D-21266, a new heterocyclic alkylphospholipid with antitumour activity.

The aim of this study was to determine the antitumour effects of D-21266 in a rodent tumour model. Hexadecylphosphocholine (INN: Miltefosine) represents the first anticancer agent which was specifically formulated for topical use in cancer patients. The development as an oral drug was hampered by the gastrointestinal toxicity. Hexadecylphosphocholine derivatives were sought with a better therapeutic index. Octadecyl-(1,1-dimethyl-4-piperidylio) phosphate (D-21266) was identified as a suitable candidate. This compound is highly active in vitro inhibiting the growth of a number of human cancer cell lines. Mammary carcinomas were induced in Sprague-Dawley rats using DMBA, and oral doses of D-21266, in various schedules, were given to the animals. A high antineoplastic potency was observed without inducing loss of body weight at highly effective doses. The antitumour effect could be enhanced by introducing a dose schedule consisting of a high loading dose followed by a low maintenance dose, both of which are only marginally active when given alone. Therefore, D-21266 with its favourable pharmacological and toxicological profile, warrants evaluation in the clinic. However, the concept of clinical trials requires new approaches to dose finding and response evaluation, because the dose-response relationship of this compound is distinctly different from that of classical cytostatic agents.

Alkylphosphate esters as inhibitors of phospholipase D.

Alkylphosphate esters were shown to be potent inhibitors of phospholipase D. Using phosphatidyl choline/sodium dodecylsulfate (2:1) as substrate, IC50 values were determined for alkylphosphocholines of different chain length (C10-C18) and for various octadecylphosphate esters with different polar head groups. The inhibitory potency strongly increased with increasing chain length of the alkyl chain. The substitution of choline for heterocyclic nitrogen compounds or for 2-trimethylarsonio-ethanol also affected the inhibition of phospholipase D. Octadecylphosphocholine proved to be the most efficient inhibitor (IC50 = 6.4 microM).

Early stage monitoring of miltefosine induced apoptosis in KB cells by multinuclear NMR spectroscopy.

Synthetic ether lipids, like miltefosine (hexadecylphosphocholine), an alkylphosphocholine, are antineoplastic agents in vitro and in vivo. Their mode of action is mediated via the cell membrane, but the mechanism is still unclear. Miltefosine induces apoptosis in human epithelial KB cells, but slows down only proliferation in rat C6 glioma cells. NMR spectroscopy on lipid extracts reveals increased diacylglycerol and triacyglycerol biosynthesis in KB cells prior to DNA fragmentation indicating a CTP:phosphocholine-cytidylyl-transferase (CT) inhibition by the drug. Although C6 cells were morphologically affected by alterations in phospholipid composition and metabolism by a long term treatment (23 days) with the drug, no persistent diacylglycerol increase is observed.

Antineoplastic activity and tolerability of a novel heterocyclic alkylphospholipid, D-20133.

Octadecyl-[2-(N-methylpiperidinio)ethyl]-phosphate (OMPEP, D-20133), a heterocyclic analogue of hexadecylphosphocholine (MIL), has been synthesized in an attempt to increase the therapeutic range of the parent compound. The antineoplastic activity of the novel alkylphospholipid was compared with that of MIL in dimethylbenz(a)anthracene-induced mammary carcinoma of the rat. Using tumors of different sizes and repeated daily doses as well as high single doses, we achieved marked remissions with either compound. However, the therapeutic range of OMPEP was broader than that of the parent drug. Furthermore, the emetic potential of OMPEP tested on ferrets was distinctly less pronounced than that of MIL. In vitro the new alkylphospholipid proved to be more active than MIL in all cell lines tested, and its differentiation-inducing capacity turned out to be superior to that of MIL. No hematological toxicity was observed at various OMPEP doses during a 3-week treatment period.

Morphiceptin analogs containing 2-aminocyclopentane carboxylic acid as a peptidomimetic for proline.

As part of a program to study the structure-activity relationship of peptide opioids we report the synthesis, conformational characterization and biological activity of four analogs related to morphiceptin in which the proline at position two has been substituted with 2-aminocyclopentane carboxylic acid (beta Ae5c). The beta Ac5c residue is a beta amino acid with two chiral centers resulting in four possible configurations; two configurational cis (R,S and S,R) and two configurational trans (R,R and S,S) forms. Utilizing high resolution n.m.r. at 500 MHz and computer simulations with NOE restraints the chirality of the beta Ac5c residues are assigned. The analog containing the R,S-beta Ac5c is active at both the mu and delta-opioid receptors, with a slight preference for the mu-receptor. The (S,R), (S,S), and (R,R) analogs show minimal activity at the mu-receptor and are inactive at the delta-receptor. A comparison of the findings from the conformational analysis and biological assays lends insight into the structure-activity relationship of this important peptide opiate.