Synthesis of Novel Potent Archazolids: Pharmacology of an Emerging Class of Anticancer Drugs

Vacuolar type ATPase (V-ATPase) has
recently emerged as a promising
novel anticancer target based on extensive in vitro and in vivo studies with archazolids, complex polyketide
macrolides, which present the most potent V-ATPase inhibitors known
to date. Herein, we report a biomimetic, one-step preparation of archazolid
F, the most potent and least abundant archazolid, the design and synthesis
of five novel, carefully selected archazolid analogues, and the biological
evaluation of these antiproliferative agents, leading to the discovery
of a very potent but profoundly simplified archazolid analogue. Furthermore,
the
first general biological profiling of the archazolids against a broad
range of more than 100 therapeutically relevant targets is reported,
leading to the discovery of novel and important targets. Finally,
first pharmacokinetic data of these natural products are disclosed.
All of these data are relevant in the further preclinical development
of the archazolids as well as the evaluation of V-ATPases as a novel
and powerful class of anticancer targets.