Glycoside hydrolases (GH) are a large family of hydrolytic enzymes found in all domains of life. As such, they control a plethora of normal and pathogenic biological functions. Thus, understanding selective inhibition of GH enzymes at the atomic level can lead to the identification of new classes of therapeutics. In these studies, we identified a 4-⍺-glucoside of valienamine (8) as an inhibitor of Streptomyces coelicolor (Sco) GlgE1-V279S which belongs to the GH13 Carbohydrate Active EnZyme family. The results obtained from the dose–response experiments show that 8 at a concentration of 1000 µM reduced the enzyme activity of Sco GlgE1-V279S by 65%. The synthetic route to 8 and a closely related 4-⍺-glucoside of validamine (7) was achieved starting from readily available D-maltose. A key step in the synthesis was a chelation-controlled addition of vinylmagnesium bromide to a maltose-derived enone intermediate. X-ray structures of both 7 and 8 in complex with Sco GlgE1-V279S were solved to resolutions of 1.75 and 1.83 Å, respectively. Structural analysis revealed the valienamine derivative 8 binds the enzyme in an E2 conformation for the cyclohexene fragment. Also, the cyclohexene fragment shows a new hydrogen-bonding contact from the pseudo-diaxial C(3)–OH to the catalytic nucleophile Asp 394 at the enzyme active site. Asp 394, in fact, forms a bidentate interaction with both the C(3)–OH and C(7)-OH of the inhibitor. In contrast, compound 7 disrupts the catalytic sidechain interaction network of Sco GlgE1-V279S via steric interactions resulting in a conformation change in Asp 394. These findings will have implications for the design other aminocarbasugar-based GH13-inhibitors and will be useful for identifying more potent and selective inhibitors.
An effective reaction condition for the rapid transformation of nitrile derivatives into thioamide derivatives has been developed by the treatment with a combination of carbon disulfide and sodium sulfide. The reaction condition is equally effective for the transformation of alkyl, aryl nitriles. C‐Glycosyl nitriles also furnished C‐glycosyl thioamide derivatives in satisfactory yield under the reported reaction condition. The reaction condition is simple, high yielding and suitable for scaled up.
Tuberculosis is a
disease caused primarily by the organism
Mycobacterium
tuberculosis
(
Mtb
),
which claims about 1.5 million lives every year. A challenge that
impedes the elimination of this pathogen is the ability of
Mtb
to remain dormant after primary infection, thus creating
a reservoir for the disease in the population that reactivates under
more ideal conditions. A better understanding of the physiology of
dormant
Mtb
and therapeutics able to kill these phenotypically
tolerant bacilli will be critical for completely eradicating
Mtb
. Our groups are focusing on characterizing the activity
of derivatives of the marine natural product (+)-puupehenone (
1
). Recently, the Rohde group reported that puupehedione (
2
) and 15-α-methoxypuupehenol (
3
) exhibit
enhanced activity in an in vitro multi-stress dormancy model of
Mtb.
To optimize the antimycobacterial activity of these
terpenoids, novel 15-α-methoxy- and 15-α-acetoxy-puupehenol
esters were prepared from (+)-puupehenone (
1
) accessed
through a (+)-sclareolide-derived β-hydroxyl aldehyde. For added
diversity, various congeners related to (
1
) were also
prepared from a common borono-sclareolide donor, which resulted in
the synthesis of
epi
-puupehenol and the natural products
(+)-chromazonarol and (+)-yahazunol. In total, we generated a library
of 24 compounds, of which 14 were found to be active against
Mtb
, and the most active compounds retained the enhanced
activity against dormant
Mtb
seen in the parent compound.
Several of the 15-α-methoxy- and 15-α-acetoxy-puupehenol
esters possessed potent activity against actively dividing and dormant
Mtb
. Intriguingly, the closely related triisobutyl derivative
16
showed similar activity to
1
in actively dividing
Mtb
but lost about 178-fold activity against dormant
Mtb
. However, the monopivaloyl compound
13
showed
a modest 3- to 4-fold loss in activity in both actively dividing and
dormant
Mtb
relative to the activity of
1
revealing the importance of the free OH at C19 supporting the potential
role of quinone methide formation as critical for activity in dormant
Mtb
. Elucidating important structure–activity relationships
and the mechanism of action of this natural product-inspired chemical
series may yield insights into vulnerable drug targets in dormant
bacilli and new therapeutics to more effectively target dormant
Mtb
.
The pentasaccharide repeating unit of the cell wall O-antigen ofEscherichia coliO156 containing 4,6-O-(R)-pyruvate acetal was synthesized using stereoselective [2 + 3] block glycosylation in satisfactory yield.
A convergent [3+2] block synthetic strategy was developed for the synthesis of the pentasaccharide repeating unit of the cell wall O‐antigen of Escherichia coli O11 strain in excellent yield in a minimum number of steps. Several suitably functionalized thioglycoside derivatives were used as glycosyl donors during the synthesis of the target compound. A thioglycoside was the glycosyl donor used to couple with another thioglycoside derivative in a highly stereoselective manner exploiting the difference of their reactivity profile. A combination of Niodosuccinimide (NIS) and perchloric acid supported over silica gel (HClO4−SiO2) was used as a thiophilic glycosylation activator system in all stereoselective glycosylation reactions. HClO4−SiO2 acted as a user‐friendly solid acid catalyst. Yields were very good in all glycosylation steps with a high stereoselective outcome. The synthetic pentasaccharide could be coupled to an appropriate protein to furnish a glycoconjugate derivative for its use in immunochemical studies.
A concise convergent synthetic strategy has been developed for the first synthesis of the glycerol phosphate‐containing tetrasaccharide repeating unit of the capsular polysaccharide of S. pneumoniae 11 A strain in very good yield. A stereoselective [2+2] block glycosylation strategy has been adopted for the synthesis of the tetrasaccharide derivative. All glycosylations were highly stereoselective with satisfactory yield.
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