Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioorg Med Chem ; 37: 116107, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33735799

RESUMO

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer with high mortality and recurrence rates. Hecogenin, a steroidal sapogenin, is reported as a potential anti-tumor agent against breast cancer. However, the moderate activity limits its further application in clinical. With the aim to identify novel analogues that are especially efficacious in therapy of TNBC, a series of novel hecogenin thiosemicarbazone and semicarbazone derivatives were designed, synthesized and biologically evaluated. Screening of cytotoxicity revealed that 4c could potently inhibit the proliferation of breast cancer cells (MCF-7 and MDA-MB-231 cells), lung cancer cells (A549) and colon cancer cells (HT-29) at low µM level. Importantly, further mechanism studies indicated the ability of 4c in inducing apoptosis of MDA-MB-231 cells by arresting the cell cycle. Moreover, 4c notably suppressed the migration and invasion of MDA-MB-231 cells compared to its parent hecogenin at the equal concentration.

2.
Bioorg Chem ; 109: 104714, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33618254

RESUMO

Selective estrogen receptor degraders (SERDs) not only block ERα activity but degrade this receptor at the same time and are effective in relapsed ERα positive breast cancer patients who have accepted other endocrine therapies. Herein, through scaffold hopping of coumarin skeleton, a series of 2H-chromene-3-carbonyl-based SERDs with phenyl acrylic acid group as the side chain were designed and synthesized. Compound XH04 containing 7-hydroxy-2H-chromene-3-carbonyl skeleton exhibited the most potent activities in 2D (IC50 = 0.8 µM) and 3D cells culture models (MCF-7) and had the best ERα binding affinity as well. Furthermore, the significant antiestrogen property of compound XH04 was confirmed by inhibiting the expression of progesterone receptor (PgR) mRNA in MCF-7 cells. On the other hand, the outgoing ERα degradation property of compound XH04 was qualitatively and quantificationally verified by immunofluorescence analysis and Western blot assay in MCF-7 cells. Besides, compound XH04 repressed the expression level of Ki67 in MCF-7 cells and induced the apoptosis increase of this tumor cells in a dose-dependent manner like approved-SERD fulvestrant (2), while compound XH04 exhibited better preliminary pharmacokinetics in human and rat liver microsomes in vitro and a lower LogD7.4 value than fulvestrant. And further molecular docking study revealed that compound XH04 possessed a proverbial and typical binding model with ERα like other reported SERD. All these results confirmed that 7-hydroxy-2H-chromene-3-carbonyl structure could be a feasible skeleton for design of ERα antagonists including SERDs and compound XH04 is a promising candidate for further development of ERα + breast cancer therapy agents.

3.
Eur J Med Chem ; 209: 112910, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33049605

RESUMO

Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity.

4.
Eur J Med Chem ; 208: 112865, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32987316

RESUMO

Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC50 = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.

5.
Bioorg Med Chem ; 28(23): 115763, 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32992255

RESUMO

A series of novel steroidal-chalcone derivates were designed and synthesized based on the molecular hybridization strategy and further evaluated for their growth inhibitory activity against three human cancer cell lines. The MTT results indicated that most compounds were apparently more sensitive to human breast cancer cells MDA-MB-231. Compounds 8 and 18 exerted the best cytotoxic activity against triple-negative MDA-MB-231 cells with the IC50 values of 0.42 µM and 0.52 µM respectively, which were 23-fold increase or more compared with 5-Fu. Further mechanism studies demonstrated that compound 8 could induce cells apoptosis through regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. Moreover, compound 8 could upregulate the cellular ROS levels which accelerated the apoptosis of MDA-MB-231 cells. In addition, interestingly, cell cycle assay showed that compound 8 could arrest MDA-MB-231 cells at S phase but not commonly anticipated G2/M phase. These evidences fully confirmed that compound 8 could be a potential candidate that deserves further development as an antitumor agent against triple-negative breast cancer.

6.
Eur J Med Chem ; 206: 112689, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32829249

RESUMO

Estrogen receptor alfa (ERα) is expressed in approximate 70% of breast cancer (BC) which is the most common malignancy in women worldwide. To date, the foremost intervention in the treatment of ER positive (ER+) BC is still the endocrine therapy. However, resistance to endocrine therapies remains a major hurdle in the long-term management of ER + BC. Although the mechanisms underlying endocrine resistance are complex, cumulative evidence revealed that ERα still plays a critical role in driving BC tumor cells to grow in resistance state. Fulvestrant, a selective estrogen receptor degrader (SERD), has moved to first line therapy for metastatic ER + BC, suggesting that removing ERα would be a useful strategy to overcome endocrine resistance. Proteolysis-Targeting Chimera (PROTAC) technology, an emerging paradigm for protein degradation, has the potential to eliminate both wild type and mutant ERα in breast cancer cells. Excitingly, ARV-471, an ERα-targeted PROTAC developed by Arvinas, has been in phase 1 clinical trials. In this review, we will summarize recent progress of ER-targeting PROTACs from publications and patents along with their therapeutic opportunities for the treatment of endocrine-resistant BC.

7.
Eur J Med Chem ; 199: 112339, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32402933

RESUMO

Bruton's tyrosine kinase (BTK), as a key regulator of the B cell receptor (BCR) signaling pathway, is an attractive therapeutic target for the treatment of various diseases such as leukemia and B-cell malignancies. Herein, a series of compounds bearing 1, 3, 5-triazine core were prepared, and their biological activities on BTK were determined. Then the molecular docking study and ADME property prediction were made and a highly potent selective BTK inhibitor B8 (IC50 = 21.0 nM) was discovered. Compound B8 exhibited excellent activity with 5.14 nM inhibition of Raji cells and 6.14 nM inhibition of Ramos cells respectively. Additionally, B8 potently inhibited BTK kinase Y223 auto-phosphorylation, arrested cell cycle in G2/M phase and induced apoptosis in Ramos cells. The high selectivity for BTK and high potency in TMD8 cells of B8 suggested a low risk of off-target related adverse effects. Further molecular docking and dynamic simulation on B8 furnished insights into its binding profile within BTK. With significant efficacy in cellular assays and good ADME and safety profiles, B8 can be identified as a promising BTK inhibitor worthy of further profiling.

8.
Bioorg Chem ; 97: 103666, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32088420

RESUMO

Selective estrogen receptor degrader (SERD) that acts as not only ER antagonist, but also ER degrader, would be useful for the treatment for drug-resistance ER+ breast cancer. However, most of currently available SERD candidates involve very limited molecular scaffolds and are still in clinical trials. In this study, we introduced a 1,3,5-triazine ring into a homobibenzyl motif extracted from amounts of ER ligands and synthesized sixteen SERDs bearing acrylic acid or acrylic amide side chains that possess both ERα antagonism and degradation properties. And all compounds were screened for their anti-proliferative activity against ER+ MCF-7 and Ishikawa cell lines. Among them, compound XHA1614 displayed potent growth inhibition activity against MCF-7 and Ishikawa cells with IC50 values of 3.15 µM and 3.11 µM, respectively. Moreover, XHA1614 could dramatically degrade ER level at 1 nM in a Western blotting assay and afforded an outstanding antagonistic activity via suppressing the expression of progesterone receptor messenger RNA in MCF-7 cells in a RT-PCR assay. Further molecular docking and dynamic simulation on properly selected derivative furnished insights into its binding profile within ERα. Our findings suggest that the 1,3,5-triazine core was a feasible alternative to currently reported SERD scaffold, and provide information that will be useful for further development of promising SERDs candidates for breast cancer therapies.

9.
Eur J Med Chem ; 186: 111876, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761384

RESUMO

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) is a negative immune checkpoint pathway that inhibit immune responses, and upregulation of this pathway has implications in many malignancies. The search for effective PD-1/PD-L1 inhibitors has been at the forefront of academic and industrial medicinal chemistry, leading to 16 clinical candidates and the launch of six monoclonal antibodies (mAbs) drugs. Despite the unprecedented success achieved, the limitations of mAbs, including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, impelled researchers to turn their attention to the development of peptide-based and non-peptide small-molecule inhibitors as potential alternatives or supplements to mAbs. However, no small-molecule inhibitors have been approved so far, indicating a challenging process of developing marketable small-molecule PD-1/PD-L1 targeted therapeutics. This review will summarize and provide insight into recent advances in the PD-1/PD-L1 pathway, including its structural basis and biology, along with the crystal structures with mAbs, peptides and small molecules. We place great emphasis on design strategies underlying reported small-molecule inhibitors and attempt to provide an outlook at the future of small-molecule PD-1/PD-L1inhibitors.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Peptídeos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Antígeno B7-H1/metabolismo , Relação Dose-Resposta a Droga , Humanos , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Estrutura Molecular , Peptídeos/química , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
10.
Org Lett ; 21(8): 2493-2497, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30816719

RESUMO

Successive nucleophilic and electrophilic allylation mediated by the bis-Boc-carbonate derived from 2-methylene-1,3-propane diol enables formation of enantiomerically enriched 2,4-disubstituted pyrrolidines. An initial enantioselective iridium-catalyzed transfer hydrogenative carbonyl C-allylation is followed by Tsuji-Trost N-allylation using 2-nitrobenzenesulfonamide. Subsequent Mitsunobu cyclization provides the N-protected 2,4-disubstituted pyrrolidines.


Assuntos
Compostos Alílicos/química , Pirrolidinas/síntese química , Catálise , Complexos de Coordenação/química , Reação de Cicloadição , Irídio/química , Nitrocompostos/química , Estereoisomerismo , Sulfonamidas/química
11.
Steroids ; 150: 108384, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30885648

RESUMO

Both AR and CYP17 are important targets for blocking androgen signaling, and it has been accepted that multifunctional drugs have a low risk of drug resistance in the treatment of cancer. Thus, herein a series of steroidal imidazoles were designed, synthesized and evaluated as dual AR/CYP17 ligands. Several compounds displayed good biological profiles in both enzymatic and cellular assays. SAR studies showed that introducing oximino at the C-3 position of steroidal scaffold is beneficial to the enhancement of AR antagonistic activity. Among these compounds, the most potent compound 13a exhibited the best AR inhibition (IC50 = 0.5 µM) that was 27-fold increase compared with the hit compound 5 as well as comparable CYP17 inhibition (IC50 = 11 µM). Additionally, 13a displayed promising anti-proliferative effects on LNCap cell lines with the IC50 value of 23 µM which was superior to positive control Flutamide (IC50 = 28 µM). Furthermore, the docking results of 13a revealed that the oxygen atom at the position of C-3 connected to the heme of CYP17, which may be helpful for its satisfactory dual-target inhibition. In summary, this study provides an efficient strategy for multi-targeting drug discovery in the treatment of prostate cancer.


Assuntos
Antagonistas de Androgênios/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Masculino , Modelos Moleculares , Conformação Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ratos , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroides/síntese química , Esteroides/química , Esteroides/farmacologia , Relação Estrutura-Atividade
12.
Bioorg Chem ; 85: 140-151, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30612080

RESUMO

There is much interest in the use of phytoestrogens such as coumestrol in breast cancer intervention due to their antiestrogenic activity and multiple modes of tumor cell death. However, the clear beneficial effects of naturally occurring estrogen mimetic coumestrol remain controversial due to experimental evidence that it has been shown to stimulate MCF-7 cell proliferation via agonist effect on estrogen receptor at low concentration. Herein, to disconnect the ER interaction and apoptosis-specific mechanism of coumestrol, various 3, 9-di-O-substituted coumestrols (7a-7e) and their furan ring-opened analogs (5a-5e) were synthesized and assessed for antiproliferative properties. Attachment of a dimethylamine-containing side chain to 3-O of coumestrol led to the most promising compound 7e with improved antiproliferative activity (1.7-fold increase) against MCF-7 cells, decreased estrogen activity (>20 times weaker ERα binder) and a novel action to induce apoptosis. Mechanistic studies revealed that 7e is a tubulin polymerization inhibitor, which could arrest cell cycle at G2/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, such subtle modifications to the 3, 9-di-hydroxyl groups of coumestrol allow the generation of a novel apoptosis inducer with distinct pharmacological properties, providing an excellent starting point to future development of novel tumor-vascular disrupting agents targeting tubulin.


Assuntos
Aminas/farmacologia , Inibidores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Cumestrol/análogos & derivados , Cumestrol/farmacologia , Aminas/síntese química , Aminas/metabolismo , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumestrol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia
13.
Chem Commun (Camb) ; 55(7): 981-984, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30608076

RESUMO

Highly enantioselective iridium catalyzed carbonyl (2-vinyl)allylation or "isoprenylation" is achieved via hydrogen auto-transfer or 2-propanol-mediated reductive coupling from primary alcohol or aldehyde reactants, respectively. Using this method, asymmetric total syntheses of the terpenoid natural products (+)-ipsenol and (+)-ipsdienol were achieved.

14.
Eur J Med Chem ; 161: 445-455, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384047

RESUMO

SERMs are a series of important small molecular compounds to modulate estrogen receptor, such as tamoxifen. Although these drugs have showed great benefits in the treatment of breast cancer, the risk of endometrial cancer and endocrine resistance restrict their use. The reasonable designing of multi-target drugs can decrease the side effects and improve the tolerance of antineoplastic agents Studies have identified that VEGFR-2 plays a pivotal role in tumor angiogenesis and drug resistance. Besides, a combination of Tamoxifen and low dose of a VEGFR-2 inhibitor was reported to maximize therapeutic efficacy as well as to retard SERM resistant tumor growth. In this work, a series of 3-aryl-quinolin derivatives were designed to target to ERα and VEGFR-2 to eliminate the disadvantages of SERMs. We identified that compounds 12f and 13f displayed highly ERα binding affinities as well as relative intensity VEGFR-2 inhibitory activities. Moreover, this two compounds exhibited excellent anti-proliferative activities against MCF-7 and HUVEC cell lines with low micromolar IC50 (1-8 µM). A further study confirmed that compound 13f can reduce the expression of PgR mRNA, arrest cell cycle in MCF-7 breast cancer cells, and restrain the cell migration. Overall, based on the biological activities data, 13f can be chosen as a potential anti-cancer lead compound for further studying.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Bioorg Med Chem Lett ; 28(23-24): 3726-3730, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30342957

RESUMO

Our group has previously reported a series of isoflavone derivatives with antidyslipidemic activity. With this background, a series of isoflavone analogs of GW4064 were designed, synthesized and evaluated the lipid-lowering activity of analogs. As a result, most of compounds significantly reduced the lipid accumulation in 3T3-L1 adipocytes and four of them (10a, 11, 15c and 15d) showed stronger inhibitory than GW4064. The most potent compound 15d exhibited promising agonistic activity for FXR in a cell-based luciferase reporter assay. Meanwhile, 15d up-regulated FXR, SHP and BSEP gene expression and down-regulated the mRNA expression of lipogenesis gene SREBP-1c. Besides, an improved safety profile of 15d was also observed in a HepG2 cytotoxicity assay compared with GW4064. The obtained biological results were further confirmed by a molecular docking study showing that 15d fitted well in the binding pocket of FXR and interacted with some key residues simultaneously.


Assuntos
Adipócitos/efeitos dos fármacos , Isoflavonas/química , Isoflavonas/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Desenho de Fármacos , Células Hep G2 , Humanos , Isoflavonas/síntese química , Isoxazóis/síntese química , Camundongos , Simulação de Acoplamento Molecular , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Bioorg Med Chem ; 26(15): 4537-4543, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30077608

RESUMO

Btk inhibitors and PI3Kδ inhibitors play crucial roles in the treatment of leukemia, and studies confirmed that the synergetic inhibition against Btk and PI3Kδ could gain an optimal response. Herein, a series of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives were designed and synthesized as dual Btk/PI3Kδ kinases inhibitors for the treatment of leukemia. Studies indicated that most compounds could suppress the proliferation of multiple leukemia or lymphoma cells (Raji, HL60 and K562 cells) at low micromolar concentrations in vitro. Further kinase assays identified several compounds could simultaneously inhibit Btk kinase and PI3Kδ kinase. Thereinto, compound 16b exhibited the best inhibitory activity (Btk: IC50 = 139 nM; PI3Kδ: IC50 = 275 nM) and showed some selectivity against PI3Kδ compared to PI3Kß/γ. Finally, the SAR of target compounds was preliminarily discussed combined with docking results. In brief, 16b possessed of the potency for the further optimization as anti-leukemia drugs by inhibiting simultaneously Btk kinase and PI3Kδ kinase.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Antineoplásicos/síntese química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 28(17): 2879-2884, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30031618

RESUMO

In continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 µM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.


Assuntos
Ácido Quenodesoxicólico/farmacologia , Desenho de Fármacos , Isoxazóis/farmacologia , Lipídeos/antagonistas & inibidores , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Ácido Quenodesoxicólico/síntese química , Ácido Quenodesoxicólico/química , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Isoxazóis/química , Lipídeos/biossíntese , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
18.
Bioorg Chem ; 80: 396-407, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29986186

RESUMO

Bile acids, initially discovered as endogenous ligands of farnesoid X receptor (FXR), play a central role in the regulation of triglyceride and cholesterol metabolism and have recently emerged as a privileged structure for interacting with nuclear receptors relevant to a large array of metabolic processes. In this paper, phenoxy containing cholic acid derivatives with excellent drug-likeness have been designed, synthesized, and assayed as agents against cholesterol accumulation in Raw264.7 macrophages. The most active compound 14b reduced total cholesterol accumulation in Raw264.7 cells up to 30.5% at non-toxic 10 µM and dosage-dependently attenuated oxLDL-induced foam cell formation. Western blotting and qPCR results demonstrate that 14b reduced both cholesterol and lipid in Raw264.7 cells through (1) increasing the expression of cholesterol transporters ABCA1 and ABCG1, (2) accelerating ApoA1-mediated cholesterol efflux. Through a cell-based luciferase reporter assay and molecular docking analysis, LXR was identified as the potential target for 14b. Interestingly, unlike conventional LXR agonist, 14b did not increase lipogenesis gene SREBP-1c expression. Overall, these diverse properties disclosed herein highlight the potential of 14b as a promising lead for further development of multifunctional agents in the therapy of cardiovascular disease.


Assuntos
Colesterol/metabolismo , Ácido Cólico/química , Ácido Cólico/farmacologia , Desenho de Fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Ácido Cólico/síntese química , Descoberta de Drogas , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
19.
Org Lett ; 20(13): 4144-4147, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29938513

RESUMO

Cyclometalated π-allyliridium C,O-benzoates modified by ( S)-SEGPHOS or ( S)-Cl,OMe-BIPHEP catalyze enantioselective 2-propanol-mediated reductive couplings of diverse nonmetallic allyl pronucleophiles with the acetylenic aldehyde TIPSC≡CCHO. Absolute stereochemistries of the resulting secondary homoallylic-propargylic alcohols were assigned using Rychnovsky's competing enantioselective conversion method.

20.
Eur J Med Chem ; 150: 783-795, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29587221

RESUMO

Both ERα and VEGFR-2 are important targets for cancer therapies. Here a series of 2, 4-disubstituted pyrimidine derivatives were designed, synthesized and evaluated as dual ERα/VEGFR-2 ligands. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section is important factors for the enhancement of ERα-binding affinity. The most potent compound II-9OH, an analog of 2-(4-hydroxylphenyl)pyrimidine, was 19-fold more efficacious than tamoxifen in MCF-7 cancer cells and exhibited the best ERα binding affinity (IC50 = 1.64 µM) as well as excellent VEGFR-2 inhibition (IC50 = 0.085 µM). Furthermore, this dual targeted compound II-9OH exerted significantly antiestrogenic property via suppressing the expression of progesterone receptor (PgR) mRNA in MCF-7 cells and also showed obvious in vivo angiogenesis inhibitory effects in CAM assay. An induction of apoptosis and a decrease in cell migration, accompanied by transduction inhibition of Raf-1/MAPK/ERK pathway, were observed in MCF-7 cells after treatment with II-9OH, suggesting that II-9OH is a promising candidate for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/antagonistas & inibidores , Pirimidinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Células MCF-7 , Estrutura Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...