Design and synthesis of potent antileishmanial cycloalkylidene-substituted ether phospholipid derivatives.

Two series of novel ether phospholipids (EPs) have been synthesized. The first includes cyclodecylidene- or cyclopentadecylidene-substituted EPs carrying N,N,N-trimethylammonium or N-methylpiperidino or N-methylmorpholino head groups. The second series encompasses more rigid head groups in combination with cycloalkylidene moieties in the lipid portion. In addition, hydrogenated derivatives were obtained. All the new analogues, except 33, were 1.5- to 62-fold more potent than miltefosine against the intracellular L. infantum, and the most active ones were also less cytotoxic against the human monocytic cell line THP1 and less hemolytic than miltefosine. The analogues that combine high potency with low cytotoxicity and hemolytic activity were 19, 37, 21 23, 38, 39, and 40. Cyclopentadecylpentylphosphocholine (38) possesses an IC50 of 0.7 microM against L. infantum amastigotes and is the least cytotoxic analogue, since it does not present toxicity against THP1 macrophages, even at a concentration that is 800-fold the antiparasitic IC50 value, and does not present significant hemolytic activity.

Structure-activity relationships of antineoplastic ring-substituted ether phospholipid derivatives.

PURPOSE: Previous studies have shown that alkylphosphocholines (APCs) exhibit strong antineoplastic activity against various tumour cell lines in vitro and in several animal models. The current study was designed to investigate the influence of cycloalkane rings on the antiproliferative activity of APCs against a panel of eight human and animal cell lines (PC3, MCF7, A431, Hela, PC12, U937, K562, CHO). Specifically, we explored the effect of the presence of 4-alkylidenecyclohexyl and cycloalkylidene groups in alkoxyethyl and alkoxyphosphodiester ether lipids, respectively. In addition, the haemolytic activity of the new ring-substituted ether phospholipids (EP) was evaluated. METHODS: Cells were exposed to various concentrations of the compounds for 72 h. The cytotoxicity was determined with the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] dye reduction assay. Similarly, red blood cells were distributed in 96-well microplates and treated with the test compounds at concentrations ranging from 100 to 6.25 microM for 1 h. After centrifugation, the absorbance of the supernatants was measured at 550 nm. RESULTS: The majority of the compounds tested exhibited significant cytotoxic activity which depended on both the ring size and position with respect to the phosphate moiety, as well as the head group. Among the cycloalkylidene series the 11-adamantylideneundecyl-substituted N-methylmorpholino EP 13 was the most potent and exhibited broad-spectrum anticancer activity comparable to or superior to that of hexadecylphosphocholine (HePC). All the adamantylidene-substituted EPs were nonhaemolytic (concentration that exhibits 50% haemolytic activity, HC(50), >100 microM). Furthermore, the cyclohexylidene-substituted analogues were more potent against the cell lines tested, with the exception of U937 and K562, than the cyclodecapentylidene-substituted compounds. Hydrogenation of the double bond in the cycloalkylidene-substituted EPs (compounds 14 and 15) resulted in improvement of anticancer activity. Among the 2-(4-alkylidenecyclohexyloxy)ethyl EPs, 2-(4-hexadylidenecyclohexyloxy)ethyl phosphocholine (22) possessed the highest broad-spectrum cytotoxic activity than all the other analogues of this series and was nonhaemolytic (HC(50) >100 microM). In general, the 2-(4-alkylidenecyclohexyloxy)ethyl-substituted EPs were more active against the more resistant cell lines U937, K562 and CHO than HePC. CONCLUSIONS: The presence of cycloalkane rings in the lipid portion of APCs reduces haemolytic effects compared to HePC and in several analogues results in improved antineoplastic activity.