A convergent synthesis of alkyne–azide cycloaddition derivatives of 4-α,β-2-propyne podophyllotoxin depicting potent cytotoxic activity

• Synthesis of O-propargylated 4α and 4β-(1,2,3-triazol-4-yl)-podophyllotoxin derivatives by means of click chemistry.
• Some O-propargylated 4α and 4β isomers were more cytotoxic than podophyllotoxin (1).
• Compound 9k, showed maximum cytotoxicity having IC50 ∼ 3.8–22 nM in four cell lines.
• Compound 9k strongly inhibited cancer cells migration ability at concentration of 10 nM.
• Compound 9k significantly induced apoptosis in PC-3 cells.

A facile synthetic approach to construct the O-propargyl derivatives of 4α and 4β-(1,2,3-triazol-4-yl)-podophyllotoxin (9a–k & 10a–k) and 4′-Demethyl-4′-4β-(1,2,3-triazol-4-yl)-epipodophyllotoxin (12a–d) were synthesized by means of click chemistry. The chemical structures were confirmed by 1H, 13C, 2D NMR and HRMS spectral analysis and their cytotoxicities were measured against diverse human cancer cell lines viz. PC-3, PANC-1, COLO-205 and A-549 by MTT assay. Some of the compounds were found more potent than the parent molecule Podophyllotoxin, like; 9a & 10a, 9h & 10h, 9k & 10k, 10d, 8 and 12a. The most potent molecule discovered was compound 9k that exhibited the highest cytotoxicity on all the four cancer cell lines with IC50 values of 3.8–22 nM. The compound further found to induce apoptosis and strongly hindered the motility of aggressive prostate cancer PC-3 cells.

O-propargyl derivatives of 4α and 4β-(1,2,3-triazol-4-yl)-podophyllotoxin exhibited potent in vitro cytotoxicities. Compound 9k, was evaluated for its effect on apoptosis induction, inhibition of cell motility and migration of prostate cancer PC-3 cells.Figure optionsDownload as PowerPoint slide