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

Abstract

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.

Synthesis and Biological Applications of Phosphinates and Derivatives

“…In the late 1980s, Eibl and Unger identified miltefosine 180 as the minimal structure to observe an anti-tumour activity for synthetic analogues of phospholipids [130]. In the 1990s, Stekar et al synthesized perifosine 181, a second generation of phospholipid analogues with potent anti-tumour activity [131,132] (Fig. 22).…”

Novel Inhibitors of AKT: Assessment of a Different Approach Targeting the Pleckstrin Homology Domain

“…3A, compound 9 ). This new compound named D-21266 (aka perifosine) showed a significantly improved gastrointestinal tract tolerance [92] and inhibited cancer cell growth with IC 50 ranging from 0.2 μM to 19.9 μM as compared to its parent compound, miltefosine with IC 50 ranging from 2.3 μM to 18.7 μM. In vivo , oral doses of perifosine exhibited antitumor effects in a DMBA-induced mammary carcinoma model in Sprague-Dawley rats [91].…”

Phospholipases Used in Lipid Transformations

“…While in earlier reports PLD from cabbage was mostly used, more recently PLDs from Streptomyces strains have been preferred for synthetic purposes ( Table 3). These compounds possess antitumor properties and are therefore important drugs (Eibl et al, 1992;Stekar et al, 1993). In fact, PLDs from some Streptomyces strains seem to be predestined for transesterification of glycerophospholipids whereas PLDs from other strains, e.g., from Streptomyces chromofuscus fail in this function.…”