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[ CAS No. 484-29-7 ] {[proInfo.proName]}

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Chemical Structure| 484-29-7
Chemical Structure| 484-29-7
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Product Citations

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Bui, Dinh ; McWilliams, Lenora A ; Wu, Lei , et al. DOI: PubMed ID:

Abstract: This study reports the first clinical evidence of significantly high secretion of matrine in a multi-component botanical (Antitumor B, ATB) into human saliva from the systemic circulation. This is of high clinical significance as matrine can be used as a monitoring tool during longitudinal clinical studies to overcome the key limitation of poor patient compliance often reported in cancer chemoprevention trials. Both matrine and dictamine were detected in the saliva and plasma samples but only matrine was quantifiable after the oral administration of ATB tablets (2400 mg) in 8 healthy volunteers. A significantly high saliva/plasma ratios for Cmax (6.5 2.0) and AUC0–24 (4.8 2.0) of matrine suggested an active secretion in saliva probably due to entero-salivary recycling as evident from the long half-lives (t1/2 plasma = 10.0 2.8 h, t1/2 saliva = 13.4 6.9 h). The correlation between saliva and plasma levels of matrine was established using a population compartmental pharmacokinetic co-model. Moreover, a species-relevant PBPK model was developed to adequately describe the pharmacokinetic profiles of matrine in mouse, rat, and human. In conclusion, matrine saliva concentrations can be used as an excellent marker compound for mechanistic studies of active secretion of drugs from plasma to saliva as well as monitor the patient’s compliance to the treatment regimen in upcoming clinical trials of ATB.

Keywords: cancer chemoprevention ; OCT transporter ; PBPK modeling ; plasma-saliva correlation ; entero-salivary recycling ; pharmacokinetics ; saliva excretion marker ; patient compliance tracker

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Bui, Dinh ; Yin, Taijun ; Duan, Shengnan , et al. DOI: PubMed ID:

Abstract: This study aims to characterize the pharmacokinetic (PK) profiles and identify important bioavailability barriers and pharmacol. pathways of the key active components (KACs) of Antitumor B (ATB), a chemopreventive agent. KACs (matrine, dictamine, fraxinellone, and maackiain) of ATB were confirmed using the antiproliferative assay and COX-2 inhibition activities in oral cancer cells. The observed in vitro activities of KACs were consistent with their cell signaling pathways predicted using the in silico network pharmacol. approach. The pharmacokinetics of KACs were determined after i.v., i.p., and p.o. delivery using ATB extract and a mixture of four KACs in mice. Despite good solubilities and permeabilities, poor oral bioavailabilities were estimated for all KACs, mostly because of first-pass metabolism in the liver (for all KACs) and intestines (for matrine and fraxinellone). Multiple-dose PK studies showed 23.2-fold and 8.5-fold accumulation of dictamine and maackiain in the blood, resp. Moreover, saliva levels of dictamine and matrine were found significantly higher than their blood levels. In conclusion, the systemic bioavailabilities of ATB-KACs were low, but significant levels of dictamine and matrine were found in saliva upon repeated oral administration. Significant salivary concentrations of matrine justified its possible use as a drug-monitoring tool to track patient compliance during chemoprevention trials.

Keywords: Antitumor B ; Zeng-sheng-ping ; pharmacokinetics ; oral squamous cell cancer ; matrine, maackiain ; dictamine ; fraxinellone ; entero-saliva recycling

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Bui, Dinh T ;

Abstract: Purpose and Specific Aims: Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants and approved for use in China for dysplasia treatment. Many studies in rodents and humans have been published demonstrating the chemopreventive activity of ATB against the upper aerodigestive tract tumors as well as other types of cancer (e.g. lung, esophageal and oral carcinoma). The overall objectives of this project are to confirm the key active compounds(KACs) of ATB against oral cancer and their plausible mechanisms of action via a network pharmacology approach, characterize fully KAC’pharmacokinetic behaviors in vitro and in vivo and build appropriate PK models to describe the PK behaviors and enhance their distribution to the oral tissues via the use of an oral adhesive patch. Methods: The KAC of ATB were confirmed using antiproliferation and antiinflammation assays using human oral cancer cell lines SCC-9 and Cal-27. Pharmacokinetic studies of ATB were conducted in healthy mice, rats, and adult humans to determine the pharmacokinetics and bioavailability of KACs. Phoenix NLMETM and GastroPlus® software were used to build the PK models to describe the correlation between drug concentration in human plasma & saliva and to do interspecies scaling of the drug concentration in animals and humans. The buccal delivery formulation was made by solvent casting method for local delivery of ATB to the targeted oral tissue. Results: Matrine, dictamine, maackiain, and fraxinellone were confirmed as the key active compounds(KACs) based on the antiproliferation assay and PGE2 assays. A LC-MS/MS method was adapted and then validated to analyze these compounds in several biological matrixes simultaneously. Matrine and dictamine were detected in both the rodent and human plasma and saliva, suggesting their distribution to the targeted site of action. The oral bioavailability values in mice of KACs were 3.2 ± 1.8%, 4.6 ± 2.8%, 3.9 ± 1.9%, and 0.2 ± 0.1% for matrine, dictamine, maackian, and fraxinellone, respectively. Significant higher concentration of Matr in the saliva human and mouse samples suggested an active secrection of this compound to human and mouse saliva. Compartmental co-modeling strategy and PBPK models were successfully constructed to correlate the matrine concentration in plasma and saliva and to enable interspecies scaling, respectively. The buccal adhesive patch formulation efficiently delivered certain KACs to the oral tissues. Conclusion and Significance: This study contributes to the pharmacokinetics of antitumor B in rodents and healthy adults. We report the first clinical evidence of significantly high secretion of certain active compounds(matrine) in a multi-component botanical (Antitumor B, ATB) into human saliva from the systemic circulation. Saliva matrine can be used as a compliance monitoring tool during upcoming clinical trials of ATB. The pharmacokinetic models were successfully constructed to correlate the matrine concentration in plasma and saliva and to enable interspecies scaling. Matrine may be used to check a patient’s compliance with ATB dosing. The buccal adhesive patch was developed, tested, and is a promising lead for localized and targeted delivery of ATB and/or its KACs.

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Product Details of [ 484-29-7 ]

CAS No. :484-29-7 MDL No. :MFCD00221742
Formula : C12H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :WIONIXOBNMDJFJ-UHFFFAOYSA-N
M.W : 199.21 Pubchem ID :68085
Synonyms :
Dectamine;Dictamine
Chemical Name :4-Methoxyfuro[2,3-b]quinoline

Calculated chemistry of [ 484-29-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 13
Fraction Csp3 : 0.08
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 58.01
TPSA : 35.26 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.46 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.38
Log Po/w (XLOGP3) : 2.9
Log Po/w (WLOGP) : 2.99
Log Po/w (MLOGP) : 1.96
Log Po/w (SILICOS-IT) : 2.89
Consensus Log Po/w : 2.63

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.48
Solubility : 0.0664 mg/ml ; 0.000333 mol/l
Class : Soluble
Log S (Ali) : -3.3
Solubility : 0.0996 mg/ml ; 0.0005 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.72
Solubility : 0.00378 mg/ml ; 0.000019 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.48

Safety of [ 484-29-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 484-29-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 484-29-7 ]

[ 484-29-7 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 186581-53-3 ]
  • [ 530-52-9 ]
  • [ 484-74-2 ]
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  • 2
  • [ 111163-82-7 ]
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  • 4
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  • [ 75-03-6 ]
  • [ 136296-29-2 ]
  • 5
  • [ 484-29-7 ]
  • [ 93-97-0 ]
  • 9-benzoyl-9<i>H</i>-furo[2,3-<i>b</i>]quinolin-4-one [ No CAS ]
  • 7
  • [ 484-29-7 ]
  • [ 530-52-9 ]
YieldReaction ConditionsOperation in experiment
91% With hydrogen bromide; In water; acetic acid; for 8.0h;Heating / reflux; A mixture of <strong>[484-29-7]4-methoxyfuro[2,3-b]quinoline</strong> (compound 1; 0.20 g, 1 mmol), 48% HBr (10 ml), and AcOH (20 ml) was refluxed for 8 h. After cooling, the mixture was poured into an ice-cold sat. NaHCO3 solution (60 ml), and extracted with AcOEt (3×60 ml). The AcOEt extracts were combined, washed with H2O, dried on MgSO4, and evaporated to yield a residual solid, which was purified by flash column chromatography (FC; silica gel; AcOEt). The proper fractions were combined and evaporated to obtain compound 2 (0.17 g, 91%). Detected Properties of the Title Compound: M.p. 236-237 C. 1H-NMR (200 MHz, DMSO): 7.06 (d,J=2.4, H-C(3)) 7.29 (m,H-C(6)); 7.56-7.68 (m,H-C(2), H-C(7), H-C(8)); 8.28 (d,J)=7.6, H-C(5)). 13C-NMR (50 MHz, DMSO): 104.85; 105.84; 121.60; 122.12; 123.08; 124.60; 130.06; 140.04; 142.53; 160.70; 166.69.
  • 11
  • [ 112071-08-6 ]
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  • 12
  • [ 67-56-1 ]
  • [ 95874-16-1 ]
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  • 14
  • [ 111736-15-3 ]
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  • 15
  • [ 74121-01-0 ]
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  • 18
  • [ 51179-18-1 ]
  • [ 2181-42-2 ]
  • [ 484-29-7 ]
  • [ 827303-64-0 ]
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