Kinesin motor protein inhibitors: toward the synthesis of adociasulfate analogs

Cell division and intracellular functions are dependent on kinesin motor proteins. These proteins convey their cellular cargos by walking along the microtubule tracks. Specific inhibitors of kinesin would selectively abolish its activity in vivo, and knowledge regarding this inhibition pathway would aid our understanding regarding the enzyme mechanism. Currently, few inhibitors of kinesins exist. The marine natural products adociasulfates (AS) might act as lead compounds toward designing analogous inhibitors. Only AS-1 has been synthesized, requiring twenty-eight steps; therefore, we envisioned the synthesis of simpler analogs via shorter routes. We attempted functionalizing commercial steroids at one end, while the other end was transformed into an anionic moiety pivotal for binding with the kinesin motor domain. Though our AS analog does not inhibit the ATPase activity of human kinesin, this synthetic approach is practical and with some modifications, offers the potential to generate bioactive analogs of therapeutic importance.