Chemistry and Biology of Novel Microtubule-Destabilizing Agents that Bind α-Tubulin

Bioactive compounds capable of interacting with tubulins and microtubules represent powerful weapons in cancer chemotherapy. Most of these compounds, including the well-established chemotherapeutic agents colchicine (1), podophyllotoxin (3), vinblastine (4) and vincristine (5) that interfere with the formation and growth of microtubules, or Taxol (11) and the epothilones (12-13), which promote tubulin polymerization and stabilize microtubules, share an interaction with β-tubulin, one of the two subunits of the globular heterodimeric protein tubulin. In contrast, few compounds have been identified as interacting with α-tubulin. A select group of natural compounds are pironetin (18) and the hemiasterlins, and the synthetic compounds cyanoacrylates (21-22), dinitroanilines (23-25) and tetrahydrofuranyl derivatives COBRA-0 (133) and COBRA-1 (26). In addition to their interaction with the α-tubulin subunit, all these compounds share the capacity of destabilizing microtubules. In the present review, we will discuss the most relevant aspects of the biology and chemistry of these compounds, with an emphasis on their antiproliferative properties and potential as anticancer drugs.