Discovering Podophyllotoxin Derivatives as Potential Anti‐Tubulin Agents: Design, Synthesis and Biological Evaluation

Abstract

Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for development of anticancer agents. Tubulin is known as an attractive target for drug discovery and cancer therapies. There are few studies on the treatment of breast cancer with podophyllotoxin and its derivatives targeting tubulin. Here, a series of novel aryl 1,3,4‐oxadiazole/1,3,4‐thiadiazole acid podophyllotoxin ester derivatives (D1–D16) were synthesized. Among these compounds, D9 exhibited excellent antiproliferation activity against MCF‐7 cells (IC50=2.46±0.12 μM). Furthermore, D9 caused cell cycle arrest at the G2/M phase and induced cell apoptosis. Confocal microscopy showed that D9 inhibited microtubule polymerization by causing cancer cell growth inhibition. Molecular docking results suggested D9 could bind to the active binding site of tubulin. In a mouse model, compound D9 suppressed malignant growth without causing significant toxicity to normal tissues. Our findings support the utility of D9 as a novel compound for the development of anticancer agent.

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

“…Wang and colleagues and Han et al both obtained 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives of podophyllotoxin using an alternative path of synthesizing the heterocycle before it joining to podophyllotoxin [ 137 , 138 ]. First, they synthesized 1,3,4-oxa(thia)diazole-acid intermediates ( 97 ) from benzoate derivatives, as shown in Scheme 22 .…”

“…At the same time, Han and colleagues synthesized both 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives of podophyllotoxin and compounds 99m and 99i , belonging to the 1,3,4-oxadiazole series and bearing an halogen atom; these were the most notorious derivatives ( Figure 13 ) [ 138 ]. Compound 99m showed better anticancer activity than podophyllotoxin against MDA-MB-231 cells (IC 50 = 7.28 µM), while compound 99i displayed better antiproliferative against MCF7 cells (IC 50 = 2.46 µM).…”

“…The antiproliferative activity of Compound 99i was further investigated in other breast cancer cell lines such as the BT474, SK-BR-3, and MDA-MB-453 cell lines, exhibiting excellent antiproliferative activity in all the breast cancer cell lines tested (IC 50 values = 5.23, 4.48, and 8.23 µM, respectively). In addition, compound 99i could arrest the MCF7 cell cycle in the G2/M phase by increasing the protein levels of cyclin B1 and CDK1 and also could induce apoptosis by increasing the levels of proapoptotic proteins [ 138 ].…”

Synthesis and Antiproliferative Activity of 4β‐O‐Substituted, 4β‐N‐Substituted Deoxypodophyllotoxin Derivatives, and 4β‐OH‐ 4’‐O‐Substituted Podophyllotoxin

“…[1,2] The antineoplastic activity of PPT is based on the inhibition of tubulin assembly into microtubules. [3,4] However, Its undesirable effects; especially gastrointestinal toxicity; hampered its clinical use. [5] Whereas, epipodophyllotoxin derivatives, which are semisynthetic epimers of PPT (4β epimers) possess a potent inhibitory effect on the DNA topoisomerase II.…”

“…Podophyllotoxin (PPT), a natural lignin, and its 4β epimers: compound 1 (4′‐O‐substituted 4′‐O‐demethylpodphyllotoxin) and compound 2 (4′‐N‐substituted 4′‐O‐demethyl‐4‐deoxypodophyllotoxin) (figure 1) possess various biological activities including antineoplastic and antiviral [1,2] . The antineoplastic activity of PPT is based on the inhibition of tubulin assembly into microtubules [3,4] . However, Its undesirable effects; especially gastrointestinal toxicity; hampered its clinical use [5] .…”