Molecular design and synthesis of new heterobivalent compounds based on chlorambucil and colchicine

Two new heterobivalent molecules were designed by linking a DNA-alkylating agent chlorambucil with tubulin-targeting compound colchicine or its adamantyl containing C(7)-derivative. Target compounds were synthesized via acid coupling with N-deacetylcolchicine. According to preliminary biotests, both conjugates caused microtubule depolymerization and strong tubulin clustering, and colchicine–chlorambucil conjugate was found to be one order of magnitude more potent and to exhibit some selectivity to A549 carcinoma cells.