásicos , Besouros , Neoplasias , Animais , Besouros/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Alcaloides/farmacologia , Oxindóis/farmacologia , Estrutura Molecular
2.
Bioorg Med Chem Lett ; 30(11): 127168, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32273216

RESUMO

Fourteen ansamycin derivatives including seven new herbimycins G-L (1-6) and divergolide O (7), and seven known analogues were isolated from a culture broth of the marine-derived Streptomyces sp. SCSGAA 0027. Their complete structures were determined by detailed analysis of spectroscopic data and quantum chemical calculations. Compounds 1-5 and 7 featured an additional eight-membered O-heterocycle that has rarely been reported for ansamycins, and the Z,Z- and E,E-configurations for Δ2,Δ4 were reported for the first time in geldanamycin analogues. Compound 1 exhibited weak inhibition activity towards Hsp90α with an IC50 value of 96 µM, 2-5 showed mild cytotoxicity against four human cancer cell lines with IC50 values ranging from 13 µM to 86 µM, and 7 had moderate anti-HSV-1 activity with an IC50 value of 19 µM and very weak cytotoxicity towards Vero cell. The possible biosynthetic pathways for 1-5 were proposed. And their structure-bioactivity relationship was also discussed.


Assuntos
Antivirais/química , Rifabutina/análogos & derivados , Streptomyces/química , Antivirais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Rifabutina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Streptomyces/metabolismo , Relação Estrutura-Atividade
3.
Bioorg Chem ; 102: 104086, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32688114

RESUMO

Pipajiains H-J (1-3), three new phenolic derivatives with an unusual sulfone group, pipajiamides A-C (4-6), three new amide derivatives, pipajiaine A (7), one new imidazole analogue, and pipajiaine B (8), a pair of new pyrrolidine derivatives, along with three known compounds were isolated from the insect Blaps japanensis. Their structures were identified by spectroscopic and computational methods. Chiral HPLC was used to separate the (-)- and (+)-antipodes of 4 and 8. Biological activities of all the new compounds against extracellular matrix in rat renal proximal tubular cells, human cancer cells (A549, Huh-7, and K562), COX-2, ROCK1, and JAK3 were evaluated. The results show that compounds 2, (+)-4, and (-)-4 are active against kidney fibrosis, whereas, compound 9 is active toward human cancer cells, inflammation, and JAK3 kinase.


Assuntos
Besouros/química , Compostos de Nitrogênio/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Enxofre/farmacologia , Animais , Células Cultivadas , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Fibrose/tratamento farmacológico , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Estrutura Molecular , Compostos de Nitrogênio/química , Compostos de Nitrogênio/isolamento & purificação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Ratos , Relação Estrutura-Atividade , Enxofre/química , Enxofre/isolamento & purificação , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
4.
J Asian Nat Prod Res ; 21(6): 542-550, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29985069

RESUMO

Three pairs of meroterpenoids (±) cochlearoids N-P (1-3) were isolated from the fruiting bodies of Ganoderma cochlear. Their structures including absolute configurations were assigned by spectroscopic techniques. All the isolated compounds were tested for their inhibitory activities toward BRD4, human cancer cells, and micro-organisms. The results show that the enantiomers of (±)-1 are BRD4 inhibitors, (-)-1 and (+)-3 are cytotoxic against human cancer cells (K562) with IC50 values of 7.68 and 6.68 µM, respectively. Besides compounds (±)-2 and (±)-3 exhibit potent inhibitory activity against Staphylococcus aureus with IC50 values in the range of 5.43-17.99 µM.


Assuntos
Ganoderma/química , Fenóis/química , Terpenos/química , Antibacterianos/química , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Carpóforos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Nucleares/antagonistas & inibidores , Fenóis/farmacologia , Terpenos/farmacologia , Fatores de Transcrição/antagonistas & inibidores
5.
J Nat Prod ; 80(1): 61-70, 2017 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-27996259

RESUMO

Spiroapplanatumines A-Q (1-12, 14-16, 18, and 20), new spiro meroterpenoids respectively bearing a 6/5/7 or 6/5/5 ring system, along with three known compounds, spirolingzhines A, B, and D, were isolated from the fruiting bodies of the fungus Ganoderma applanatum. Their structures including absolute configurations were assigned by using spectroscopic methods, ECD and 13C NMR calculations, and single-crystal X-ray diffraction analysis. Biological evaluation of all the compounds disclosed that compounds 7 and 8 inhibited JAK3 kinase with IC50 values of 7.0 ± 3.2 and 34.8 ± 21.1 µM, respectively.


Assuntos
Agaricales/química , Carpóforos/química , Ganoderma/química , Janus Quinase 3/antagonistas & inibidores , Terpenos/isolamento & purificação , Terpenos/farmacologia , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Concentração Inibidora 50 , Janus Quinase 3/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Terpenos/química , Triterpenos/química , Difração de Raios X
6.
Bioorg Med Chem Lett ; 25(12): 2469-72, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25980909

RESUMO

Blapsols A-D (1-4), four new compounds possessing a 2,3-dihydrobenzo[b][1,4]dioxin group, together with five known N-acetyldopamine dimers (5-9), were isolated from Blaps japanensis. Their structures including the absolute configuration of (+)-1 were determined by means of spectroscopic and X-ray crystallographic methods. Chiral HPLC was used to separate (-)- and (+)-enantiomers of compounds 1-4, which were isolated from this insect as racemic mixtures. All the compounds were found to have inhibitory effects towards COX-2 with IC50 values in the range of 1.3-17.8µM.


Assuntos
Besouros/química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase/química , Animais , Besouros/metabolismo , Cristalografia por Raios X , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dioxinas/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estereoisomerismo
7.
Molecules ; 20(9): 15589-96, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26343619

RESUMO

Recent studies focusing on identifying the biological agents of Catharsius molossus have led to the identification of three new N-acetyldopamine dimers molossusamide A-C (1-3) and two known compounds 4 and 5. The structures of the new compounds were identified by comprehensive spectroscopic evidences. Compound 4 was found to have inhibitory effects towards COX-1 and COX-2.


Assuntos
Besouros/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dopamina/análogos & derivados , Inibidores Enzimáticos/farmacologia , Animais , Linhagem Celular , Besouros/química , Cães , Dopamina/química , Dopamina/farmacologia , Células HeLa , Humanos , Proteínas de Insetos/química , Proteínas de Insetos/farmacologia , Células MCF-7 , Células Madin Darby de Rim Canino , Estrutura Molecular
8.
Molecules ; 21(1): E34, 2015 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-26712735

RESUMO

Two new asteltoxins named asteltoxin E (2) and F (3), and a new chromone (4), together with four known compounds were isolated from a marine sponge-derived fungus, Aspergillus sp. SCSIO XWS02F40. The structures of the compounds (1-7) were determined by the extensive 1D- and 2D-NMR spectra, and HRESIMS spectrometry. All the compounds were tested for their antiviral (H1N1 and H3N2) activity. Compounds 2 and 3 showed significant activity against H3N2 with the prominent IC50 values of 6.2 ± 0.08 and 8.9 ± 0.3 µM, respectively. In addition, compound 2 also exhibited inhibitory activity against H1N1 with an IC50 value of 3.5 ± 1.3 µM.


Assuntos
Antivirais/farmacologia , Aspergillus/metabolismo , Poríferos/microbiologia , Pironas/farmacologia , Animais , Antivirais/química , Antivirais/isolamento & purificação , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pironas/química , Pironas/isolamento & purificação
9.
Int J Syst Evol Microbiol ; 64(Pt 9): 2944-2948, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24899653

RESUMO

A polyphasic study was undertaken to determine the taxonomic position of 13 Campylobacter fetus-like strains from humans (n = 8) and reptiles (n = 5). The results of matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS and genomic data from sap analysis, 16S rRNA gene and hsp60 sequence comparison, pulsed-field gel electrophoresis, amplified fragment length polymorphism analysis, DNA-DNA hybridization and whole genome sequencing demonstrated that these strains are closely related to C. fetus but clearly differentiated from recognized subspecies of C. fetus. Therefore, this unique cluster of 13 strains represents a novel subspecies within the species C. fetus, for which the name Campylobacter fetus subsp. testudinum subsp. nov. is proposed, with strain 03-427(T) ( = ATCC BAA-2539(T) = LMG 27499(T)) as the type strain. Although this novel taxon could not be differentiated from C. fetus subsp. fetus and C. fetus subsp. venerealis using conventional phenotypic tests, MALDI-TOF MS revealed the presence of multiple phenotypic biomarkers which distinguish Campylobacter fetus subsp. testudinum subsp. nov. from recognized subspecies of C. fetus.


Assuntos
Campylobacter fetus/classificação , Filogenia , Répteis/microbiologia , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Animais , Técnicas de Tipagem Bacteriana , Campylobacter fetus/genética , Campylobacter fetus/isolamento & purificação , DNA Bacteriano/genética , Humanos , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
10.
Bioorg Med Chem Lett ; 24(22): 5164-9, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25442305

RESUMO

Recent studies focusing on unveiling the biological agents of Aspongopus chinensis have led to the identification of four new norepinephrine derivatives (1-4), three new sesquiterpenoids (5-7), and one new lactam (8). In addition, twenty-three known compounds have been identified, most of which were isolated from this insect for the first time. Selected members of insect-derived substances were evaluated for their biological activities against renal protection in high-glucose-induced mesangial cells and COX-2 inhibition.


Assuntos
Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Insetos , Animais , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Humanos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/fisiologia , Ratos
11.
Bioorg Med Chem Lett ; 24(11): 2433-6, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24767845

RESUMO

Four dihydrothiophene-condensed chromones including two new compounds oxalicumones D-E (1-2) and known oxalicumones A-B (3-4), along with five other known chromones were isolated from a culture broth of the marine gorgonian-associated fungus Penicillium oxalicum SCSGAF 0023. The structures of 1-2 were elucidated by spectroscopic analysis. Eleven derivatives 3a-3i and 4a-4b were obtained from the acylation of 3 and 4, respectively. Compounds 1-4, 3a-3e, 3g-3h, and 4b showed significant cytotoxicity against several carcinoma cell lines with IC50 ≤ 10 µM. And their structure-bioactivity relationship was discussed.


Assuntos
Antineoplásicos/farmacologia , Cromonas/farmacologia , Penicillium/química , Tiofenos/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/química , Cromonas/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Células K562 , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Células U937
12.
Bioorg Med Chem ; 21(7): 1749-55, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23434133

RESUMO

A novel dipeptidyl peptidase IV inhibitor hit (5, IC50=0.86 µM) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 18o (IC50=1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T1/2: 2h vs 4.9h).


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Inibidores da Dipeptidil Peptidase IV/sangue , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
J Nat Prod ; 76(5): 983-7, 2013 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-23701598

RESUMO

Two new benzodiazepine alkaloids, circumdatins K and L (1, 2), two new prenylated indole alkaloids, 5-chlorosclerotiamide (3) and 10-epi-sclerotiamide (4), and one novel amide, aspergilliamide B (5), together with six known alkaloids were isolated from the deep-sea-derived fungus Aspergillus westerdijkiae DFFSCS013. Their structures were elucidated by extensive spectroscopic analysis. All of the compounds were tested for cytotoxicity toward human carcinoma A549, HL-60, K562, and MCF-7 cell lines.


Assuntos
Alcaloides/isolamento & purificação , Amidas/isolamento & purificação , Aspergillus/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides/química , Alcaloides/farmacologia , Amidas/química , Amidas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HL-60 , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Indolizinas , Células K562 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oceanos e Mares , Compostos de Espiro
14.
J Nat Prod ; 76(6): 1182-6, 2013 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-23806112

RESUMO

A new cytotoxic and antiviral cyclic tetrapeptide, asperterrestide A (1), a new alkaloid, terremide C (2), and a new aromatic butenolide, aspernolide E (3), together with 10 known compounds were isolated from the fermentation broth of the marine-derived fungus Aspergillus terreus SCSGAF0162. Their structures were elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by the Mosher ester technique and analysis of the acid hydrolysates using a chiral-phase HPLC column. Compound 1 contains a rare 3-OH-N-CH3-Phe residue and showed cytotoxicity against U937 and MOLT4 human carcinoma cell lines and inhibitory effects on influenza virus strains H1N1 and H3N2.


Assuntos
4-Butirolactona/análogos & derivados , Alcaloides/isolamento & purificação , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antivirais/isolamento & purificação , Antivirais/farmacologia , Aspergillus/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , Alcaloides/química , Antineoplásicos/química , Antivirais/química , China , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peptídeos Cíclicos/química
15.
J Med Chem ; 66(3): 1873-1891, 2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-36695404

RESUMO

AXL kinase is heavily involved in tumorigenesis, metastasis, and drug resistance of many cancers, and several AXL inhibitors are in clinical investigations. Recent studies demonstrated that the N-terminal distal region of AXL plays more important roles in cell invasiveness than its C-terminal kinase domain. Therefore, degradation of AXL may present a novel superior therapeutic approach than the kinase inhibitor therapy. Herein, we report the discovery of a series of new AXL PROTAC degraders. One representative compound 6n potently depletes AXL with a DC50 value of 5 nM in MDA-MB-231 TNBC cells. It also demonstrates significantly improved potencies against the AXL signaling activation, cell proliferation, migration and invasion of TNBC cells comparing with the corresponding kinase inhibitor. Moreover, the compound exhibits promising therapeutic potential both in patient-derived organoids and a xenograft mouse model of MDA-MB-231 cells.


Assuntos
Receptores Proteína Tirosina Quinases , Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Proto-Oncogênicas/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Proliferação de Células , Modelos Animais de Doenças
16.
Phytochemistry ; 211: 113699, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37105351

RESUMO

(+) and (-)-Eugenilones A-K, 11 pairs of undescribed enantiomeric sesquiterpenoids, together with three undescribed biogenetically related members eugenilones L-N, were discovered from the fruits of Eugenia uniflora Linn. (Myrtaceae). Structurally, eugenilones A-D were four caged sesquiterpenoids featuring 9,10-dioxatricyclo [6.2.2.02,7]dodecane, 11-oxatricyclo [5.3.1.03,8]undecane, and tricyclo [4.4.0.02,8]decane cores, respectively. Eugenilones E-K were eudesmane-type sesquiterpenoids, while eugenilones L-N were epoxy germacrane-type sesquiterpenoids. Notably, eugenilones A-K were efficiently resolved by chiral HPLC to give 11 pairs of optically pure enantiomers. The structures and absolute configurations of eugenilones A-N were determined through spectroscopic analyses, X-ray crystallography, and ECD calculations. The putative biosynthetic pathways for these undescribed isolates were proposed. Moreover, eugenilones A and E exhibited significant anti-inflammatory effects by inhibiting LPS-stimulated NO overproduction in RAW264.7 cells (IC50 values of 4.89 ± 0.37 µM and 20.89 ± 1.49 µM, respectively) and TNF-α-induced NF-κB activation in HEK293 cells (IC50 values of 10.97 ± 1.03 µM and 28.63 ± 1.59 µM, respectively).


Assuntos
Eugenia , Sesquiterpenos , Animais , Camundongos , Humanos , Frutas , Células HEK293 , Estrutura Molecular , Células RAW 264.7 , Sesquiterpenos/farmacologia , Sesquiterpenos/química
17.
J Med Chem ; 65(4): 3249-3265, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35119278

RESUMO

Aberrant FGF19/FGFR4 signaling is an oncogenic driver force for the development of human hepatocellular carcinoma (HCC). A series of 2-formyl tetrahydronaphthyridine urea derivatives were designed and synthesized as new covalently reversible inhibitors of FGFR4. The representative compound 9ka exhibited an IC50 value of 5.4 nM against FGFR4 and demonstrated extraordinary kinome selectivity. Compound 9ka also exhibited good oral pharmacokinetic properties with an AUC(0-t) value of 38 950.06 h·ng/mL, a T1/2 value of 3.06 h, and an oral bioavailability of 50.97%, at an oral dose of 25 mg/kg in Sprague-Dawley (SD) rats. Furthermore, compound 9ka induced significant tumor regressions in a xenograft mouse model of Hep3B2.1-7 HCC cell line without an obvious sign of toxicity upon 30 mg/kg oral administration. Compound 9ka may serve as a promising lead compound for further anticancer drug development.


Assuntos
Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antineoplásicos/farmacologia , Área Sob a Curva , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Desenho de Fármacos , Meia-Vida , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Modelos Moleculares , Inibidores de Proteínas Quinases , Ratos , Ratos Sprague-Dawley , Ureia/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Eur J Med Chem ; 244: 114862, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36308779

RESUMO

REarranged during Transfection (RET) is a validated target for anticancer drug discovery and two selective RET inhibitors were approved by US FDA in 2020. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) becomes a major challenge for selective RET inhibitor therapies. Herein, we report a structure-based design of 1-methyl-3-((4-(quinolin-4-yloxy)phenyl)amino)-1H-pyrazole-4-carboxamide derivatives as new RET kinase inhibitors which are capable of suppressing the RETG810 C/R resistant mutants. One of the representative compounds, 8q, potently suppressed wild-type RET kinase with an IC50 value of 13.7 nM. It also strongly inhibited the proliferation of BaF3 cells stably expressing various oncogenic fusions of RET kinase with solvent-front mutations, e.g. CCDC6-RETG810C, CCDC6-RETG810R, KIF5B-RETG810C and KIF5B-RETG810R, with IC50 values of 15.4, 53.2, 54.2 and 120.0 nM, respectively. Furthermore, 8q dose-dependently inhibited the activation of RET and downstream signals and obviously triggered apoptosis in Ba/F3-CCDC6-RETG810 C/R cells. The compound also exhibited significant anti-tumor efficacy with a tumor growth inhibition (TGI) value of 66.9% at 30 mg/kg/day via i. p. in a Ba/F3-CCDC6-RETG810C xenograft mouse model. Compound 8q may be utilized as a lead compound for drug discovery combating acquired resistance against selective RET inhibitor therapies.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-ret , Humanos , Camundongos , Animais , Solventes , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Mutação , Transfecção , Neoplasias Pulmonares/tratamento farmacológico
19.
Nat Prod Bioprospect ; 11(1): 51-62, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32876846

RESUMO

Ten neolignans or norlignans (1-10) including eight new compounds were isolated from the whole bodies of Polyphaga plancyi Bolivar. Their structures were identified by spectroscopic data. Compounds 3, 4, 8, and 9 are racemates indicated by chiral HPLC analysis. Chiral separation followed by ECD calculations allowed to clarify the absolute configurations of all the antipodes. All the new compounds were evaluated for their biological properties toward extracellular matrix in rat renal proximal tubular cells, human cancer cells (K562, A549, and Huh7), EV71, ROCK2, JAK3, DDR1, and coagulation.

20.
ACS Med Chem Lett ; 12(4): 647-652, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33859803

RESUMO

Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds 6a, 6h, and 6i selectively suppressed FGFR4 enzymatic activity with IC50 values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound 6h bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound 6i with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. 6h and 6i might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

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