A comparative molecular field analysis of inhibitors of tubulin polymerization

Tubulin is an important target for cancer chemotherapy as its polymerizatio n and depolymerization is necessary for cell division. Compounds that inter fere with this process (Vinca alkaloids and taxanes) are valuable drugs in cancer chemotherapy. To further improve the effectiveness of cancer chemoth erapy the development of new compounds with this mode of action is promisin g. Several of 2-phenyl-4-quinolone and 2-phenyl-1,8-naphthyridin-4-one deri vatives were synthesized by Lee and coworkers. Several of them had high tub ulin polymerization inhibitory activity, but no general structural pattern related to potency could be seen for the synthesized compounds. Therefore w e tried to develop quantitative structure-activity relationships For these compounds to gain some insight into the structural requirements for high in hibitory activity. Using both the CoMFA and the classical Free-Wilson appro ach similar structural features were identified that influence activity. Th e CoMFA models had high internal and external predictivity and were only ma rginally influenced by the various parameters set. Thus the derived QSAR mo dels seem to be stable and help to understand the underlying structure acti vity relationship. From the performed analyses it became apparent that a co mplex relationship between substitution pattern and tubulin polymerization inhibition potency of these compounds exist.