Sulfonyl-Containing Aldophosphamide Analogues as Novel Anticancer Prodrugs Targeted against Cyclophosphamide-Resistant Tumor Cell Lines
摘要:
A series of sulfonyl-group containing analogues of aldophosphamide (Aldo) were synthesized as potential anticancer prodrugs that liberate the cytotoxic phosphoramide mustards (PM, IPM, and tetrakis-PM) via beta-elimination, a nonenzymatic activation mechanism. Kinetic studies demonstrated that all these compounds spontaneously liberate phosphoramide mustards with half-lives in the range of 0.08-15.2 h under model physiological conditions in 0.08 M phosphate buffer at pH 7.4 and 37 degreesC. Analogous to Aldo, the rates of beta-elimination in all compounds was enhanced in reconstituted human plasma under same conditions. The compounds were more potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung fibroblasts in vitro (IC50 = 1.8-69.1 muM). Several compounds showed excellent in vivo antitumor activity in CD2F1 mice against both P388/0 (Wild) and P388/CPA (CP-resistant) tumor cell lines.
SN2 Displacement on 2-(alkylthio)ethyl derivatives
作者:M. R. Sedaghat-Herati、Samuel P. McManus、J. Milton Harris
DOI:10.1021/jo00246a025
日期:1988.5
SEDAGHAT-HERATI, M. R.;MCMANUS, SAMUEL P.;HARRIS, J. MILTON, J. ORG. CHEM., 53,(1988) N 11, C. 2539-2543
作者:SEDAGHAT-HERATI, M. R.、MCMANUS, SAMUEL P.、HARRIS, J. MILTON
DOI:——
日期:——
Sulfonyl-Containing Aldophosphamide Analogues as Novel Anticancer Prodrugs Targeted against Cyclophosphamide-Resistant Tumor Cell Lines
作者:Monish Jain、Junying Fan、Nesrine Z. Baturay、Chul-Hoon Kwon
DOI:10.1021/jm0304764
日期:2004.7.1
A series of sulfonyl-group containing analogues of aldophosphamide (Aldo) were synthesized as potential anticancer prodrugs that liberate the cytotoxic phosphoramide mustards (PM, IPM, and tetrakis-PM) via beta-elimination, a nonenzymatic activation mechanism. Kinetic studies demonstrated that all these compounds spontaneously liberate phosphoramide mustards with half-lives in the range of 0.08-15.2 h under model physiological conditions in 0.08 M phosphate buffer at pH 7.4 and 37 degreesC. Analogous to Aldo, the rates of beta-elimination in all compounds was enhanced in reconstituted human plasma under same conditions. The compounds were more potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung fibroblasts in vitro (IC50 = 1.8-69.1 muM). Several compounds showed excellent in vivo antitumor activity in CD2F1 mice against both P388/0 (Wild) and P388/CPA (CP-resistant) tumor cell lines.
Hydrolysis of mustard derivatives. remarkable tosylate/chloride and chloride/dinitrophenolate rate ratios
Comparisons of leavinggroupsolvolyticrate ratios for mustard derivatives with other substrate types reveals unusual OTs/Cl and Cl/ODNP rate ratios for mustards. A very tight transition state is suggested.