The challenging synthesis of a quaternary center within the highly oxygenated setting of tedanolide C can be performed via a Kiyooka aldol reaction. Here, the diastereomeric analog of tedanolide C with the configurations between C10 and C20 opposite compared to the proposed structure was chosen as the synthetic target. The tetra-substituted silyl ketene acetal provides the southern hemisphere of tedanolide C in useful selectivities, and the absolute configuration of the newly generated quaternary center was determined by NOE experiments of the corresponding acetonide.
Soraphens, discovered from the myxobacterial strain Sorangium cellulosum, have intrigued chemists and biologists due to their diverse biological effects mediated by the potent inhibition of acetyl CoA carboxylase.
Extraintestinal pathogenic
Escherichia
coli
(ExPEC) is a major health concern due to emerging
antibiotic resistance.
Along with O1A, O2, and O6A,
E. coli
O25B is a major serotype within the ExPEC group, which expresses
a unique
O
-antigen. Clinical studies with a glycoconjugate
vaccine of the above-mentioned
O
-types revealed O25B
as the least immunogenic component, inducing relatively weak IgG titers.
To evaluate the immunological properties of semisynthetic glycoconjugate
vaccine candidates against
E. coli
O25B,
we here report the chemical synthesis of an initial set of five O25B
glycan antigens differing in length, from one to three repeat units,
and frameshifts of the repeat unit. The oligosaccharide antigens were
conjugated to the carrier protein CRM
197
. The resulting
semisynthetic glycoconjugates induced functional IgG antibodies in
mice with opsonophagocytic activity against
E. coli
O25B. Three of the oligosaccharide–CRM
197
conjugates
elicited functional IgGs in the same order of magnitude as a conventional
CRM
197
glycoconjugate prepared with native O25B
O
-antigen and therefore represent promising vaccine candidates
for further investigation. Binding studies with two monoclonal antibodies
(mAbs) revealed nanomolar anti-O25B IgG responses with nanomolar
K
D
values and with varying binding epitopes.
The immunogenicity and mAb binding data now allow for the rational
design of additional synthetic antigens for future preclinical studies,
with expected further improvements in the functional antibody responses.
Moreover, acetylation of a rhamnose residue was shown to be likely
dispensable for immunogenicity, as a deacylated antigen was able to
elicit strong functional IgG responses. Our findings strongly support
the feasibility of a semisynthetic glycoconjugate vaccine against
E. coli
O25B.
The tedanolides are biologically active polyketides that exhibit a macrolactone constructed from a primary alcohol. Since polyketidal transformations only generate secondary alcohols, it has been hypothesized by Taylor that this unique lactone could arise from a postketidal transesterification. In order to probe this hypothesis and to investigate the biological profile of the putative precursor of all members of the tedanolide family, we embarked on the synthesis of desepoxyisotedanolide and its biological evaluation in comparison to desepoxytedanolide. The biological experiments unraveled a second target for desepoxytedanolide and provided evidence that the proposed transesterification indeed provides a survival advantage for the producing microorganism.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.