Total Synthesis and Biological Evaluation of Asterriquinol D Dimethyl Ether, Candidusin D, Kumbicins A–B, and Petromurins C–D as α‑Glucosidase Inhibitors

The first total synthesis of asterriquinol D dimethyl
ether, candidusin
D, kumbicins A–B, and petromurins C–D has been accomplished
in a concise fashion. The convergent route featured a key double Suzuki
coupling and a set of judicious late-stage functional group transformations.
Biological evaluation demonstrated these natural products and their
derivatives to be a novel class of α-glucosidase inhibitors
with unique structural scaffolds. N-Boc-kumbicin
A exhibited the most potent inhibitory activity (IC50 =
8.84 ± 3.38 μM) in comparison to the positive control acarbose
(IC50 = 564.28 ± 4.68 μM). Kinetic studies indicated
that N-Boc-kumbicin A was a reversible and mixed-type
inhibitor of α-glucosidase. CD spectral analysis revealed that
the interaction of N-Boc-kumbicin A with α-glucosidase
caused significant conformational changes and modifications in the
microenvironment of the enzyme’s secondary structure, principally
through the formation of hydrogen bonds and hydrophobic interactions
as demonstrated by molecular docking studies.