Structure-Based Design and Synthesis of N‑Substituted 3‑Amino-β-Carboline Derivatives as Potent αβ-Tubulin Degradation Agents

So far, relatively few small molecules
have been reported to promote
tubulin degradation. Our previous studies have found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting
αβ-tubulin degradation. To further improve its antiproliferative
activity, 66 derivatives or analogues of 2 were designed
and synthesized based on 2-tubulin cocrystal structure.
Among them, 12b displayed nanomolar potency against a
variety of tumor cells, including paclitaxel- and adriamycin-resistant
cell lines. 12b binds to the colchicine site and promotes
αβ-tubulin degradation in a concentration-dependent manner
via the ubiquitin–proteasome pathway. The X-ray crystal structure
revealed that 12b binds in a similar manner as 2, but there is a slight conformation change of the B ring,
which resulted in better interaction of 12b with surrounding
residues. 12b effectively suppressed tumor growth at
an i.v. dose of 40 mg/kg (3 times a week) on both A2780S (paclitaxel-sensitive)
and A2780T (paclitaxel-resistant) ovarian xenograft models, with respective
TGIs of 92.42 and 79.75% without obvious side effects, supporting
its potential utility as a tumor-therapeutic compound.