Synthesis, screening and docking of small heterocycles as Glycogen Phosphorylase inhibitors

Abstract

A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.1 mM-23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9-13 and 19 with Glycogen Phosphorylase.

The Elusive Seven-Membered Cyclic Imino Ether Tetrahydrooxazepine

“…In conclusion, we demonstrate the first synthesis of seven-membered 2-THOx leading to the structural reassignment of all previously reported non-fused seven-membered 2-THOx CIEs, which were demonstrated to be the N-acylated pyrrolidines instead, misassigned as imino ether isomers. [24][25][26][27][28][29] Moreover, we have also investigated the CROP of 2-THOx, and found a significant retardation in the seven-membered CIE polymerization, attributed to a non-coplanar arrangement of the imino ether moiety in this strained unsaturated ring system. Our work opens up the possibility for the exploration of 2-THOx both in asymmetric ligand, drug development and in monomer design.…”

“…A suitable monomer was purportedly found in the literature in the form of 2-phenyl-4,5,6,7-tetrahydro-1,3-oxazepine (2-phenyl-2-THOx) 1, the synthesis of which had been described in four independent literature reports using two different methods (Scheme 2). [24][25][26][27][28][29] However, the 2-phenyl-2-THOx 1 prepared according to the literature procedure reported by Mollo et al, 29 did not have the expected physical and chemical properties, based on our experience with 2-oxazolines and 2-DHOx. The obtained product showed a complete lack of any kind of reactivity in CROP, and even any type of alkylation reactivity.…”

“…This apparent hiatus in the literature on CIE CROP may be related to the fact that the synthesis of 2-THOx is also only sparingly reported in the literature, and these compounds are thus not readily available as monomers. [24][25][26][27][28][29] Intrigued by the possibility to introduce a four-carbon linker between the repeating amide units, we set out to investigate the polymerization of such seven-membered CIE monomers. A suitable monomer was purportedly found in the literature in the form of 2-phenyl-4,5,6,7-tetrahydro-1,3-oxazepine (2-phenyl-2-THOx) 1, the synthesis of which had been described in four independent literature reports using two different methods (Scheme 2).…”

“…In order to confirm our reassignment, we prepared the isomeric amide 2 by benzoylation of pyrrolidine, and found this material to be indistinguishable to the previously obtained compound, also showing 1 H and 13 C NMR data completely consistent with literature data reported for the compound mistakingly assigned in literature to the structure of 2-phenyl-2-THOx 1. [24][25][26][27][28][29] A careful analysis, and comparison with their Nacylated pyrrolidine analogues, of all literature data that was reported for 4,5,6,7-unsubstituted-2-THOx, (SI table S1 to table S11) then led us to the remarkable conclusion that the parent heterocyclic structure, a non-ring fused seven membered CIE, has in fact never been prepared, and that all previously claimed reports are based on a misassignment of the (rearranged) amide isomer, i.e. the N-acylated pyrrolidine ring system rather than the claimed CIE structure.…”

“…In the supporting information (SI) a comparison of all reassigned putative 2-THOx with the literature data of the related N-acylated pyrrolidones is provided. [24][25][26][27][28][29] In addition copies of 1 H and 13 C NMR for the phenyl based monomers (6, 7 and 1) are provided. The synthesis procedures, polymerization procedures and analysis of all molecules and polymers synthesized in this work are also included in the SI.…”