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Catalysis

Nucleotide construction gets new chiral tool

Reagent developed through Scripps and BMS collaboration couples nucleosides with potential applications in antisense therapeutics

by Tien Nguyen
August 2, 2018 | APPEARED IN VOLUME 96, ISSUE 32

 

09632-scicon6-rxn.jpg
A new phosphorus(V) reagent developed by researchers at BMS and Scripps couples nucleosides diastereoselectively.

Antisense drugs are on the rise. The U.S. FDA has approved two antisense therapies to treat genetic diseases in the past two years with more in the pipeline. These compounds often consist of nucleoside chains connected by phosphorothioates—chiral linkages that make the agents more stable in the body yet exponentially increase their complexity. For example, the 18-mer Spinraza, which is a spinal muscular atrophy drug from Ionis and Biogen that costs $125,000 per dose, incorporates these linkages and is delivered as a mixture of more than 130,000 isomers theoretically.

Controlling the stereochemistry at phosphorus, though, could increase a drug candidate’s potency by reducing the number of less active isomers in these mixtures. To gain that control, chemists have mostly turned to phosphorus(III)-based chemistry. Now, scientists at Bristol-Myers Squibb and Scripps Research Institute California report a novel P(V)-based reagent that couples nucleosides with high diastereoselectivity (Science 2018, DOI: 10.1126/science.aau3369).

P(V) reagents are generally less reactive than P(III) but they let chemists skip cumbersome protection and deprotection steps required by P(III) chemistry, the authors say. Building on work by Wojciech J. Stec and colleagues, the team synthesized a P(V) reagent in one step from limonene oxide, which served as the chiral scaffold. The researchers point out that P(III)-based reagents are air and moisture sensitive and require specialized equipment to handle, while the new reagent is bench-stable, which they say could improve medicinal chemists ability to rapidly synthesize these molecules and discover new medicines.

The collaborators used their reagent to make a variety of dinucleotides in 61–97% yield. They also synthesized several oligonucleotides and cyclic dinucleotides, a class of compounds that has attracted attention as possible anticancer agents. The P(V) reagent produced a single diastereomer of a cyclic dinucleotide in five steps while the traditional P(III) approach produced four diastereomers in nine steps.

“It is exciting to see new developments in this challenging and important area of nucleotide chemistry,” says Jonathan Hall at ETH Zurich. “If it can be extended to pharmaceutically relevant oligonucleotide derivatives, it will represent a game-changer for oligonucleotide therapeutics.”

Chandra Vargeese, head of drug discovery at Wave Life Sciences, which develops stereopure nucleotides using a P(III)-based platform with industrial partners such as Takeda and Pfizer, says the approach is elegant and offers excellent diastereoselectivities on par with P(III) chemistry. The stepwise coupling yields, however, are on the low side compared to Wave’s platform and would need to be optimized for commercial production, she says. Another challenge for the P(V) reagent, Vargeese says, is that it doesn’t offer the same level of access as P(III) reagents do to structures with mixed phophorothioate and phosphodiester backbones that are important to the field.

The BMS-Scripps team says the P(V) reagent will soon be available for purchase through MilliporeSigma.

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