Enantioselective synthesis and antiproliferative properties of an ilmofosine analog, 2'-(trimethylammonio)ethyl 3-(hexadecyloxy)-2-(methoxymethyl)propyl phosphate, on epithelial cancer cell growth.
An asymmetric synthesis of the 1-alkyloxy analog of the thioether phosphocholine ilmofosine (BM 41.440, rac-1), 2'-(trimethylammonio)ethyl 3-(hexadecyloxy)-2-(methoxymethyl)propyl phosphate (2), is described. Stereoselectivity was obtained in an asymmetric hydroboration-oxidation sequence carried out on a 2,2-disubstituted 1-alkene, 3-(hexadecyloxy)-2-(methoxymethyl)-1-propene (9), which was prepared by starting with either ethyl acrylate or ethyl alpha-(hydroxymethyl)acrylate (3). (R)- and (S)-2 and rac-1 were highly effective in inhibiting the proliferation of the breast adenocarcinoma cell line MCF-7 (IC50, 2 microM), moderately effective against A549 (non-small-cell lung adenocarcinoma) (IC50, 8-10 icroM), and less effective against A427 (large cell lung carcinoma) (IC50, approximately 20 microM). The in vitro cytotoxicity against the three epithelial cancer cell lines was independent of the configuration about C-2 of the glycerol backbone of 2 and was also not altered by substitution of oxygen for sulfur in the sn-1 ether linkage of ilmofosine.
Bittman
R
R
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing 11367-1597, USA. bittman@qcvaxa.acc.qc.edu
Byun
H S
HS
Reddy
K C
KC
Samadder
P
P
Arthur
G
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010742:Phospholipid Ethers / Q000494:pharmacology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
C105935:2'-(trimethylammonio)ethyl 3-(hexadecyloxy)-2-(methoxymethyl)propyl phosphate; D000970:Antineoplastic Agents; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; C043297:ilmofosine