Development of a Flexible and Robust Synthesis of Tetrahydrofuro[3,4-b]furan Nucleoside Analogues

Abstract

In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro­[3,4-b]­furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derived from d-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the desired S-isomer. After deprotection of 1.3-A, a late-stage glycosylation was performed under Mitsunobu conditions to install the pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31–48% yield. Compound 1.1-C was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a PRMT5-MEP50 biochemical IC50 of 0.8 nM, a MCF-7 target engagement EC50 of 3 nM, and a Z138 cell proliferation EC50 of 15 nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate drug discovery programs.

The Structural Effects of Phosphorylation of Protein Arginine Methyltransferase 5 on Its Binding to Histone H4

“…The explanation of the difference in enzymatic activity (activation energy) of the two PRMT5 variants necessitates the atomic resolution structures of the H4-PRMT5 complexes. However, PRMT5(-MEP50) in complex with the full-length histone H4 has not been measured yet (see Table S1 for available PRMT5 structures [ 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]). Although the number of experimental human PRMT5 complexes increased recently due to its importance in cancer therapy, only one structure (PDB code: 4gqb, [ 17 ]) contains an eight-amino-acid-long N-terminal peptide fragment of histone H4 bound to the catalytic domain of PRMT5.…”

Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies

“…In an effort to improve the PK profiles of compound 11, a cyclization strategy was employed by Quiroz and co-workers to afford two novel 5,5-fused bicyclic PRMT5 inhibitors derived from nucleoside, including compounds 12 and 13 (Figure 1). 117,118 Compound 12 with a fused ribose-carbocycle core demonstrated higher affinity in a cell-based target engagement assay with an EC 50 value of 4.7 nM, and it potently inhibited the proliferation of the Z138 cell line with an EC 50 value of 17 nM. The cocrystal structure of 12 with the PRMT5:MEP50 complex (Figure 4B) confirmed that all major interactions are maintained compared with those of compound 11.…”

Synthesis of Methylene Tetrahydrofurane‐Fused Carbohydrates

“…A recent example is the peptidyl nucleoside antibiotic Miharamycin A reported by the group of Tang [17] . Because of their potential, several groups have derivatized nucleosides with this motif [18–20] …”

“…[17] Because of their potential, several groups have derivatized nucleosides with this motif. [18][19][20] Carbohydrates present an important class of biological compounds and the challenges associated with their synthesis and manipulation have made carbohydrate chemistry an intriguing domain for organic chemists. The challenge in carbohydrate chemistry comes from the existence of multiple hydroxy groups of similar reactivity.…”