Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists.

Nuno Pereira,Mercedes Amat,Francesc Sureda,Maria Pérez,Maria Santos

doi:10.3390/molecules21081027

Abstract

Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson’s disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.

Highlights

Chiral pool synthesis uses chiral natural products by incorporating part of them into the target structure
In the last few years, starting from chiral 1,2-aminoalcohols, we have developed libraries of novel enantiopure bicyclic lactams which were screened for activity as N-Methyl D-Aspartate (NMDA) receptor antagonists
Tryptophanol is used as synthesis the source of chirality, but is used to In incorporate the tryptamine present in target for the several indole alkaloids. This synthetic strategy, moiety tryptophanol is the used as thealkaloids source of chirality, but is used to incorporate the tryptamine moiety present in the target order to explore the potential of the indolo[2,3-a]quinolizidine scaffold for the development alkaloids In of novel receptor antagonists, we synthesized a series of compounds containing different

Summary

Introduction

Chiral pool synthesis uses chiral natural products by incorporating part of them into the target structure. A wide range of enantiopure amino acids, isolated from natural sources, have been used in academia and pharmaceutical companies as chiral auxiliaries/inductors to synthesize biologically active enantiopure compounds [1]. The asymmetric syntheses of natural products, or biological active molecules can be achieved using enantiopure 1,2-aminoalcohols containing a stereogenic centre (which can be obtained by reduction of the parent natural amino acids) as chiral inductors [2]. In the last few years we have developed several novel bioactive compounds in this area of research starting from the enantiopure 1,2-aminoalcohols tryptophanol and phenylalaninol Using this versatile synthetic approach we have developed libraries of enantiopure phenylalaninol-derived oxazolopyrrolidone lactams [3], tryptophanol-derived oxazolopiperidone lactams [4,5], oxazoloisoindolinones [6,7], and indolizinoindolones [8] designed to act on important therapeutic targets (Scheme 1)

Methods

Results

Conclusion