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

A photoreactive analogue of the antitumor ether lipid 1-O-octadecyl-2-O-met hyl-glycero-3-phosphocholine (ET-18-OCH3, 1) was synthesized for the first time. The 3-(trifluoromethyl)-3-(m-iodophenyl)diazirine (TID) moiety was us ed 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 2 a was found to qualitatively mimic the antiproliferative effects of 1 in th e dark (i.e. in the absence of carbene generation), suggesting that this ph otoactivatable probe may be suitable for identification of the proteins tha t mediate the biological activities of 1. Analogue 2a was converted by Stil le reaction to stannane intermediate 2b, which was subjected to ipso [I-125 ] -iododestannylation to afford I-125-labeled ether lipid 2c. Photolysis (l ong wavelength UV light, 30 min) of 2c in the presence of cytosolic protein s obtained from a breast cancer cell line (MCF-7), followed by NaDodSO(4)/P AGE and autoradiography, showed radioiodination of primarily two polypeptid es (with molecular masses of about 47- and 170-kDa), both of which were sub ject to competition by prior addition of excess 2a. This study indicates th at analogue 2c may have utility in the characterization of the putative pro teins that interact specifically with antitumor ether lipid 1. (C) 2001 Els evier Science Ltd. All rights reserved.