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A Novel Synthesis of Highly Substituted Perhydropyrrolizines, Perhydroindolizines, and Pyrrolidines: Inhibition of the Peptidyl‐Prolyl cis / trans Isomerase (PPIase) Pin1
Author(s) -
Siegrist Romain,
Zürcher Martina,
Baumgartner Corinne,
Seiler Paul,
Diederich François,
Daum Sebastian,
Fischer Gunter,
Klein Christian,
Dangl Markus,
Schwaiger Manfred
Publication year - 2007
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200790028
Subject(s) - chemistry , pin1 , isomerase , ww domain , stereochemistry , isomerization , serine , heteronuclear single quantum coherence spectroscopy , proline , enzyme , nuclear magnetic resonance spectroscopy , biochemistry , amino acid , catalysis , gene
In this paper, we describe the synthesis and biological evaluation of highly substituted perhydropyrrolizines that inhibit the peptidyl‐prolyl cis / trans isomerase (PPIase) Pin1, an oncogenic target. The enzyme selectively catalyzes the cis / trans isomerization of peptide bonds between a phosphorylated serine or threonine, and proline, thereby inducing a conformational change. Such structural modifications play an important role in many cellular events, such as cell‐cycle progression, transcriptional regulation, RNA processing, as well as cell proliferation and differentiation. Based on computer modeling ( Fig. 2 ), the new perhydropyrrolizinone derivatives (−)‐ 1a,b , decorated with two substituents, were selected and synthesized ( Schemes 1–3 ). While enzymatic assays showed no biological activity, 15 N, 1 H‐HSQC‐NMR spectroscopy revealed that (−)‐ 1a,b bind to the WW recognition domain of Pin1, apparently in a mode that does not inhibit PPIase activity. To enforce complexation into the larger active site rather than into the tighter WW domain of Pin1 and to enhance the overall binding affinity, we designed a perhydropyrrolizine scaffold substituted with additional aromatic residues ( Fig. 5 ). A novel, straightforward synthesis towards this class of compounds was developed ( Schemes 4 and 5 ), and the racemic compounds (±)‐ 22a – 22d were found to inhibit Pin1 with K i values ( K i = inhibition constant) in the micromolar range ( Table 2 ). To further enhance the potency of these inhibitors, the optically pure ligands (+)‐ 22a and (+)‐ 33b,c were prepared ( Schemes 6 and 7 ) and shown to inhibit Pin1 with K i values down to the single‐digit micromolar range. According to 15 N, 1 H‐HSQC‐NMR spectroscopy and enzymatic activity assays, binding occurs at both the WW domain and the active site of Pin1. Furthermore, the new synthetic protocol towards perhydropyrrolizines was extended to the preparation of highly substituted perhydroindolizine ((±)‐ 43 ; Scheme 8 ) and pyrrolidine ((±)‐ 48a,b ; Scheme 9 ) derivatives, illustrating a new, potentially general access to these highly substituted heterocycles.