Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 39
Filter
1.
Bioorg Chem ; 151: 107714, 2024 Aug 10.
Article in English | MEDLINE | ID: mdl-39167867

ABSTRACT

Aberrant activation or mutation of the EGFR-PI3K-Akt-mTOR signaling pathway has been implicated in a wide range of human cancers, especially non-small-cell lung cancer (NSCLC). Thus, dual inhibition of EGFR and PI3K has been investigated as a promising strategy to address acquired drug resistance resulting from the use of tyrosine kinase inhibitors. A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. The optimal compound 30k showed potent kinase inhibitory activities with IC50 values of 3.6 and 30.0 nM against EGFRL858R/T790M and PI3Kα, respectively. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.

2.
J Med Chem ; 67(9): 7330-7358, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38661655

ABSTRACT

The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinase-selective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC50: 0.74 µM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Drug Design , MTOR Inhibitors , Mice, Nude , TOR Serine-Threonine Kinases , Triazines , Humans , Animals , Triazines/chemical synthesis , Triazines/pharmacology , Triazines/chemistry , Triazines/pharmacokinetics , Triazines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Mice , MTOR Inhibitors/pharmacology , MTOR Inhibitors/chemical synthesis , MTOR Inhibitors/therapeutic use , MTOR Inhibitors/chemistry , Structure-Activity Relationship , MCF-7 Cells , Cell Proliferation/drug effects , Xenograft Model Antitumor Assays , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Mice, Inbred BALB C , Autophagy/drug effects
3.
Bioorg Chem ; 140: 106781, 2023 11.
Article in English | MEDLINE | ID: mdl-37597440

ABSTRACT

The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 µM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 µM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 µM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.


Subject(s)
Colorectal Neoplasms , Early Detection of Cancer , Humans , Animals , Rats , MTOR Inhibitors , TOR Serine-Threonine Kinases , HCT116 Cells , Colorectal Neoplasms/drug therapy
4.
Eur J Med Chem ; 260: 115754, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37651880

ABSTRACT

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 µM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.


Subject(s)
Colorectal Neoplasms , Phosphatidylinositol 3-Kinases , Humans , HCT116 Cells , Quinoxalines/pharmacology , Signal Transduction , Colorectal Neoplasms/drug therapy
5.
RSC Adv ; 13(16): 10873-10883, 2023 Apr 03.
Article in English | MEDLINE | ID: mdl-37033434

ABSTRACT

Protoporphyrinogen oxidase (PPO) is a key enzyme in chlorophyll and heme biosynthesis, and the development of its inhibitors is of great importance both in the pharmaceutical and pesticide industries. However, the currently developed PPO inhibitors have insignificant bio-selectivity and have a serious impact on non-target organisms. In this study, a docking-based virtual screening approach combined with bio-activity testing was used to obtain novel selective inhibitors of PPO. The results of the bio-activity test showed that thirteen compounds showed 10-fold selectivity over human PPO. And the best selective compound, ZINC70338, has a K i value of 2.21 µM for Nicotiana tabacum PPO and >113-fold selectivity for human PPO. The selectivity mechanism of ZINC70338 in different species of PPO was then analyzed by molecular dynamics simulations to provide a design basis and theoretical guidance for the design of novel selective inhibitors.

6.
J Med Chem ; 65(24): 16033-16061, 2022 12 22.
Article in English | MEDLINE | ID: mdl-36503229

ABSTRACT

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.


Subject(s)
Phosphatidylinositol 3-Kinase , Proto-Oncogene Proteins c-akt , Humans , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Prospective Studies , Phosphoinositide-3 Kinase Inhibitors , Signal Transduction , TOR Serine-Threonine Kinases
7.
J Org Chem ; 87(24): 16492-16505, 2022 12 16.
Article in English | MEDLINE | ID: mdl-36473149

ABSTRACT

A convenient method was developed for the preparation of thiolated compounds via a DBU-catalyzed aerobic cross-dehydrogenative coupling (CDC) reaction. The established protocol is environmentally friendly and operationally simple. Substrates like (hetero)aryl acetates, (hetero)aryl ketones, and indoles could be transformed into the corresponding thiolated products in moderate to high yields and further applied in the preparation of bioactive compounds in a prefunctionalization-free manner.


Subject(s)
Ketones , Sulfhydryl Compounds , Catalysis , Molecular Structure , Ketones/chemistry
8.
Org Biomol Chem ; 20(32): 6423-6431, 2022 08 17.
Article in English | MEDLINE | ID: mdl-35880643

ABSTRACT

An efficient radical annulation of N-arylacrylamides with disulfides is developed for the synthesis of sulfurated oxindoles. The reaction occurs in a facile manner using CoBr2 as both an initiator and a promoter for the first time and (NH4)2S2O8 as the oxidant. By controlling the CoBr2/(NH4)2S2O8 ratio, a wide range of sulfurated and brominated/sulfurated oxindoles are selectively prepared in good to excellent yields. The present protocol is simple and highly atom economical, and can tolerate a broad range of substrates.


Subject(s)
Cobalt , Disulfides , Indoles , Oxindoles
9.
J Mol Model ; 28(5): 123, 2022 Apr 19.
Article in English | MEDLINE | ID: mdl-35438328

ABSTRACT

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors.


Subject(s)
Benzimidazoles , Phosphatidylinositol 3-Kinases , Benzimidazoles/pharmacology , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology
10.
Eur J Med Chem ; 229: 114055, 2022 Feb 05.
Article in English | MEDLINE | ID: mdl-34971874

ABSTRACT

The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 µM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.


Subject(s)
Antineoplastic Agents/chemistry , Colorectal Neoplasms/drug therapy , Enzyme Inhibitors/chemical synthesis , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Urea/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Mice, Inbred BALB C , Models, Molecular , Molecular Docking Simulation , Morpholines/pharmacology , Neoplasms, Experimental , Protein Binding , Protein Conformation , Signal Transduction , Structure-Activity Relationship , Triazines/pharmacology , Urea/pharmacokinetics
11.
Bioorg Med Chem Lett ; 52: 128410, 2021 11 15.
Article in English | MEDLINE | ID: mdl-34626784

ABSTRACT

Four series of cajanonic acid A (CAA) derivatives have been designed and synthesized. The newly prepared compounds have been screened for glucose consumption activity in HepG2 cell lines and PPARγ antagonistic activity in HEK293 cell lines. Compound 26g bearing a tetrahydroisoquinolinone scaffold showed the most potent PPARγ antagonistic and hypoglycemic activities. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 26g was a potent hypoglycemic agent. In addition, the possible binding modes for compound 26g in the PPARγ protein have been investigated in this study.


Subject(s)
PPAR gamma/antagonists & inhibitors , Plant Extracts/pharmacology , Stilbenes/pharmacology , Cajanus/chemistry , Cell Line , Dose-Response Relationship, Drug , Humans , Molecular Structure , PPAR gamma/metabolism , Plant Extracts/chemical synthesis , Plant Extracts/chemistry , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity Relationship
12.
Eur J Med Chem ; 225: 113824, 2021 Dec 05.
Article in English | MEDLINE | ID: mdl-34509167

ABSTRACT

Hepatocellular carcinoma (HCC) is a major contributor to global cancer incidence and mortality. Many pathways are involved in the development of HCC and various proteins including mTOR and HDACs have been identified as potential drug targets for HCC treatment. In the present study, two series of novel hybrid molecules targeting mTOR and HDACs were designed and synthesized based on parent inhibitors (MLN0128 and PP121 for mTOR, SAHA for HDACs) by using a fusion-type molecular hybridization strategy. In vitro antiproliferative assays demonstrated that these novel hybrids with suitable linker lengths exhibited broad cytotoxicity against various cancer cell lines, with significant activity against HepG2 cells. Notably, DI06, an MLN0128-based hybrid, exhibited antiproliferative activity against HepG2 cells with an IC50 value of 1.61 µM, which was comparable to those of both parent drugs (MLN0128, IC50 = 2.13 µM and SAHA, IC50 = 2.26 µM). In vitro enzyme inhibition assays indicated that DI06, DI07 and DI17 (PP121-based hybrid) exhibited nanomolar inhibitory activity against mTOR kinase and HDACs (e.g., HDAC1, HDAC2, HDAC3, HADC6 and HADC8). Cellular studies and western blot analyses uncovered that in HepG2 cells, DI06 and DI17 induced cell apoptosis by targeting mTOR and HDACs, blocked the cell cycle at the G0/G1 phase and suppressed cell migration. The potential binding modes of the hybrids (DI06 and DI17) with mTOR and HDACs were investigated by molecular docking. DI06 displayed better stability in rat liver microsomes than DI07 and DI17. Collectively, DI06 as a novel mTOR and HDACs inhibitor presented here warrants further investigation as a potential treatment of HCC.


Subject(s)
Antineoplastic Agents/pharmacology , Benzoxazoles/pharmacology , Carcinoma, Hepatocellular/drug therapy , Histone Deacetylase Inhibitors/pharmacology , Liver Neoplasms/drug therapy , Protein Kinases/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Hep G2 Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/metabolism , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Protein Kinases/chemical synthesis , Protein Kinases/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Tumor Cells, Cultured
13.
Bioorg Chem ; 115: 105172, 2021 10.
Article in English | MEDLINE | ID: mdl-34303898

ABSTRACT

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.


Subject(s)
Carbazoles/chemistry , Drug Design , Hypoglycemic Agents/chemical synthesis , AMP-Activated Protein Kinases/chemistry , AMP-Activated Protein Kinases/metabolism , Animals , Binding Sites , Carbazoles/pharmacology , Carbazoles/therapeutic use , Drug Stability , Glucose/metabolism , Glucose Tolerance Test , Half-Life , Hep G2 Cells , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Male , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
14.
J Org Chem ; 86(13): 8620-8629, 2021 07 02.
Article in English | MEDLINE | ID: mdl-34097828

ABSTRACT

An efficient aerobic iron-catalyzed annulation of unsaturated carboxylic acids with disulfides has been developed. This procedure proceeds using FeCl3 as the catalyst and KI as an iodine source under an air atmosphere, which provides practical access to a wide range of substituted γ-lactone derivatives. The disclosed method is quite simple, highly atom-economic, environmentally friendly, and tolerates a broad substrate scope.


Subject(s)
Iron , Lactones , Carboxylic Acids , Catalysis , Disulfides
15.
Bioorg Chem ; 108: 104641, 2021 03.
Article in English | MEDLINE | ID: mdl-33517004

ABSTRACT

LC-MS guided chemical investigation of the periploside-rich extract of the root barks of Periploca sepium afforded six new minor pregnane glycosides, named periplosides A1-A6 (1-6). Their structures were characterized on the basis of extensive spectroscopic analysis. Compounds 1-6 were evaluated for their inhibitory activities against the proliferation of T and B lymphocytes in vitro, among them, compound 5 exhibited significant inhibitory activities and the most favorite selective index (SI) values against the proliferation of T lymphocyte (IC50 = 0.30 µM, SI = 176) and B lymphocyte (IC50 = 0.55 µM, SI = 97).


Subject(s)
B-Lymphocytes/drug effects , Glycosides/pharmacology , Periploca/chemistry , Plant Roots/chemistry , Pregnanes/pharmacology , T-Lymphocytes/drug effects , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Female , Glycosides/chemistry , Glycosides/isolation & purification , Mice , Mice, Inbred BALB C , Molecular Structure , Pregnanes/chemistry , Pregnanes/isolation & purification , Structure-Activity Relationship
16.
Eur J Med Chem ; 204: 112637, 2020 Oct 15.
Article in English | MEDLINE | ID: mdl-32717477

ABSTRACT

A series of novel substituted triazines bearing a benzimidazole scaffold were designed and synthesized based on the structures of known anti-cancer agents, namely gedatolisib and alpelisib. All the target compounds were screened for inhibitory activity against PI3Kα and mTOR kinases. Notably, most analogs exhibited IC50 in the nanomolar range. Investigation of the isozyme selectivity indicated that the compounds exhibited remarkable inhibitory activity against PI3Kδ, especially compound 19f showed an IC50 value of 2.3 nM for PI3Kδ and moderate δ-isozyme selectivity over other class I PI3K isoforms and mTOR (with IC50 values of 14.6, 34.0, 849.0 and 15.4 nM for PI3Kα, ß, γ and mTOR, respectively). An in vitro MTT assay was conducted to assess the antiproliferative and cytotoxic effects of the prepared analogs. It was revealed that the compounds displayed significant inhibitory activities against the HCT116 human colon cancer cell line. Compound 19i showed 4.7-fold higher potency than the positive control gedatolisib (0.3 vs. 1.4 µM, IC50 values). Phosphoblot studies demonstrated that 19c and 19i could significantly suppress the PI3K/Akt/mTOR signaling pathway at 10 µM. Moreover, analogs 19b, 19c and 19i displayed better stability in artificial gastric fluids than gedatolisib, while 19i was indicated not very stable in rat liver microsomes, and may occur phase I metabolic transformations.


Subject(s)
Drug Design , Phosphatidylinositol 3-Kinases/drug effects , Phosphoinositide-3 Kinase Inhibitors/chemistry , Phosphoinositide-3 Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triazines/chemistry , Triazines/pharmacology , Cell Proliferation/drug effects , HCT116 Cells , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Triazines/chemical synthesis
17.
BMC Complement Med Ther ; 20(1): 61, 2020 Feb 22.
Article in English | MEDLINE | ID: mdl-32087732

ABSTRACT

BACKGROUND: Pharmacokinetic interaction is one of the most important indices for the evaluation of the compatibility of herbal medicines. Both Gancao (Glycyrrhizae Radix et Rhizoma) and Huanglian (Coptidis Rhizoma) are commonly used traditional Chinese medicines (TCMs). In this study, the influence of Gancao on the pharmacokinetics of Huanglian was systematically studied by using berberine as a pharmacokinetic marker. METHODS: Extracts of the herbal pieces of Huanglian and the herb pair (Huanglian plus Gancao) were prepared with boiling water. The concentration of berberine in the samples was analyzed using liquid chromatography-mass spectrometry. The total amounts of berberine in all extract samples were compared. Comparative pharmacokinetic studies of Huanglian and the herb pair were conducted in ICR mice. In vitro berberine absorption and efflux were studied using mice gut sacs. The equilibrium solubility of berberine in the extracts was determined. The in vitro dissolution of berberine was comparatively studied using a rotating basket method. RESULTS: Gancao significantly reduced berberine exposure in the portal circulation (425.8 ng·h/mL vs. 270.4 ng·h/mL) and the liver (29,500.8 ng·h/mL vs. 15,422.4 ng·h/mL) of the mice. In addition, Gancao decreased the peak concentration (Cmax) of berberine in the portal circulation (104.3 ng·h/mL vs. 76.5 ng·h/mL) and liver (4926.1 ng·h/mL vs. 2642.8 ng·h/mL) of mice. Significant influences of Gancao on the amount of berberine extracted (32% reduction), the solubility of berberine (34.7% compared with the control group), and dissolution (88.7% vs. 66.1% at 15 min in acid buffer and 68% vs. 51.8% at 15 min in phosphate buffer) were also revealed. Comparative pharmacokinetic studies in ICR mice indicated that the formation of sediment was unfavorable in terms of berberine absorption (345.3 ng·h/mL vs. 119.8 ng·h/mL). CONCLUSIONS: Gancao was able to reduce intestinal absorption and in vivo exposure of berberine in Huanglian via the formation of sediment, which caused reductions in the extracted amount, solubility, and dissolution of berberine.


Subject(s)
Berberine/pharmacokinetics , Drugs, Chinese Herbal/pharmacokinetics , Plant Extracts/pharmacokinetics , Animals , Chromatography, Liquid , Drug Therapy, Combination , Female , Glycyrrhiza , Male , Mass Spectrometry , Medicine, Chinese Traditional , Mice, Inbred ICR , Plant Roots
18.
RSC Adv ; 10(70): 42912-42915, 2020 Nov 23.
Article in English | MEDLINE | ID: mdl-35514906

ABSTRACT

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives was established, which is compatible with a broad range of substrates and delivers the final products in excellent yields (up to 99%) and ee values (up to 99%) with low catalyst loading (down to 1 mol%). The synthetic potential of this methodology was also demonstrated in the gram scale level.

19.
Bioorg Med Chem Lett ; 29(23): 126709, 2019 12 01.
Article in English | MEDLINE | ID: mdl-31629632

ABSTRACT

Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway.


Subject(s)
Berberine/therapeutic use , Hypoglycemic Agents/therapeutic use , Berberine/analogs & derivatives , Berberine/pharmacology , Humans , Hypoglycemic Agents/pharmacology
20.
Biomed Chromatogr ; 33(11): e4649, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31301694

ABSTRACT

Rhodojaponin III is a bioactive diterpenoid isolated from the medicinal plant Rhododendron molle G. Don. Quantitative analysis of rhodojaponin III was challenging and the pharmacokinetics of oral rhodojaponin III remained to be investigated. Here, a rapid and sensitive liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated. The calibration curve was linear over the concentration range of 1-200 ng/mL (r = 0.992). The method was further validated following internationally approved guidelines and all the issues including intra- and inter-day precision, accuracy, carryover, extraction recovery, matrix effects and stability met the recommended limits. The method was then applied to study the pharmacokinetics of rhodojaponin III in mice after intravenous (0.06 mg/kg) or oral (0.24 mg/kg) administration. The results showed that rhodojaponin III had fast oral absorption (time to peak concentration, 0.08 h) and good oral bioavailability (73.6%). In addition, rhodojaponin III was quickly eliminated after it was intravenously or orally administered, with half-life values of 0.19 and 0.76 h, respectively. After oral administration, it was widely distributed in tissues including kidney, lung, heart, spleen and thymus, but had extremely low concentrations in liver and brain. The data presented in this study is beneficial for the further study of rhodojaponin III.


Subject(s)
Diterpenes , Administration, Oral , Animals , Biological Availability , Chromatography, Liquid/methods , Diterpenes/administration & dosage , Diterpenes/analysis , Diterpenes/pharmacokinetics , Female , Injections, Intravenous , Limit of Detection , Linear Models , Male , Mice , Mice, Inbred ICR , Reproducibility of Results , Tandem Mass Spectrometry/methods , Tissue Distribution
SELECTION OF CITATIONS
SEARCH DETAIL