Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity.

Rocío Recio,Miguel López-Lázaro,Inmaculada Fernández,Estefanía Burgos-Morón,Patricia Lerena,Noureddine Khiar,Manuel Pernia Leal,Bernard Mouillac,Esther Pozo,Juan Ángel Organero,Victoria Valdivia,José Manuel Calderón-Montaño

doi:10.1021/acs.jmedchem.1c00793

Abstract

NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α, as an interesting hit exhibiting significant NK1R antagonist effect (kinact 0.209 ± 0.103 μM) and high binding affinity for NK1R (IC50 = 50.4 nM, Ki = 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.

Highlights

The NK1 receptor (NK1R), known as tachykinin receptor 1 (TACR1),[1] belongs to the superfamily of G-protein coupled receptors, which constitute ∼35% of the therapeutic targets of all of the pharmaceutical products on the market.[2]
A turning point in this race was the discovery of the first nonpeptide NK1R antagonist CP-96,345,17 which has been instrumental in the development of a number of antagonists with improved pharmacological properties; Figure 1.16,18 Structural optimizations around the central skeleton led to the development of Aprepitant,[19] which became the first oral drug approved to enter the clinic, targeting NK1R for the treatment of chemotherapy-induced nausea and vomiting.[20]
Preliminary structure−activity relationship studies carried out on a large number of NK1R antagonists developed after the discovery of CP-96,345 allowed the proposition of a pharmacophore model, which consists of a heterocyclic scaffold substituted with at least two aromatic rings in a cis orientation; Figure 1A.25

Summary

Introduction

The NK1 receptor (NK1R), known as tachykinin receptor 1 (TACR1),[1] belongs to the superfamily of G-protein coupled receptors, which constitute ∼35% of the therapeutic targets of all of the pharmaceutical products on the market.[2]. We report on the stereoselective synthesis of carbohydrate-based NK1R antagonists (CarbNK1RAnt) and the determination of Received: May 1, 2021 Published: July 8, 2021

Methods

Results

Conclusion