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|Title: ||Identification and Characterization of in-vitro Metabolites of Some Investigational Anti-Cancer Compounds (KM-1081 and KM-1082) Using Liquid Chromatography Ion Trap Mass Spectrometry|
|Authors: ||Attwa, Mohamed Wagih Zeidan|
Kadi, Adnan Ahmed
|Keywords: ||Pharmaceutical Analytical Chemistry|
Liquid Chromatography Ion Trap Mass Spectrometry
|تاريخ النشر: ||28-ماي-2011 |
|Abstract: ||The in-vitro metabolic profile of two investigational anti-cancer agents, 2-amino-5-(4-bromophenyl)-9-chloro-3-phenylpyrimido [4,5-c]quinolin-1(2H)-one (KM-1081), 2-amino-9-chloro-3,5-bis(4-chlorophenyl)pyrimido[4,5-c]quinolin-1 (2H)-one (KM-1082), using rat liver microsomes and hepatocytes is described. KM-1081 and KM-1082 are members of the Pyrimido [4,5-c] quinolin-1(2H)-ones, which is a new class of antimitotic agents. The two compounds exhibited a promising antitubular activity as part of a series of members of the same class newly synthesized and tested .
Rat liver microsomes (RLMs) and isolated rat hepatocytes were prepared in-house. KM-1081 and KM-1082 were incubated with rat liver microsomes and rat hepatocytes according to published methodologies. Purified incubation mixtures were analyzed by liquid chromatography-Ion trap mass spectrometry (LC-ITMS) to identify possible metabolic products. Mass spectrometric analysis of the incubated compounds revealed the presence of several peaks representing potential metabolites. These peaks
were proposed to be the results of N-deamination of KM-1081and KM-1082, as well as several other products. Screening of total ion current (TIC) chromatograms of RLMs incubations for KM-1081 show a peak eluting at ~ 54 minutes with a molecular ion peak at m/z 475 corresponding to KM-1081 and peak eluting at ~57 minutes with a molecular ion peak of m/z 460 is proposed to be of the N-deaminated KM-1081.
Additionally peaks with m/z of 460, 494.2 and 510.3 were found in the TIC chromatogram and were proposed to be enol form of the N-deaminated KM-1081, hydroxy reduced KM-1081 and dihydoxy reduced KM-1081, representing. The peaks appeared in a smaller concentration than the N-deaminated product. Screening of TIC chromatogram of rat liver microsomal incubations for KM-1082 showed a peak eluting at ~ 63 minutes with a molecular ion peak at m/z 465 corresponding to the KM-1082. A peak eluting at ~ 65 minutes with a molecular ion peak of 450 was, similar to KM-1081, proposed to be of the N-deaminated KM-1082. As with the case of KM-1081, peaks corresponding to enol form of N-deaminated KM-1082, Dihydroxylated KM-1082 and Trihydoxylated KM-1082 were found but with smaller concentration. Based on these results, the N-deaminated derivative of both compounds appears to be the major metabolic product of RLMs metabolism.
Screening of TIC chromatograms of rat hepatocytes incubations for both compounds showed the proposed N-deamination, albeit representing a higher proportion compared to that resulting from RLMs metabolism. These results suggest the extensive, though number-limited nature of the metabolism of KM-1081 and KM-1082.|
|يظهر في المجموعات:||College of Pharmacy|
جميع جميع الابحاث محمية بموجب حقوق الطباعة، جميع الحقوق محفوظة.