title: A new ligustrazine derivative--pharmacokinetic evaluation and antitumor activity by suppression of NF-kappaB/p65 and COX-2 expression in S180 mice.
abstract: A new anticancer ligustrazine derivative, 3beta-hydroxyolea-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (T-OA, C38H58O3N2), was previously reported. It was synthesized via conjugating the effective antitumor ingredients of a classic traditional Chinese medicine (TCM) formulation. In the present study, anticancer efficacy of T-OA was evaluated in vivo using a murine sarcoma S180 model. Reduction of the tumor weight and tumor HE staining regions demonstrated that T-OA had promising inhibition effects and a 50% inhibitory rate in S180 mice. Combining the immunohistochemistry, we found T-OA exerted its antitumor activity by preventing the expression of nuclear transcription factor NF-kappaB/p65 and COX-2 in S180 mice. The acute toxic test showed that LD50 value of T-OA exceeded 6.0 g/kg via gavage in mice. In addition, a simple and rapid HPLC-UV method was developed and validated to study the pharmacokinetic characteristics of the compound. After single-dose oral administration, time to reach peak concentration of T-OA (3.97 microg/mL) was 8.33 h; the elimination half-life and area under the concentration-time curve from t = 0 to the last time of T-OA was 4.50 h and 48.01 microg x h/mL, respectively.
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Penglong
authors.initials: P
authors.lastname: Wang
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kuo
authors.initials: K
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Honggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Dandan
authors.initials: D
authors.lastname: Pang
authors.forename: Yatao
authors.initials: Y
authors.lastname: Cheng
authors.forename: Haimin
authors.initials: H
authors.lastname: Lei
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors; D003627:Data Interpretation, Statistical; D004355:Drug Stability; D005260:Female; D007150:Immunohistochemistry; D057230:Limit of Detection; D008297:Male; D051379:Mice; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012510:Sarcoma 180 / Q000188:drug therapy / Q000473:pathology; D013056:Spectrophotometry, Ultraviolet; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors*
chemical_list: C584608:3beta-hydroxyolea-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester; D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D011719:Pyrazines; D051996:Transcription Factor RelA; D051546:Cyclooxygenase 2; C017953:tetramethylpyrazine