Development of lipids and
lipid analogues as potential drugs

The biological activities of lipids underscore their potential for development as novel therapeutics. To date, the alkyl phospholipids probably have been the most intensively studied lipid-based therapeutics, with miltefosine having value in the treatment of skin cancers and leishmaniasis and perifosine in certain lymphomas. However, the broad roles of many lipids in diverse cellular processes also could detract from their clinical value because of undesired side reactions. In contrast, certain lipid biotransformation products have narrower spectrums of activities that could produce better-targeted drugs.

The 20-carbon ω-6 polyunsaturated fatty acid arachidonic acid undergoes biotransformation mediated by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes to prostaglandins, leukotrienes, epoxides and more complex prostanoids. The analogous biotransformation of ω-3 PUFA, such as eicosapentaenoic acid and docosahexaenoic acid, generates structurally similar but functionally quite different eicosanoids. In cells, these endogenously produced ω-6 and ω-3 PUFA metabolites are extremely potent molecules whose properties could be adapted in novel therapeutics.

Structures of the ω-6 arachidonic acid-derived prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2) and the ω-3 eicosapentaenoic acid-derived prostaglandin E3 (PGE3). Arrows indicate sites at which biotransformation may occur.

Structures of the clinically useful prostaglandin analogues sulprostone and bimatoprost.

A significant problem to overcome in the development of prostanoid-based drugs is their low in vivo stability due to rapid secondary metabolism. Several clinically useful agents that have been developed are prostaglandins that have been modified structurally to stabilize chemical moieties that readily are degraded. Important deactivation pathways in prostanoids include oxidation at hydroxyl groups at the ω-end of the molecules or at carbon atoms — to the fatty acid carboxyl group.

Incorporation of bulky substituents adjacent to susceptible hydroxyl groups, replacement of the β-carbon with heteroatoms such as oxygen or sulfur, and inclusion of aromatic systems at the ω-end of the fatty-acid chain has produced stabilized prostaglandin analogues suitable for therapy.

For example, stabilization of the ω-end of PGE2 and replacement of the carboxylate with a substituted sulfonamide produced sulprostone (see figure) that has utility in postpartum hemorrhage after childbirth. The PGF2α analogue bimatoprost, which carries an N-ethylamide substituent in place of the carboxylate and a phenyl ring at the ω-end (see figure), is favored in primary glaucoma, because it effectively decreases intraocular pressure and has a low incidence of side effects. Recently, PGE3 (see figure) — the cyclooxygenase-derived metabolite of the ω-3 PUFA EPA — has been shown to possess anti-angiogenic properties that could be adapted to cancer chemotherapy.

P450-mediated epoxides also have considerable potential as novel therapeutics. ω-6 PUFA epoxides regulate vasoactivity, while the ω-3-17,18-epoxide of EPA, but not its regioisomers, kills tumor cells and DHA epoxides suppress angiogenesis and metastasis. Some of these properties have been reproduced in synthetic analogues (See Dyari, et al., Falck, et al., Imig, et al., and Khan, et al.). Thus, bioisosteric replacement of the epoxide moiety with urea, carbamate, amide or related systems has enabled the retention of the pharmacological activity of the endogenous lipid metabolite precursor (See Falck, et al. and Imig, et al.).

Recently, the in vivo antihypertensive actions of ω-6 PUFA epoxides were replicated in an orally active bioisosteric analogue. It may be possible to capture the anticancer activities of EPA and DHA epoxides and other prostanoid metabolites, such as PGE3, using suitable chemical modifications that inhibit metabolic degradation to facilitate the development of novel anticancer agents.

Michael Murray Michael Murray is a professor of pharmacology at the Sydney Medical School. The work described has been supported by grants from the Australian National Health and Medical Research Council.