Synthesis and antiproliferative properties of a photoactivatable analogue of ET-18-OCH3

Abstract

A photoreactive analogue of the antitumor ether lipid 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (ET-18-OCH3, 1) was synthesized for the first time. The 3-(trifluoromethyl)-3-(m-iodophenyl)diazirine (TID) moiety was used as the photolabel in ether lipid 2a. The TID group was tethered through an O-undecyloxy linkage to the sn-1 position of the ether lipid. Compound 2a was found to qualitatively mimic the antiproliferative effects of 1 in the dark (i.e. in the absence of carbene generation), suggesting that this photoactivatable probe may be suitable for identification of the proteins that mediate the biological activities of 1. Analogue 2a was converted by Stille reaction to stannane intermediate 2b, which was subjected to ipso [125I]-iododestannylation to afford 125I-labeled ether lipid 2c. Photolysis (long wavelength UV light, 30min) of 2c in the presence of cytosolic proteins obtained from a breast cancer cell line (MCF-7), followed by NaDodSO4/PAGE and autoradiography, showed radioiodination of primarily two polypeptides (with molecular masses of about 47- and 170-kDa), both of which were subject to competition by prior addition of excess 2a. This study indicates that analogue 2c may have utility in the characterization of the putative proteins that interact specifically with antitumor ether lipid 1.