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

Abstract

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.

Recent Progress on Microtubule Degradation Agents

“…Additionally, the cytotoxicities and degradation efficiencies of MDgAs show no significant positive correlations. For example, while the antiproliferative activity of 14 was better than that of 12 , no superior degradation efficiency was observed . Since tubulin exists in both tumor cells and normal cells, the indiscriminate inhibition of tubulin by cytotoxic MDgAs could result in unavoidable side effects.…”

“…However, while LBHB calculations could account for one possible mechanism, the degradation effect promoted by 12 and BML284 must be experimentally verified further. On the basis of the 12-tubulin cocrystal structure, Li et al 33 synthesized a large amount of 3-amino-β-carboline derivatives and analogues to identify new MDgAs with improved activities via SAR analysis. Among these, compound 14 (N- (3-(benzo[d] [1,3]dioxol-5-yloxy)benzyl)-9H-pyrido [3,4-b]indol-3-amine; Figure 6) was determined to be the optimal compound, having a potent in vitro antitumor activity with the potential to overcome multidrug resistance.…”

Xanthatin and 8-epi-xanthatin as new potential colchicine binding site inhibitors: a computational study

“…The assembly between the MTs and the kinetochores is crucial for the correct formation of the mitotic spindle and the subsequent alignment and segregation of the chromosomes [4]. Drugs that target the MTs can be classi ed into three main groups based on their mechanism of action: MTs-destabilizing agents (MDAs), MTs-stabilizing agents (MSAs) [5], and more recently tubulin degradation agents (TDAs) [6][7][8]. MDAs promote depolymerization and prevent polymerization of tubulin when it is administrated in high concentrations [9], while MSAs have an opposing effect.…”

“…MDAs promote depolymerization and prevent polymerization of tubulin when it is administrated in high concentrations [9], while MSAs have an opposing effect. On the other hand, TDAs destabilize the tubulin heterodimer, promoting its unfolding, thereby inducing its degradation in a proteasome-dependent pathway [7,8]. MDAs exert their mechanism of action over ve binding sites in tubulin: colchicine binding site (CBS) [10], vinca domain [11], maytansine binding site [12], pironetin binding site [13], and the seventh site [8,14].…”

“…MSAs interact by two well-de ned pockets in the tubulin heterodimer: taxoid binding site [15] and LAU/PEL binding site [16]. Interestingly, TDAs known to date do not have distinct binding sites, they are able to bind into the colchicine domain or the seventh site [7,8].…”