Journal of Medicinal Chemistry p. 1491 - 1496 (1989)
Update date:2022-08-05
Topics:
Kwon
Borch
The activation mechanisms of the N-substituted 4-hydroxycyclophosphamide analogues 4-hydroxyifosfamide (2b), 4-hydroxytrofosfamide (2c), and 3-methyl-4-hydroxycyclophosphamide (2d) were compared with that of the unsubstituted parent compound 2a. The reaction kinetics of cis-2b, -2c, and -2d are qualitatively similar to those of 2a in that they undergo ring opening to the respective aldophosphamide intermediates 3, which can reclose to the cis- or trans-4-hydroxy isomers or undergo base-catalyzed β-elimination to generate the corresponding phosphoramide mustard products 4. In contrast to the general acid catalysis observed for ring opening of 2a and 2d, the N-(chloroethyl)-substituted analogues 2b and 2c undergo specific base-catalyzed ring opening. This mechanistic difference was also illustrated by the rapid action of 2a and 2d with sodium 2-mercaptoethanesulfonate (Mesna) under acidic conditions to give the 4-(alkylthio)-substituted cyclophosphamide derivatives 5a and 5d. Compounds 2b and 2c did not react with Mesna to generate 5b and 5c under these conditions. Both the fraction of aldehyde/hydrate present at equilibrium and the cytotoxicity against L1210 cells in vitro decreased in the order 2c > 2b > 2a > 2d. The plasma-catalyzed acceleration of phosphoramide mustard generation previously reported for 2a was also observed for these analogues.
View MoreFREEBARQUE DEVELOPMENT GROUP LIMITED
Contact:+86(0)10-5109 5335 or 5109 5345
Address:Room602,Block1-B,LINGDI OFFICE,NO.13 BEIYUAN ROAD
Contact:86-513-84128750/13773795976
Address:No.48.Youyi West Road ,Rudong Development Zone,Jiangsu Province,China
Hebei Think-Do Environment Co., Ltd
website:http://www.thinkdo-environment.com
Contact:0311-86510809
Address:No 6, Shilian Middle Street, Circular Chemical Industry Park
Jiangsu Allyrise Pharmaceutical Co., Ltd.
Contact:+86-523-86818997
Address:Taizhou,Jiangsu Province,CHINA
Neworld Chemical Co., Ltd Shanghai
Contact:+86-21-62202658
Address:11F, Blvd 2, No. 1969 PuXing Rd, Shanghai
Doi:10.1002/chem.200903369
(2010)Doi:10.1016/j.jorganchem.2010.08.032
(2010)Doi:10.1002/chem.201001133
(2010)Doi:10.1016/0223-5234(89)90029-9
(1989)Doi:10.1002/mrc.1260280516
(1990)Doi:10.1016/S0040-4039(00)97006-0
(1990)