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KAR‐2 (3″‐(β‐chloroethyl)‐2″,4″‐dioxo‐3,5″‐spiro‐oxazolidino‐4‐deacetoxy‐vinblastine), is a bis‐indol derivative; catharantine is coupled with the vindoline moiety which contains a substituted oxazolidino group. Our binding studies showed that KAR‐2 exhibited high affinity for bovine purified brain tubulin (Kd=3 μM) and it inhibited microtubule assembly at a concentration of 10 nM. Anti‐microtubular activity of KAR‐2 was highly dependent on the ultrastructure of microtubules: while the single tubules were sensitive, the tubules cross‐linked by phosphofructokinase (ATP: D‐fructose‐6‐phosphate‐1‐phosphotransferase, EC 2.7.1.11) exhibited significant resistance against KAR‐2. The cytoplasmic microtubules of Chinese hamster ovary mammalian and Sf9 insect cells were damaged by 1 μg ml−1 KAR‐2, as observed by indirect immunofluorescence and transmission electron microscopy. Scanning electron microscopy revealed intensive surface blebbing on both types of cells in the presence of KAR‐2. KAR‐2 was effective in the mouse leukaemia P338 test in vivo without significant toxicity. Studies on a primary cerebro‐cortical culture of rat brain and differentiated PC12 cells indicated that the toxicity of KAR‐2 was significantly lower than that of vinblastine. The additional property of KAR‐2 that distinguishes it from bis‐indol derivatives is the lack of anti‐calmodulin activity.

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