Bioinspired design for the assembly of Glypromate (R) neuropeptide conjugates with active pharmaceutical ingredients

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Silva Reis, SC (Author) Other; dos Santos, ACVD (Author) Other; Garcia Mera, X (Author) Other; Rodriguez Borges, JE (Author) FCUP; Sampaio Dias, IE (Author) Other

Journal

Title: New Journal of Chemistry

Vol. 44

ISSN: 1144-0546

Publisher: Royal Society of Chemistry

Indexing

ISI Web of Knowledge - 3 Citations

Scopus - 3 Citations

Other information

Authenticus ID: P-00T-8PA

DOI: 10.1039/d0nj04851h

Abstract (EN): Neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, are a class of heterogeneous pathologies of the central nervous system (CNS) affecting millions of people worldwide. CNS-related pathologies represent a global health burden in developed and developing countries with no curative treatments currently available. Thus, the development of novel multitarget neuroprotective drugs is a health priority. In this work, a bioinspired methodology in solution-phase for the assembly and regioselective conjugation of Glypromate (R) neuropeptide with active pharmaceutical ingredients (APIs) is described. The main purpose is to design new hybrid molecules which may offer increased systemic resistance of Glypromate (R) towards proteases and/or allow the controlled release of both APIs and the neuroprotective peptide within CNS. For the synthesis of such peptide-hybrid compounds (R)-1-aminoindane, amantadine, and memantine were selected as APIs for conjugation with Glypromate (R). Furthermore, capping strategies are explored to prepare Glypromate (R) conjugates with more favorable pharmacodynamic profiles by masking polar exposed groups. Overall, this synthetic approach led to the development of a small library of 12 conjugates with improved drug-like properties in comparison with Glypromate (R), paving the way for the discovery of novel CNS multitarget drugs. Additionally, by exploring the bis-functionalization of glutamate, the formation of chiral glutarimides is disclosed for the first time employing TBTU as the coupling reagent. This unusual reactivity of TBTU with glutamate offers a new synthetic approach for the preparation of chiral glutarimide alkaloids.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15