Colchicine, the main active
alkaloid from Colchicum autumnale L., is a potent
tubulin binder and represents an interesting lead structure for the development of potential anticancer chemotherapeutics. We report on the synthesis and investigation of potentially reactive colchicinoids and their surprising
biological activities. In particular, the previously undescribed colchicinoid
PT-100, a B-ring contracted 6-exo-methylene colchicinoid, exhibits extraordinarily high antiproliferative and apoptosis-inducing effects on various types of
cancer cell lines like
acute lymphoblastic leukemia (Nalm6),
acute myeloid leukemia (HL-60), Burkitt-like
lymphoma (BJAB), human
melanoma (MelHO), and human breast
adenocarcinoma (MCF7) cells at low nanomolar concentrations. Apoptosis induction proved to be especially high in multidrug-resistant Nalm6-derived
cancer cell lines, while healthy human leukocytes and hepatocytes were not affected by the concentration range studied. Furthermore,
caspase-independent initiation of apoptosis via an intrinsic pathway was observed.
PT-100 also shows strong synergistic effects in combination with
vincristine on BJAB and Nalm6 cells. Cocrystallization of
PT-100 with
tubulin dimers revealed its (noncovalent) binding to the
colchicine-binding site of β-
tubulin at the interface to the α-subunit. A pronounced effect of
PT-100 on the cytoskeleton morphology was shown by fluorescence microscopy. While the reactivity of
PT-100 as a weak Michael acceptor toward
thiols was chemically proven, it remains unclear whether this contributes to the remarkable
biological properties of this unusual colchicinoid.