Synthesis and antitumor properties of activated cyclophosphamide analogs

A series of 5- and 6-substituted cyclophosphamide analogues has been prepared, and their 31P NMR kinetics of phosphoramide mustard (PDA) release and in vitro and in vivo cytotoxicity have been evaluated. cis-4-Hydroxy-5-methoxycyclophosphamide equilibrated very slowly and to a minor extent with the...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-10, Vol.34 (10), p.3044-3052
Main Authors: Borch, Richard F, Canute, Gregory W
Format: Article
Language:English
Subjects:
Acetylcholinesterase - blood
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Cholinesterase Inhibitors
Cyclophosphamide - analogs & derivatives
Cyclophosphamide - chemistry
Cyclophosphamide - therapeutic use
General aspects
Kinetics
Leukemia L1210 - drug therapy
Leukemia P388 - drug therapy
Magnetic Resonance Spectroscopy
Medical sciences
Mice
Molecular Conformation
Molecular Structure
Pharmacology. Drug treatments
Phosphoramide Mustards - metabolism
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Summary:A series of 5- and 6-substituted cyclophosphamide analogues has been prepared, and their 31P NMR kinetics of phosphoramide mustard (PDA) release and in vitro and in vivo cytotoxicity have been evaluated. cis-4-Hydroxy-5-methoxycyclophosphamide equilibrated very slowly and to a minor extent with the ring-opened aldophosphamide analogues in aqueous buffer; release of PDA was observed to a minor extent and only at high (1 M) buffer concentrations. This analogue was essentially inactive in vitro against L1210 and P388 leukemia cells. 6-Phenylcyclophosphamide and its 4-hydroperoxy derivative were potent inhibitors of blood acetylcholinesterase and were lethal at therapeutic doses in mice. In contrast, 4-hydroperoxy-6-(4-pyridyl)cyclophosphamide did not inhibit acetylcholinesterase and showed significant antitumor activity in vitro and in vivo against both wild-type and cyclophosphamide-resistant L1210 leukemia. The 4-hydroperoxy-6-arylcyclophosphamides were generally active in vitro against both wild-type and cyclophosphamide-resistant L1210 and P388 cells, and several analogues showed significant activity in vivo. Surprisingly, there was no correlation between antitumor activity in vitro and the rate of PDA release in aqueous buffer. Several compounds that showed essentially no release of PDA in aqueous buffer over several hours were highly cytotoxic to leukemia cells following a 1-h exposure in vitro. These results show that activated cyclophosphamide analogues substituted at the 6-position are not cross-resistant in these leukemia cell lines, and that a specific intracellular activation mechanism may be catalyzing PDA release in these analogues.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00114a013