Tubuloclustin [N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-
deacetylcolchicine], a highly cytotoxic anti-
tubulin compound is known for its ability to promote microtubule disassembly followed by the formation of
tubulin clusters of unique morphology. Three series of
antimitotic agents related to
tubuloclustin were designed and synthesized in order to enhance the molecular diversity of "
tubuloclustin-like" family of compounds. The series of compounds with modified
adamantane moiety was highly potent in cytotoxic effect on human lung
carcinoma A549 cells (EC50 = 6-400 nM) and was active in affecting the microtubule arrays and induction of strong
tubulin clusterization. In two other sets of compounds, the
colchicine moiety of
tubuloclustin was replaced by
podophyllotoxin or
combretastatin A-4. All
combretastatin A-4 derivatives displayed noticeable cytotoxic activity ([Formula: see text]) but their effect on microtubules depended on the position of the linker attachment.
Podophyllotoxin derivatives were also toxic to A549 cells ([Formula: see text]) and caused both microtubule depolymerization and some
tubulin clustering. The data obtained gave additional evidence that the whole panel of C7-colchicine,
podophyllotoxin and
combretastatin derivatives could manifest clustering effect, and the strength of this effect correlated with cytotoxic activity of the compounds.