title: O-Phosphonatomethylcholine, its analogues, alkyl esters, and their biological activity.
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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, CZ-16610 Praha 6, Czech Republic. holy@uochb.cas.cz
authors.forename: A
authors.initials: A
authors.lastname: Holý
authors.forename: B
authors.initials: B
authors.lastname: Otová
authors.forename: M
authors.initials: M
authors.lastname: Budesínský
authors.forename: D
authors.initials: D
authors.lastname: Emerson
authors.forename: M E
authors.initials: ME
authors.lastname: Wiles
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002794:Choline / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D063065:Organophosphonates; C442809:hexadecyl O-phosphonomethylcholine; D010767:Phosphorylcholine; D002794:Choline