AIM: Cytarabine is an efficient anticancer agent for acute myelogenous leukemia, but with short plasma half-life and rapid deamination to its inactive metabolite. The aim of this study was to design and synthesize novel cholic acid-cytarabine conjugates to improve its pharmacokinetic parameters. METHODS: The in vitro stability of novel cholic acid-cytarabine conjugates was investigated in simulated gastric and intestinal fluid, mouse blood and liver homogenate using HPLC. The portacaval samples of the conjugates were examined in male Sprague-Dawley rats using LC/MS, and in vivo distribution was examined in male Kunming mice using LC/MS. Antitumor activities were tested in HL60 cells using MTT assay. RESULTS: Cholic acid-cytarabine compounds with four different linkers were designed and synthesized. All the four cholic acid-cytarabine conjugates could release cytarabine when incubated with the simulated gastric and intestinal fluid, mouse blood and liver homogenate. The conjugates 6, 12, and 16 were present in the portacaval samples, whereas the conjugate 7 was not detected. The conjugates 6 and 16 showed high specificity in targeting the liver (liver target index 34.9 and 16.3, respectively) and good absorption in vivo, as compared with cytarabine. In cytarabine-sensitive HL60 cells, the conjugates 6, 12, and 16 retained potent antitumor activities. CONCLUSION: Three novel cholic acid-cytarabine conjugates with good liver-targeting properties and absorption were obtained. Further optimization of the conjugates is needed in the future.
AIM: Cytarabine is an efficient anticancer agent for acute myelogenous leukemia, but with short plasma half-life and rapid deamination to its inactive metabolite. The aim of this study was to design and synthesize novel cholic acid-cytarabine conjugates to improve its pharmacokinetic parameters. METHODS: The in vitro stability of novel cholic acid-cytarabine conjugates was investigated in simulated gastric and intestinal fluid, mouse blood and liver homogenate using HPLC. The portacaval samples of the conjugates were examined in male Sprague-Dawley rats using LC/MS, and in vivo distribution was examined in male Kunming mice using LC/MS. Antitumor activities were tested in HL60 cells using MTT assay. RESULTS:Cholic acid-cytarabine compounds with four different linkers were designed and synthesized. All the four cholic acid-cytarabine conjugates could release cytarabine when incubated with the simulated gastric and intestinal fluid, mouse blood and liver homogenate. The conjugates 6, 12, and 16 were present in the portacaval samples, whereas the conjugate 7 was not detected. The conjugates 6 and 16 showed high specificity in targeting the liver (liver target index 34.9 and 16.3, respectively) and good absorption in vivo, as compared with cytarabine. In cytarabine-sensitive HL60 cells, the conjugates 6, 12, and 16 retained potent antitumor activities. CONCLUSION: Three novel cholic acid-cytarabine conjugates with good liver-targeting properties and absorption were obtained. Further optimization of the conjugates is needed in the future.
Authors: Ondrej Jurcek; Zdenek Wimmer; Hana Svobodová; Blanka Bennettová; Erkki Kolehmainen; Pavel Drasar Journal: Steroids Date: 2009-04-24 Impact factor: 2.668
Authors: G Rosti; F Bonifazi; E Trabacchi; A De Vivo; S Bassi; G Martinelli; N Testoni; D Russo; M Baccarani Journal: Leukemia Date: 2003-03 Impact factor: 11.528
Authors: Thomas W von Geldern; Noah Tu; Philip R Kym; James T Link; Hwan-Soo Jae; Chunqiu Lai; Theresa Apelqvist; Patrik Rhonnstad; Lars Hagberg; Konrad Koehler; Marlena Grynfarb; Annika Goos-Nilsson; Johnny Sandberg; Marie Osterlund; Tomas Barkhem; Marie Höglund; Jiahong Wang; Steven Fung; Denise Wilcox; Phong Nguyen; Clarissa Jakob; Charles Hutchins; Mathias Färnegårdh; Björn Kauppi; Lars Ohman; Peer B Jacobson Journal: J Med Chem Date: 2004-08-12 Impact factor: 7.446