Disposition of orally administered a promising chemotherapeutic agent flavopiridol in the intestine

Xia, Bao‐Hui; Liu, Xi; Zhou, Qiong; Feng, Qian; Li, Ye; Liu, Wei; Liu, Zhongqiu

doi:10.3109/03639045.2012.682224

Cited by 6 publications

(2 citation statements)

References 29 publications

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“…The increased potency of flavopiridol compared to chrysin with A ring substitutions supports such an approach [16,22]. Additionally, while natural flavonoids have quite low oral bioavailability, flavopiridol does not [44], and together with the promising cellular results obtained here for 43, highlights the potential of synthetic flavonoid analogues in drug discovery projects such as this.…”

Section: Discussionmentioning

confidence: 56%

Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors

Chetter

Kyriakis

Barr

et al. 2020

Bioorganic Chemistry

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Glycogen phosphorylase (GP) is an important target for the development of new antihyperglycaemic agents. Flavonoids are novel inhibitors of GP, but their mode of action is unspecific in terms of the GP binding sites involved. Towards design of synthetic flavonoid analogues acting specifically at the inhibitor site and to exploit the site's hydrophobic pocket, chrysin has been employed as a lead compound for the in silico screening of 1169 new analogues with different B ring substitutions. QM/MM-PBSA binding free energy calculations guided the final selection of eight compounds, subsequently synthesised using a Baker-Venkataraman rearrangement-cyclisation approach. Kinetics experiments against rabbit muscle GPa and GPb together with human liver GPa, revealed three of these compounds (11, 20 and 43) among the most potent that bind at the site (Ki s < 4 µM for all three isoforms), and more potent than previously reported natural flavonoid inhibitors. Multiple inhibition studies revealed binding exclusively at the inhibitor site. The binding is synergistic with glucose suggesting that inhibition could be regulated by blood glucose levels and would decrease as normoglycaemia is achieved. Compound 43 was an effective inhibitor of glycogenolysis in hepatocytes (IC50 = 70 µM), further promoting these compounds for optimization of their druglike potential. X-ray crystallography studies revealed the B-ring interactions responsible for the observed potencies.

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Section: Discussionmentioning

confidence: 56%

Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors

Chetter

Kyriakis

Barr

et al. 2020

Bioorganic Chemistry

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“…Smaller particles are favorable for passive targeting to the tumor through the EPR effect. 65 Secondly, NaC improved the stability of micelles. PTX-CMs had lower CMC than PTX-Ms, which helped enhance the stability of micelles in the bloodstream.…”

mentioning

confidence: 99%

Sodium cholate-enhanced polymeric micelle system for tumor-targeting delivery of paclitaxel

Zhang¹,

Wu²,

Zhang³

et al. 2017

IJN

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Purpose Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of paclitaxel (PTX). High antitumor efficacy and low toxicity require that PTX mainly accumulated in tumors with little drug exposure to normal tissues. However, many PTX-loaded micelle formulations suffer from low stability, fast drug release, and lack of tumor-targeting capability in the circulation. To overcome these challenges, we developed a micellar formulation that consists of sodium cholate (NaC) and monomethoxy poly (ethylene glycol)- block -poly ( d , l -lactide) (mPEG-PDLLA). Methods PTX-loaded NaC-mPEG-PDLLA micelles (PTX-CMs) and PTX-loaded mPEG-PDLLA micelles (PTX-Ms) were formulated, and their characteristics, particle size, surface morphology, release behavior in vitro, pharmacokinetics and in vivo biodistributions were researched. In vitro and in vivo tumor inhibition effects were systematically investigated. Furthermore, the hemolysis and acute toxicity of PTX-CMs were also evaluated. Results The size of PTX-CMs was 53.61±0.75 nm and the ζ-potential was −19.73±0.68 mV. PTX was released much slower from PTX-CMs than PTX-Ms in vitro. Compared with PTX-Ms, the cellular uptake of PTX-CMs was significantly reduced in macrophages and significantly increased in human cancer cells, and therefore, PTX-CMs showed strong growth inhibitory effects on human cancer cells. In vivo, the plasma AUC 0−t of PTX-CMs was 1.8-fold higher than that of PTX-Ms, and 5.2-fold higher than that of Taxol. The biodistribution study indicated that more PTX-CMs were accumulated in tumor than PTX-Ms and Taxol. Furthermore, the significant antitumor efficacy of PTX-CMs was observed in mice bearing BEL-7402 hepatocellular carcinoma and A549 lung carcinoma. Results from drug safety assessment studies including acute toxicity and hemolysis test revealed that the PTX-CMs were safe for in vivo applications. Conclusion These results strongly revealed that NaC-mPEG-PDLLA micelles can tumor-target delivery of PTX and enhance drug penetration in tumor, suggesting that NaC-mPEG-PDLLA micelles are promising nanocarrier systems for anticancer drugs delivery.

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Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 transporters and their potential to overcome multidrug resistance in vitro

Cihalova

Štaud

Čečková

2015

Cancer Chemother Pharmacol

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Disposition of orally administered a promising chemotherapeutic agent flavopiridol in the intestine

Abstract: FLAP possesses high oral bioavailability and good absorption in the intestine, in which FLAP may be subjected to a P-gp efflux. Biliary excretion is the main elimination pathway for FLAP glucuronide and its enterohepatic cycling could be indicated.

Cited by 6 publications

References 29 publications

Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors

Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors

Sodium cholate-enhanced polymeric micelle system for tumor-targeting delivery of paclitaxel

Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 transporters and their potential to overcome multidrug resistance in vitro

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