Novel Podophyllotoxin Derivatives as Potential Tubulin Inhibitors: Design, Synthesis, and Antiproliferative Activity Evaluation

Abstract

A number of podophyllotoxin derivatives (3A-3J) had been designed and synthesized, and their biological activities were evaluated in this study. Moreover, the antiproliferation activities of these compounds against four human cancer cell lines (HepG2, HeLa, A549, and MCF-7) were also tested. The results indicated that the most promising compound 3D displayed potent inhibitory activity over the four human cancer cell lines and was further demonstrated to have potent tubulin polymerization inhibitory effects without damaging the non-cancer cells. Additionally, 3D was verified to effectively interfere with tubulin and could prevent the mitosis of cancer cells, leading to cell cycle arrest and eventually inducing apoptosis in a dose- and time-dependent manner. Moreover, the Western blotting and siRNA results showed that Bcl-2 was downregulated in HepG2 cells treated with 3D. Finally, the molecular docking simulation results revealed that 3D could fit well in the colchicine-binding pocket. Taken together, this study has provided certain novel antitubulin agents for possible cancer chemotherapy.

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

“…Inhibitor of Tubulin PTOX, whose pharmacological effects have been recognized to inhibit microtubule assembly by blocking the colchicine binding site, thereby exhibiting inhibition of microtubule protein polymerization and inducing G2/M blockade, has shown potent antitumor activity (Cortese et al, 1977). PTOX derivatives have also been shown to have the analogous ability (Han et al, 2018). Kamal et al (2011b) synthesized a series of conjugates of 4aza-2,3-didehydropodophyllotoxins Compound 21 (Figure 7), and fluorescent tubulin polymerization analysis showed these PTOX derivatives significantly reduced tubulin units.…”

Identification of novel microtubule inhibitors effective in fission yeast and human cells and their effects on breast cancer cell lines

“…Among the 11 compounds that inhibit microtubule assembly, three of them (L1, K1, E2) contained benzodioxole, which has been found in several known microtubule drugs that target colchicin-binding sites [28,29], including polygamain [19], combretastatin A-2 [30], podophyllotoxin [31], steganacin [32] and TUB091/TUB092 [33]. The crystal structure of α /β-tubulin-RB3-tubulin tyrosine ligase (TTL) complex soaked with TUB092 showed that the benzodioxole group positions at the hydrophobic pocket of β-tubulin, a position which is similar to the site that the trimethoxyphenyl moiety (A-ring) of colchicine also occupies [33].…”

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

“…Han and colleagues synthesized several new podophyllotoxin–benzoheterocyclic derivatives ( 114a – j , Figure 14 ) from podophyllotoxin and the corresponding benzoheterocyclic acid following the procedure described above ( Scheme 28 ) [ 154 ]. Among all these derivatives, compound 114d , with an indole moiety, showed the greatest cytotoxicity with IC 50 values of 1.93, 2.20, 5.94, and 10.10 µM against the HepG2, HeLa, A549, and MCF7 tumor cell lines, respectively.…”