A Novel Synthesis of Highly Substituted Perhydropyrrolizines, Perhydroindolizines, and Pyrrolidines: Inhibition of the Peptidyl‐Prolyl cis/trans Isomerase (PPIase) Pin1

Abstract

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 (À)-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 (À)-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 (AE)-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 ((AE)-43; Scheme 8) and pyrrolidine ((AE)-48a,b; Scheme 9) derivatives, illustrating a new, potentially general access to these highly substituted heterocycles.

Proline cis/trans-Isomerase Pin1 Regulates Peroxisome Proliferator-activated Receptor γ Activity through the Direct Binding to the Activation Function-1 Domain

“…In the future, it is important to investigate the possible involvement of Pin1 in atherosclerosis. There are several Pin1-targeted drugs, but most of them bind to the PPIase domain of Pin1 (29,30). To manipulate the Pin1-mediated regulation of PPAR␥, the WW domain, rather than the PPIase domain, must be targeted by drugs.…”

Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities

“…Subsequent chemical analysis revealed that (AE )-1 (and a large number of related imides) are unstable in even mildly basic solution and that the succinimide moiety undergoes rapid and regioselective ring opening by formation of (AE )-2. [2,18] The pK a of the carboxylate group (4.0) in (AE )-2 could be determined by potentiometric titration.…”

On the Cis to Trans Isomerization of Prolyl–Peptide Bonds under Tension

“…The resulting lone pair dipole interacts with the CO dipole and influences the peptide bond rotation during isomerization . Furthermore, the transition state is stabilized by the interaction between the N–H of the following peptide bond with the lone pair of the sp 3 N. , This isomerization can be catalyzed by peptidyl–prolyl cis–trans isomerases. − …”