Lipid A analogs

Parr et al. [61] showed that lipid A has the same antitumoral effect as whole endotoxin preparations on murine L5178Y lymphoma. The effects of LPS and synthetic lipid A treatments were compared by Shimizu et al. [158-161] on Meth A fibrosarcoma in BALB/c mouse. The antitumoral activity of different lipids A has also been investigated. Ribi et al. [162] used an extract from S. typhimurium containing lipid A, which when injected directly into hepatocarcinoma line 10 tumors in guinea pigs shows an antitumoral effect. This activity is attributed to a monophosphoryl diglucosamine derivative of lipid A [163], Synthetic lipid A analogs also proved to be active in this system [164], as well as... 

In a recent phase I trial the synthetic lipid A analog ONO-4007 was given by i.v. injections to patients with cancer unresponsive to the standard therapy. The limited systemic toxicity disappeared within 24 hours. The MTD was defined as 125 mg/patient [e.g. (125 65=2 mg/kg]. The lipid A increased serum concentrations of TNF-a and IL-6, without affecting the concentrations of GM-CSF, IFN-y and neopterin. There was a significant drop in lymphocyte counts after injections, but no effect on clotting parameters [190]. 

We then focused on the synthesis of lipid A analogs which contain 3-hydroxy fatty acids. For this purpose, sufficient amount of (R)-3-hydroxytetradecanoic acid ( ), which is the commonest hydroxy acid in Salmonella lipid A, was first prepared by means of an asymmetric reduction of the corresponding keto ester, i. ., methyl 3-oxotetradecanoate (j ) (7). Catalytic hydrogenation of 21 in the presence of Raney Ni modified with (R, R)-tartaric acid foaBr (8) afforded the crude (R)-ester in 85% enantiomeric excess. After saponification, the resultant acid was purified through its dicyclohexylammonium salt to give the optically and chemically pure (R)-acid In a yield of 61% from... 

Table I. Structures and physical properties of synthetic lipid A analogs...

The presence in bacterial lipopolysaccharides of phosphoryl-ated ethanolamine residues (1) prompted us to experiment with the incorporation of this group. When compound was treated with an activated phosphorylethanolamine derivative, prepared by the procedure shown in Figure 8, the a-phosphate [a]j) +66.7° (chloroform), was obtained in 46% yield. The reaction is similar to that with dibenzyl tributylstannyl phosphate. Thus, the new phosphorylation method may have wide application in the synthesis of C-l phosphorylated lipid A analogs. 

Kotani, S., Takada, H., Takahashi, I., Ogawa, T., Tsujimoto, M., Shimauchi, H., Ikeda, T., Okamura, H., Tamura, T., Harada, K. Immunobiological activities of synthetic lipid A analogs with low endotoxicity. Infect Immun 54 (1986) 673-682. 

Kusumoto, S., Fukase, K., Fukase, Y., Kataoka, M., Yoshizaki, H., Sato, K., Oikawa, M., Suda, Y. Structural basis for endotoxic and antagonistic activities investigation with novel synthetic lipid A analogs. J Endotoxin Res 9 (2003) 361-366. 

In the present manuscript, we will discuss the mechanism by which endotoxin initiates the sepsis cascade, the rationale for targeting LPS, and the most significant treatments that have been studied antibodies, vaccines, binding peptides, lipid A analog, phospholipids, and polymyixin B hemoperfusion. 

Bunnell, E., Lynn, M., Habet, K., Neumann, A., Perdomo, C.A., Friedhoff, L.T., Rogers, S.L. and Parrillo, J.E. A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia. Crit Care Med 28 (2000) 2713-2720. 

Fukase, K. et al.. Divergent synthesis and biological activities of lipid A analogs of shorter acyl chains. Tetrahedron, 54, 4033, 1998. 

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