Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

Abstract

Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

Structurally diverse arene-fused ten-membered lactams accessed via hydrolytic imidazoline ring expansion

“…Gratifyingly, the N-alkylation/HIRE protocol developed for 10a (vide supra) was found to be fully transferrable (Scheme 2) onto the other twelve substrates (10b-m). Surprisingly, N-alkylation with diethyl sulfate required refluxing temperatures, which resulted in generally lower yields of [1, 4,7]oxadiazecin-9(6H)-ones (16n-q). Notably, compounds 16a-q (Fig.…”

“…3 This particular consideration has made medium-sized cyclic scaffolds popular, among other areas, in drug discovery against poorly 'druggable' targets such as protein-protein interactions. 4 The ring closure approaches to medium-sized ring construction are encumbered by entropy constraints, 5 hence ring expansion has manifested itself as a complementary and a lot more prolific strategy. 6 The latter usually involves the construction of a polycyclic system with some degree of instability where breaking one of the central bonds leads to stabilization (e.g., via aromatization or strain relief ) and thus provides the driving force for ring expansion.…”

“…

Imidazoline-fused [1,4]oxazepines ( prepared in two simple steps from methyl 2-hydroxyaroates, ethylene diamine and bis-electrophilic aromatics) undergo a facile, good-yielding hydrolytic imidazoline ring expansion (HIRE) upon N-alkylation and treatment with aqueous K 2 CO 3 . The resulting arene-fused ten-membered lactams significantly add to the contemporary arsenal of smallmolecule scaffolds where medium-sized ring systems are severely underrepresented.

Small molecule libraries containing medium-sized (8-to 11-membered) rings are currently recognized as a drug discovery platform with many advantages compared to linear scaffolds or those based on flat heteroaromatic rings.

1 The introduction of a cycle drastically reduces the rotatable bond count (compared to a linear molecule), which improves permeability through cell membranes and intestinal absorption.

…”

Chapter 2. The Application of Diversity-oriented Synthesis in Chemical Biology

“…Recent work by Kim et al, however, has demonstrated the application of DOS in the identification of a modulator of a key PPI interaction implicated in the amino-acid-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1), a regulator of cellular growth, proliferation and autophagy with oncogenic implications. 99 In this work, the authors utilised a privileged-DOS (pDOS) strategy 100 to generate 'biological navigators' using pyrimidodiazepine and pyrimidine cores, considered 'privileged' scaffolds due to their presence within various bioactive molecules and marketed drugs. Additionally, they incorporated a diazepine motif within these fused core scaffolds, to increase the 3D character of the library via higher sp 3 content and conformational flexibility.…”

“…The results of chemoinformatic analysis indicated that the resulting library displayed a broad shape distribution, similar to that of 71 bioactive natural products, but an improved distribution compared with 15 pyrimidine-containing FDA approved drugs. 99 The leucyl-tRNA synthetase (LRS)-Ras-related GTP-binding protein D (RagD) PPI plays an important role in the amino-acid-dependent activation of mTORC1 via leucine sensing and signalling to mTORC1. 101 Initial screening for inhibition of this PPI was conducted using ELISA-based HTS using LRS and glutathione-S-transferase tagged RagD, leading to the identification of 29a and 29b as dose-dependent inhibitors.…”