Cyclic guanosine
monophosphorothioate analogue 1a is
currently showing potential as a drug for the treatment of inherited
retinal neurodegenerations. To support ongoing preclinical and clinical
work, we have developed a diastereoselective synthesis via cyclization
and sulfurization of the nucleoside 5′-H-phosphonate
monoester, which affords the desired R
P-3′,5′-cyclic phosphorothioate in 9:1 ratio to the
undesired S
P-diastereomer. This route
was made viable as a result of the silyl protection sequence used,
which achieved >80% selectivity for 2′,5′-hydroxyls
over 3′,5′-hydroxyls. Finally, the chromatography-free
process allowed for a scale-up, as intermediates and the final product
were isolated by crystallization to give 125 g of 1a (13.8%
total yield) with over 99.9% HPLC purity.
Ethyl 6-chloro-5-cyano-2-methylnicotinate (4) was coupled with 4-piperidinecarboxylic acid (isonipecotic acid) in 81% yield to pyridine acid 10. An amide coupling between 10 and benzylsulfonamide (6) afforded AZD1283 (1) in 79% yield using CDI as coupling reagent. The synthesis has been developed and scaled up to 20 kg batches of 1, supporting preclinical and clinical studies. Development work towards 2-chloropyridine 4 and benzylsulfonamide ( 6) is included.
Triphenylphosphine selenide and its polymer-supported counterpart are found to be efficient selenium-transferring reagents for the conversion of H-phosphonate diesters and phosphite triesters into the corresponding phosphoroselenoate derivatives.
The ability of Zn2+ dimethyl-dppz PNAzymes to cleave RNA target sequences with under 20 minute half-lives is critically dependent on the bulge-closing base pairs as well as their stacking interactions with the neighbouring nucleobases.
Oligonucleotide (ON)
conjugates are increasingly important tools
for various molecular diagnostics, nanotechnological applications,
and for the development of nucleic acid-based therapies. Multiple
labeling of ONs can further equip ON-conjugates and provide improved
or additional tailored properties. Typically, the preparation of ON
multiconjugates involves additional synthetic steps and/or manipulations
in post-ON assembly. This report describes the simplified methodology
allowing for multiple labeling of ONs on a solid support and is compatible
with phosphodiester as well as phosphorothioate (PS) ONs. The current
approach utilizes two novel alkyne- and amino-functionalized linker
phosphoramidites that can be readily synthesized from a common aminodiol
intermediate in three steps. The combination of new linkers provides
orthogonal functionalities, which allow for multiple attachments of
similar or varied moieties. The linkers are incorporated into ONs
during automated solid-phase ON synthesis, and the conjugation with
functional entities is achieved by either amide bond formation or
by copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC).
The versatility of the approach is demonstrated by the synthesis of
5′-site ON multiconjugates with small molecules, peptides,
and fatty acids as well as in the preparation of an internal peptide–ON
conjugate.
A practical
and chromatography-free multikilogram synthesis of
a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been
developed in eight steps and 7% overall yield starting from methyl
2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling
and an enzymatic resolution of a racemic ester.
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