Lipid solid phase synthesis

COMBINATION OF THE SCREENING APPROACH WITH COMBINATORIAL SOLID PHASE SYNTHESIS OF CATIONIC LIPIDS... 

The solid-phase synthesis strategy was based on the utilization of 4-methoxy-trityl chloride resin. To gain access to a large number of compounds, only commercially available building blocks were used and protective groups were omitted if possible. The synthesis strategy resulted in a new class of cationic lipids as shown in Figure 5 (compound 6). The structure bases on... 

For such an integrated research activity, differently modified peptides and proteins that carry modifications whose structure can be changed at will through synthesis are invaluable tools. Therefore, the synthesis of the lipidated peptides is an important theme. Lipidated peptides can typically not be accessed via standardized peptide synthesis methods. However, employing the synthetic tools developed and presented here, most types of lipidated peptides can now be synthesized and obtained in pure form. Even though solution-phase approaches still play a significant role in the synthesis of lipidated peptides, the recently developed solid-phase synthesis methods delineate the preferred strategy to access the majority of the required lipidated peptides. 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

Fig. 10 Solid-phase synthesis of cationic lipids using submonomer (a) [147, 148] and monomer (b) [151, 152] linear assembly...

Fig. 11 (a) Convergent strategy for the synthesis ofpolyamine lipids [63, 154, 155], (b) Solid-phase synthesis of quaternary ammonium double-tailed lipids [157]... 

Fig. 14 Solid-phase synthesis of aminoglycerol-based monocationic lipids [159]...

Figure 5 Solid-phase synthesis of an N-Ras lipidated peptide on hydrazide resin. (A) Fmoc-Cys(Far)-OH, FIBTU, FIOBt, IMP, CFI2CI2/DMFS (1 1). (B) piperidine/DMF (1 4). (C) Fmoc-AA-OH, HBTU, HOBt, DIPEA, DMF. (D) piperidine/DMF (1 4). (E) Fmoc-Cys(Pal)-OH, HBTU, HOBt, TMP, CH2CI2/DMF (1 1). (F) DBU (1 %) in DMF. (G) Fmoc-Gly-OH, HATU (5 eg.), DIPEA (20 eq.) CH2CI2/DMF (7 1). (H) Cu(OAc)2 (0.5 eq.), pyridine (30 eq.), acetic acid (SO eq.), methanol (215 eq.) CFI2CI2, O2.

The solid-phase synthesis of lipidated Rab peptides has relied on the hydrazide linker, similar to the lipidated Ras peptides (15). By employing geranylgeranylated or fluorescent labeled lipidated cysteines as building blocks, a highly flexible... 

Kragol G, Lumbierres M, Palomo JM, Waldmann H. Solid-phase synthesis of lipidated peptides. Angew. Chem. Int. Ed. 2004 43 5839-5842. 

Ludolph B, Eisele E, Waldmann H. Solution- and solid-phase synthesis of the polybasic lipid-modified C termini of Rho A and K-Ras 4B. ChemBioChem 2002 3901-904. 

Cao, L., U.T. Bomscheuer, and R.D. Schmid, Lipase-Catalyzed Solid-Phase Synthesis of Sugar Esters, Fett/Lipid 98 332-335 (1996). 

Solid-phase peptide synthesis (SPPS) is a fast and flexible approach and has been frequently used for the synthesis of lipidated peptides. SPPS allows for preparation of the desired peptides, including both natural and nonnatural modifications, with high purity and good yields in a short time. The linker chosen for the solid-phase synthesis of lipidated peptides is of utmost importance. High concentrations of acid during the synthesis or for the release of the peptide from the solid support should... 

SCHEME 8.4 Solid-phase synthesis methodology to attach a phosphoglycerate lipid unit to an elaborated disaccharide and cleavage from solid support. 

Ludolph B, Eisele E, Waldmarm H (2002) Solid-phase synthesis of lipidated peptides. J Am Chem Soc 124 5954-5955... 

Triola G, Gerauer M, Gormer K et al (2010) Solid-phase synthesis of lipidated ras peptides employing the Elhnan sulfonamide linker. Chem Eur J 16 9585-9591... 

NBD derivatives are building blocks in efficient solid-phase method for the synthesis of differently lipidated and additionally modified peptides <2004AGE5839>. 

In this section, an example will be given in which a (small) library of a new type of cationic lipids was synthesized and screened for TE (63). For synthesis, combinatorial solid phase chemistry was used. All cationic lipids of the example library are structurally based on 3-methylamino-1,2-dihydroxy-propane as the polar, cationic lipid part. As nonpolar lipid part, different hydrocarbon chains are boimd to the amino group of the scaffold and the amino group was further methylated to get constantly cationic-charged lipids. Lipids were synthesized in both configurations and as racemats, and the counterions were varied as well. Table 1 summarizes the structural features of these lipids. 

Considering all these features and limitations, it is understandable that currently there is no general procedure available, such as the Fmoc or Boc protocols that are available for nonfunctionalized peptides. However, several approaches have been developed in the last two decades to make lipidated peptides accessible. This chapter describes both the corresponding solution-phase approaches and solid-support approaches for the synthesis of lipidated peptides. In line with the framework sketched above, both the different protecting groups and solid-phase linker systems that have been developed will be reviewed. 

By analogy to the solution-phase approaches, the introduction of lipid functionalities on peptides on the solid support can also follow two general approaches, either using prelipidated building blocks in the standard solid-phase peptide synthesis or via selective lipidation on resin. " " ... 

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