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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

Presumed metabolic pathways of GLB and structures of two metabolites (M1 and M2) after a single oral dose (100 mg/kg) in rat plasma.
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f4: Presumed metabolic pathways of GLB and structures of two metabolites (M1 and M2) after a single oral dose (100 mg/kg) in rat plasma.

Mentions: Furthermore, under the tandem mass spectrometry positive scan mode condition, the parent compound GLB was detected as protonated molecular ions at m/z 499 ([M+H]+) and sodium adduct (520, [M+Na]+), and fragment ion m/z 441, respectively (Fig. 3C). The metabolite M1 was detected as protonated molecular ions at m/z 529 ([M+H]+) and sodium adduct (m/z 553, [M+Na]+), and fragment ions m/z 457, 449, 435 and 401, respectively. These molecular ions were 32–34 Da (2O or 2OH) higher compared to the parent compound, may suggest modification of adding two hydroxyl groups into the molecule (Fig. 3D). Therefore, M1 was tentatively identified as the di-hydroxylated metabolite and its possible metabolic pathway might be the di-hydroxylating reaction in phase I metabolism. On the other hand, the metabolite M2 produced protonated molecular ions at m/z 515 ([M+H]+), m/z 537 ([M+Na]+), and fragment ions at m/z 457, 437 and 413, respectively. The molecular ions were 16–17 Da (O or OH) higher than the parent compound (Fig. 3E), suggesting modification might be added one hydroxyl group into the parent molecule. Therefore, M2 could be tentatively identified as a hydroxylated metabolite. These results indicated that fragmentation pathway of GLB, M1 and M2 to support the metabolic site location, suggesting that di-hydroxylation (M1) and hydroxylation (M2) metabolisms might be the major metabolic pathways in rats. Furthermore, the present results showed that both of M1 and M2 had fragment ions at m/z 457, which might be attributed to the hydroxylation of the fructose group fraction (Fig. 4).


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)

Presumed metabolic pathways of GLB and structures of two metabolites (M1 and M2) after a single oral dose (100 mg/kg) in rat plasma.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Presumed metabolic pathways of GLB and structures of two metabolites (M1 and M2) after a single oral dose (100 mg/kg) in rat plasma.
Mentions: Furthermore, under the tandem mass spectrometry positive scan mode condition, the parent compound GLB was detected as protonated molecular ions at m/z 499 ([M+H]+) and sodium adduct (520, [M+Na]+), and fragment ion m/z 441, respectively (Fig. 3C). The metabolite M1 was detected as protonated molecular ions at m/z 529 ([M+H]+) and sodium adduct (m/z 553, [M+Na]+), and fragment ions m/z 457, 449, 435 and 401, respectively. These molecular ions were 32–34 Da (2O or 2OH) higher compared to the parent compound, may suggest modification of adding two hydroxyl groups into the molecule (Fig. 3D). Therefore, M1 was tentatively identified as the di-hydroxylated metabolite and its possible metabolic pathway might be the di-hydroxylating reaction in phase I metabolism. On the other hand, the metabolite M2 produced protonated molecular ions at m/z 515 ([M+H]+), m/z 537 ([M+Na]+), and fragment ions at m/z 457, 437 and 413, respectively. The molecular ions were 16–17 Da (O or OH) higher than the parent compound (Fig. 3E), suggesting modification might be added one hydroxyl group into the parent molecule. Therefore, M2 could be tentatively identified as a hydroxylated metabolite. These results indicated that fragmentation pathway of GLB, M1 and M2 to support the metabolic site location, suggesting that di-hydroxylation (M1) and hydroxylation (M2) metabolisms might be the major metabolic pathways in rats. Furthermore, the present results showed that both of M1 and M2 had fragment ions at m/z 457, which might be attributed to the hydroxylation of the fructose group fraction (Fig. 4).

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