Comprehensive Cell Biological Investigation of Cytochalasin B Derivatives with Distinct Activities on the Actin Network

In search of a more comprehensive structure–activity
relationship
(SAR) regarding the inhibitory effect of cytochalasin B (2) on actin polymerization, a virtual docking of 2 onto
monomeric actin was conducted. This led to the identification of potentially
important functional groups of 2 (i.e., the NH group
of the isoindolone core (N-2) and the hydroxy groups at C-7 and C-20)
involved in interactions with the residual amino acids of the binding
pocket of actin. Chemical modifications of 2 at positions
C-7, N-2, and C-20 led to derivatives 3–6, which were analyzed for their bioactivities. Compounds 3–5 exhibited reduced or no cytotoxicity
in murine L929 fibroblasts compared to that of 2. Moreover,
short- and long-term treatments of human osteosarcoma cells (U-2OS)
with 3–6 affected the actin network
to a variable extent, partially accompanied by the induction of multinucleation.
Derivatives displaying acetylation at C-20 and N-2 were subjected
to slow intracellular conversion to highly cytotoxic 2. Together, this study highlights the importance of the hydroxy group
at C-7 and the NH function at N-2 for the potency of 2 on the inhibition of actin polymerization.