Dipeptides hydroxyethylene isosteres

Other interesting hybrids between hydroxyethylene and hydroxyethylamine dipeptide isosteres have been reported. Getman et al (1993) developed a series of hydroxyethylureas that potently inhibited HIV-1 protease. The concept of these urea isosteres, first introduced as renin inhibitors, may be envisioned as a modification of the hydroxyethylene isostere (e.g., compound 22), in which the PV chiral a-car-bon is replaced with a trigonal nitrogen. One example of this class of inhibitors, SC-52151 (26) (Table III), inhibited HIV-1 protease with an IC50 value of 6 nMand blocked the cytopathic effect of HIV-1 in cell cul-... 

In 2003, a new Sml2-mediated carbon carbon bond-forming reaction was reported by Skrydstrup for the direct synthesis of peptide mimics for evaluation as protease inhibitors.90 For example, the low-temperature coupling of 4-thiopyridyl ester 100, derived from Cbz-protected phenylalanine, with the dipeptide acrylamide 101 gave the peptide analogue 102 in a 61% yield (Scheme 7.43). Ketone 102 represents a ketomethylene isostere of the tetra-peptide Phe Gly Leu Phe. Ketomethylene isosteres and the corresponding reduced analogues, hydroxyethylene isosteres, represent important and pharmaceutically relevant classes of protease inhibitors.91,92... 

We synthesized the ketomethylene, , and hydroxyethylene,8, isosteres of a Leu-Ala dipeptide sequence in order to explore the importance of the two extra atoms in statine relative either to substrate or to the tetrahedral intermediate (Figure 1) in another aspartyl protease system. The compounds were synthesized by the routes outlined in Scheme I. This route was chosen so as to provide steric control at C-2 and C-5 of both 7 and 8 as well as to provide ready access to C-4 labeled analogs. Details of the synthesis have been described else-where.(23.24) Inhibitors were synthesized in which Leu-Ala dipeptide Isosteres replaced either Sta or Sta-Ala in known pepstatin analogs. Inhibition of porcine pepsin was determined using the reported spectrophotometric assay (Table I).(25)... 

J. V. N. Vara Prasad and D. H. Rich, Addition of allylic metals to ot-amino aldehydes. Application to the synthesis of statine, ketomethylene and hydroxyethylene dipeptide isosteres. Tetrahedron Lett. 37 1803 (1990). 

The C/O amide bond replacements include methyleneoxy, 1-hydroxyethylene, 2-hydro-xyethylene, 1,2-dihydroxyethylene, 1-oxoethylene, and epoxide isosteres. This chapter focuses on the synthetic methods of dipeptide building blocks containing these isosteres. 

Figure 14 Profiling of aspartyl protease activity, (a) Catalytic mechanism of aspartyl proteases that cleave peptide bonds via activation of a water molecule, (b) A hydroxyethylene dipeptide isostere-based probe binds tightly to the active site and gets covalently attached via UV irradiation.

Poss, M.A., and Reid, J.A., Synthesis of the hydroxyethylene dipeptide isostere, (2S,4S,5S)-5-amino-6-cyclohexy]-4-hydroxy-2-isopropyl hexanoic acid n-butyl amide. Tetrahedron Lett., 33, 1411, 1992. Handa, S., Pattenden, G., and Li, W.-S., A new approach to steroid ring construction based on a novel radical cascade sequence, J. Chem. Soc., Chem. Commun., 311, 1998. 

Hydroxyethylene dipeptidc isosteres 35, which are of interest as transition state analogs, e.g., in renin inhibitors where they replace the scissile dipeptide unit (Leu-Val) of angiotensinogen, the natural substrate of renin, can be obtained from optically active acid 32 via iodolactoniza-tion in several steps. The synthesis of 32 is achieved using an Ireland - Claisen rearrangement as the key step which allows complete control of the three stereogenic centers44. For a stereocontrolled synthesis of peptide bond isosteres via Claisen rearrangements see also ref 448. 

Tri-O-acetyl-D-glucal (via 2,3-dideoxyglycoside 337) is the starting point for a synthesis of 339, a hydroxyethylene dipeptide isostere related to an HIV-1 protease inhibitor. The ring opening of aziridine 338 is a key step (Scheme 32). 

Yamaguchi Y, Menear K, Cohen NC, Mah R, Cumin F, Schnell C, Wood JM, Maibaum J. The PiA-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin. Bioorg. Med Chem. Lett. 2009 19(16) 4863-4867. 

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