Flex-nucleoside analogues – Novel therapeutics against filoviruses

Abstract

Fleximers, a novel type of flexible nucleoside that have garnered attention due to their unprecedented activity against human coronaviruses, have now exhibited highly promising levels of activity against filoviruses. The Flex-nucleoside was the most potent inhibitor against recombinant Ebola virus in Huh7 cells with an EC50 = 2 μM, while the McGuigan prodrug was most active against Sudan virus-infected HeLa cells with an EC50 of 7 μM.

Synthesis of a 3′-C-ethynyl-β-d-ribofuranose purine nucleoside library: Discovery of C7-deazapurine analogs as potent antiproliferative nucleosides

“…4.2.11. 6-(4-Chlorophenyl)-N9-(2 0 ,3 0 ,5 0 -tri-O-acetyl-3 0 -C-ethynyl-b-D-ribofuranosyl)-purine(11) 11 was prepared according to General procedure A. 7 (0.22 g, 0.5 mmol) gave rise to 11 (0.09 g, 0.175 mmol) as a slightly yellow foam in 35% yield.…”

Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

“…Since the proximal intermediate 2-amino-4-methoxy-5-tributylstannylpyrimidine was easily achievable starting with 2-amino-5-iodo-4-methoxypyrimidine, 9 , 10 , 11 similar methodologies were applied to obtain the 2-amino-4-methoxy-6-tributylstannylpyrimidine intermediate 6 , using various palladium catalysts as well as a range of temperatures, but none of the conditions yielded the desired organostannane 6 ( Scheme 2 ).

Scheme 2 Attempted synthesis of 6 .

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“…For some time, the Seley-Radtke group has designed and synthesized various classes of flexible purine nucleos(t)ides, or “fleximers”. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 These novel nucleosides were designed to investigate how flexibility in the nucleobase could potentially affect receptor-ligand recognition and function. In addition, their flexible design allows them to overcome issues with binding site mutations thus retaining their activity.…”

“…To date, fleximers have shown key advantages over the corresponding purine-base nucleosides. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 For example, the distal guanosine fleximer (Flex-G, Fig. 1 ) proved to be an inhibitor of S -adenosyl- l -homocysteine hydrolase by adapting a syn conformation, thereby placing the exocyclic amino group such that it mimicked the amino group from an adenosine nucleobase.…”

“… 5 , 6 Recently, a series of fleximers possessing acyclic sugars exhibited broad spectrum antiviral activities against coronaviruses, flaviviruses and filoviruses, further supporting their significance. 10 , 11

Fig. 1 Guanosine distal and proximal Fleximers.

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