Podophyllum derivatives containing fluorine atom in the 3-position of 2-aminopyridine improved the antitumor activity by inducing P53-dependent apoptosis
- 171 Downloads
In previous work, we presented experimental and theoretical evidence that podophyllum derivatives substituted by chlorine atom in the 3-posititon of 2-aminopyridine exhibited significantly elevated potency. In this study, a series of podophyllum derivatives substituted in the 3-position of 2-aminopyridine, including methyl and fluorine groups, were synthesized. Their chemical structures were confirmed by the spectral (1H-nuclear magnetic resonance, 13C-nuclear magnetic resonance, electrospray ionization mass spectrometry) and elemental analyses. These derivatives were tested for their respective cytotoxicities in HeLa, BGC-823, A549, Huh7, and MCF-7 cells by MTT assay and the pharmacological results showed that most of them displayed potent cytotoxicities against at least one of the tested cancer cell lines. Structure–activity relationship study suggested that the introduction of the fluorine atom into the 3-posititon of 2-aminopyridine had enhanced the cytotoxicity against numerous tumor cells compared to the chlorine atom, while the methyl group did not. Furthermore, other biological experiments were consistent with the beneficial effect of fluorine atom substituent in the 3-position of 2-aminopyridine, which then inhibited the microtubule polymerization and activity of topoisomerase II when 2-amino-3-fluoropyridine substituted in podophyllotoxin and 4′-O-demethylepipodophyllotoxin, and that they work by effecting the target proteins which induce P53-dependent apoptosis.
KeywordsPodophyllum derivatives 2-Aminopyridine Fluorine atom P53-dependent apoptosis
This work was supported by Science and Technology Youth Project of Education Department in Jiangxi province (NO. GJJ150109). I would like to acknowledge and thank the professors (Yajie Tang, Hubei University of Technology; Zhanpeng Yuan, Wuhan University) for their essential help. I also wish to thank the editor, the associate editor, and those anonymous reviewers for their helpful comments and suggestions, which have led to an improvement of this article.
Compliance with ethical standards
Conflict of interest
The author declares that they have no competing interests.
- Chashoo G, Singh SK, Sharma PR, Mondhe DM, Hamid A, Saxena A, Andotra SS, Shah BA, Qazi NA, Taneja SC, Saxena AK (2011) A propionyloxy derivative of 11-keto-β-boswellic acid induces apoptosis in HL-60 cells mediated through topoisomerase I & II inhibition. Chem Biol Interact 189:60–71CrossRefGoogle Scholar
- Lee KH, Beers SA, Mori M, Wang ZQ, Kuo YH, Li L, Liu SY, Chang JY, Han FS, Chen YC (1990) Antitumor agents. 111. New 4-hydroxylated and 4-halogenated anilino derivatives of 4′-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II. J Med Chem 33:1364–1368CrossRefGoogle Scholar
- Passarellla D, Giardini A, Petretto B, Gabriele F, Sacchetti A, Silvani A, Ronchi C, Cappelletti G, Caetelli D, Blorlak C, Danieli B (2008) Inhibitors of tubulin polymerization: synthesis and biological evaluation of hybrids of vindoline, anhydrovinblastine and vinorelbine with thiocolchicine, podophyllotoxin and baccatin III. Bioorg Med Chem 16:6269–6285CrossRefGoogle Scholar
- Pitts SL, Jablonksy MJ, Duca M, Dauzonne D, Monneret C, Adrimondo PB, Anklin C, Graves DE, Oscheroff N (2011) Contributions of the D-ring to the activity of etoposide against human topoisomerase IIα: potential interactions with DNA in the ternary enzyme-drug-DNA complex. Biochemistry 50:5058–5066CrossRefGoogle Scholar
- Tang YJ, Wang H, Zhao W, Li HM (2014) Preparation method and application of nitrogen substituted podophyllum derivates with antitumor activity. China Patent CN 103601732AGoogle Scholar
- Zhang YX, Zhao W, Tang YJ (2016) Multilevel induction of apoptosis by microtubule-interfering inhibitors 4β-S-aromatic heterocyclic podophyllum derivatives causing multi-fold mitochondrial depolarization and PKA signaling pathways in HeLa cells. Oncotarget 7:24303–24313PubMedPubMedCentralGoogle Scholar
- Zhao W, Yang Y, Zhang YX, Zhou C, Li HM, Tang YL, Liang XH, Chen T, Tang YJ (2015) Fluoride-containing podophyllum derivatives exhibit antitumor activities through enhancing mitochondrial apoptosis pathway by increasing the expression of caspase-9 in HeLa cells. Sci Rep 5:17175. doi: 10.1038/srep17175 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhu XK, Guan J, Tachibana Y, Bastow KF, Cho SJ, Cheng HH, Cheng YC, Gurwith M, Lee KH (1999) Antitumor agents. 194. synthesis and biological evaluations of 4-β-mono-, -di-, and -trisubstituted aniline-4′-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles. J Med Chem 42:2441–2446CrossRefGoogle Scholar