Modular Approaches to Lankacidin Antibiotics

Lankacidins are a class of polyketide
natural products isolated
from Streptomyces spp. that show promising antimicrobial
activity. Owing to their complex molecular architectures and chemical
instability, structural assignment and derivatization of lankacidins
are challenging tasks. Herein we describe three fully synthetic approaches
to lankacidins that enable access to new structural variability within
the class. We use these routes to systematically generate stereochemical
derivatives of both cyclic and acyclic lankacidins. Additionally,
we access a new series of lankacidins bearing a methyl group at the
C4 position, a modification intended to increase chemical stability.
In the course of this work, we discovered that the reported structures
for two natural products of the lankacidin class were incorrect, and
we determine the correct structures of 2,18-seco-lankacidinol
B and iso-lankacidinol. We also evaluate the ability
of several iso- and seco-lankacidins
to inhibit the growth of bacteria and to inhibit translation in vitro.
This work grants insight into the rich chemical complexity of this
class of antibiotics and provides an avenue for further structural
derivatization.