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Quantitative and qualitative analysis of the novel antitumor 1,3,4-oxadiazole derivative (GLB) and its metabolites using HPLC-UV and UPLC-QTOF-MS.

Li P, Wang X, Li J, Meng ZY, Li SC, Li ZJ, Lu YY, Ren H, Lou YQ, Lu C, Dou GF, Zhang GL - Sci Rep (2015)

Bottom Line: Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative.The lower limit of quantification was 10 ng/mL.Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, PR. China.

ABSTRACT
Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative. This research first reported a simple, specific, sensitive and stable high performance liquid chromatography-ultraviolet detector (HPLC-UV) method for the quantitative determination of GLB in plasma. In this method, the chromatographic separation was achieved with a reversed phase C18 column. The calibration curve for GLB was linear at 300 nm. The lower limit of quantification was 10 ng/mL. The precision, accuracy and stability of the method were validated adequately. This method was successfully applied to the pharmacokinetic study in rats for detection of GLB after oral administration. Moreover, the structures of parent compound GLB and its two major metabolites M1 and M2 were identified in plasma using an ultra performance liquid chromatography-electrospray ionization-quadrupole-time of flight- mass spectrometry (UPLC-ESI-QTOF-MS) method. Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites. In conclusion, the present study provided valuable information on an analytical method for the determination of GLB and its metabolites in rats, can be used to support further developing of this antitumor agent.

No MeSH data available.


Related in: MedlinePlus

Chemical structures and representative HPLC-UV chromatograms of(A) fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB); (B) megestrol acetate (internal standard, IS); (C) rat blank plasma; (D) rat blank plasma spiked with fructose-based 3-acetyl-2,3-dihydro- 1,3,4-oxadiazole (GLB, 1 μg/mL) and internal standard (IS, 1 μg/mL) and (E) a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg, n = 6).
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f1: Chemical structures and representative HPLC-UV chromatograms of(A) fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB); (B) megestrol acetate (internal standard, IS); (C) rat blank plasma; (D) rat blank plasma spiked with fructose-based 3-acetyl-2,3-dihydro- 1,3,4-oxadiazole (GLB, 1 μg/mL) and internal standard (IS, 1 μg/mL) and (E) a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg, n = 6).

Mentions: Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative1 (Fig. 1A). The introduce of fructose group into the pharmacophore of 1,3,4-oxadiazole molecule enhanced the hydrophobicity, and therefore makes GLB easier across various cellular membranes2. Compared to the 1st generation compound, 1,3,4-oxadiazole34567891011121314, GLB exhibited more potent antitumor activity and higher orally bioavailable in animals. As a thymidine phosphorylase inhibitor1516171819, GLB is shown to reduce the production and secretion of vascular endothelial growth factor (VEGF), suppress the formation of new blood vessels and especially block the tumor angiogenesis, growth and metastasis in vivo20. Moreover, it has been reported that GLB inhibited matrix metalloproteinases, induced cell cycle arrest, promoted apoptosis and inhibited proliferation in multiple human carcinoma cell lines including uterine cervix cancer cells, pulmonary adenocarcinoma cells, and prostate cancer cells (PC-3M)21. Thus further research is needed for GLB as a potential antitumor candidate.


Quantitative and qualitative analysis of the novel antitumor 1,3,4-oxadiazole derivative (GLB) and its metabolites using HPLC-UV and UPLC-QTOF-MS.

Li P, Wang X, Li J, Meng ZY, Li SC, Li ZJ, Lu YY, Ren H, Lou YQ, Lu C, Dou GF, Zhang GL - Sci Rep (2015)

Chemical structures and representative HPLC-UV chromatograms of(A) fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB); (B) megestrol acetate (internal standard, IS); (C) rat blank plasma; (D) rat blank plasma spiked with fructose-based 3-acetyl-2,3-dihydro- 1,3,4-oxadiazole (GLB, 1 μg/mL) and internal standard (IS, 1 μg/mL) and (E) a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg, n = 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493701&req=5

f1: Chemical structures and representative HPLC-UV chromatograms of(A) fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB); (B) megestrol acetate (internal standard, IS); (C) rat blank plasma; (D) rat blank plasma spiked with fructose-based 3-acetyl-2,3-dihydro- 1,3,4-oxadiazole (GLB, 1 μg/mL) and internal standard (IS, 1 μg/mL) and (E) a rat plasma sample at 6 h after a single oral administration of GLB (100 mg/kg, n = 6).
Mentions: Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative1 (Fig. 1A). The introduce of fructose group into the pharmacophore of 1,3,4-oxadiazole molecule enhanced the hydrophobicity, and therefore makes GLB easier across various cellular membranes2. Compared to the 1st generation compound, 1,3,4-oxadiazole34567891011121314, GLB exhibited more potent antitumor activity and higher orally bioavailable in animals. As a thymidine phosphorylase inhibitor1516171819, GLB is shown to reduce the production and secretion of vascular endothelial growth factor (VEGF), suppress the formation of new blood vessels and especially block the tumor angiogenesis, growth and metastasis in vivo20. Moreover, it has been reported that GLB inhibited matrix metalloproteinases, induced cell cycle arrest, promoted apoptosis and inhibited proliferation in multiple human carcinoma cell lines including uterine cervix cancer cells, pulmonary adenocarcinoma cells, and prostate cancer cells (PC-3M)21. Thus further research is needed for GLB as a potential antitumor candidate.

Bottom Line: Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative.The lower limit of quantification was 10 ng/mL.Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, PR. China.

ABSTRACT
Fructose-based 3-acetyl-2,3-dihydro-1,3,4-oxadiazole (GLB) is a novel antitumor agent and belongs to glycosylated spiro-heterocyclic oxadiazole scaffold derivative. This research first reported a simple, specific, sensitive and stable high performance liquid chromatography-ultraviolet detector (HPLC-UV) method for the quantitative determination of GLB in plasma. In this method, the chromatographic separation was achieved with a reversed phase C18 column. The calibration curve for GLB was linear at 300 nm. The lower limit of quantification was 10 ng/mL. The precision, accuracy and stability of the method were validated adequately. This method was successfully applied to the pharmacokinetic study in rats for detection of GLB after oral administration. Moreover, the structures of parent compound GLB and its two major metabolites M1 and M2 were identified in plasma using an ultra performance liquid chromatography-electrospray ionization-quadrupole-time of flight- mass spectrometry (UPLC-ESI-QTOF-MS) method. Our results indicated that the di-hydroxylation (M1) and hydroxylation (M2) of GLB are the major metabolites. In conclusion, the present study provided valuable information on an analytical method for the determination of GLB and its metabolites in rats, can be used to support further developing of this antitumor agent.

No MeSH data available.


Related in: MedlinePlus