Toward a Template for Synthetic Actin-Targeting Macrolide Analogues That Inhibit Cancer Cell Invasiveness

Actin barbed end-binding macrolides have been shown to
inhibit
cancer cell motility and invasion of extracellular matrix (ECM), evoking
their potential utility as therapies for metastatic cancers. Unfortunately,
the direct use of these compounds in clinical settings is impeded
by their limited natural abundance, challenging total synthesis, and
detrimental effects on normal tissues. To develop potent analogues
of these compounds that are simpler to synthesize and compatible with
cell-specific targeting systems, such as antibodies, we designed over
20 analogues of the acyclic side chain (tail) of the macrolide Mycalolide
B. These analogues probed the contributions of four distinct regions
of the tail towards the inhibition of actin polymerization and ECM
invasion by human lung cancer A549 cells. We observed that two of
these regions tolerate considerable substituent variability, and we
identified a specific combination of substituents that leads to the
optimal inhibition of the ECM invasion activity of A549 cells.