Abstract |
O-Phosphonatomethylcholine, an isopolar phosphocholine analogue with a phosphonomethyl ether group replacing a phosphomonoester residue, was prepared by reaction of diisopropyl 2-chloroethoxymethylphosphonate with dimethylamine followed by quaternization of the thus-obtained diisopropyl 2-dimethylaminoethoxymethylphosphonate with iodomethane; the ester groups in the quaternary intermediate were cleaved with bromotrimethylsilane. Replacement of dimethylamine in the reaction sequence by morpholine and/or pyrrolidine gave the N-methylmorpholinium or N-methylpyrrolidinium analogues of O-phosphonatomethylcholine. Reaction of O-phosphonomethylcholine monotetrabutylammonium salt with 1-bromoalkanes in acetonitrile afforded a series of the corresponding monoalkyl (C10-C16) esters. None of these compounds except for the hexadecyl ester exhibited any appreciable cytostatic activity against DU-145, H460, HT-29, or MES-SA cell lines in vitro (evaluated by 3H-Thd incorporation assay). The hexadecyl ester exhibited modest in vitro cytotoxic activity comparable to that of the anticancer drug miltefosine (hexadecyl O- phosphocholine). In vivo evaluation of hexadecyl O-phosphonomethylcholine [transplanted SD lymphoma in inbred SD/cub rats, 10 mg kg(-1) day(-1) intratumoral injection for 10 days] resulted in a 40% decrease in lymphoma mass.
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Authors | A Holý, B Otová, M Budesínský, D Emerson, M E Wiles |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 44
Issue 25
Pg. 4462-7
(Dec 06 2001)
ISSN: 0022-2623 [Print] United States |
PMID | 11728191
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Organophosphonates
- hexadecyl O-phosphonomethylcholine
- Phosphorylcholine
- Choline
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Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Choline
(analogs & derivatives, chemical synthesis, chemistry, pharmacology)
- Drug Screening Assays, Antitumor
- Humans
- Male
- Organophosphonates
(chemical synthesis, chemistry, pharmacology)
- Phosphorylcholine
(analogs & derivatives, chemical synthesis, chemistry, pharmacology)
- Rats
- Structure-Activity Relationship
- Transplantation, Heterologous
- Tumor Cells, Cultured
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