Advertisement

Medicinal Chemistry Research

, Volume 26, Issue 6, pp 1279–1290 | Cite as

Podophyllum derivatives containing fluorine atom in the 3-position of 2-aminopyridine improved the antitumor activity by inducing P53-dependent apoptosis

  • Huai WangEmail author
Original Research

Abstract

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.

Keywords

Podophyllum derivatives 2-Aminopyridine Fluorine atom P53-dependent apoptosis 

Notes

Acknowledgements

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.

Supplementary material

44_2017_1841_MOESM1_ESM.tif (9.8 mb)
Supplementary Figure
44_2017_1841_MOESM2_ESM.doc (4.6 mb)
Supplementary Information

References

  1. Abdur Rauf SM, Takaba H, Del Carpio CA, Miyamoto A (2014) How nutlin-3 disrupts the MDM2-p53 interaction: a theoretical investigation. Med Chem Res 23:1998–2006CrossRefGoogle Scholar
  2. Baldwin EL, Osheroff N (2005) Etoposide, topoisomerase II and cancer. Curr Med Chem Anticancer Agents 5:363–372CrossRefGoogle Scholar
  3. Bhat BA, Reddy PB, Kumar-Agrawal S, Saxena AK, Sampath-Kumar HM, Qazi GN (2008) Studies on novel 4β-[(4-substituted)-1,2,3-triazol-1-yl] podophyllotoxins as potential anticancer agents. Eur J Med Chem 43:2067–2072CrossRefGoogle Scholar
  4. Bhattacharyya D, Hazra S, Banerjee A, Datta R, Kumar D, Chakrabarti S, Chattopadhyay S (2016) Transcriptome-wide identification and characterization of CAD isoforms specific for podophyllotoxin biosynthesis from Podophyllum hexandrum. Plant Mol Biol 92:1–23CrossRefGoogle Scholar
  5. Bohrin L, Rosen B (1996) Drug discovery and development. Drug Discov Today 1:343–351CrossRefGoogle Scholar
  6. Castro MA, Corral JM, Gordaliza M, Garcia PA, Zurita MA, Feliciano AS (2004) Synthesis and biological evaluation of new selective cytotoxic cyclolignans derived from podophyllotoxin. J Med Chem 47:1214–1222CrossRefGoogle Scholar
  7. Chang H, Shyu HG, Lee CC, Tsai SC, Wang BW, Lee YH, Lina S (2003) GL331 inhibits HIF-1α expression in a lung cancer model. Biochem Biophys Res Commun 302:95–100CrossRefGoogle Scholar
  8. 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
  9. Chu DT, Fernandes PB (1989) Structure–activity relationships of the fluoroquinolones. Antimicrob Agents Chemother 33:131–135CrossRefGoogle Scholar
  10. Daley L, Meresse P, Bertounesque E, Monneret C (1997) A one-pot, efficient synthesis of the potent cytotoxic podophyllotoxin derivative NPF. Tetrahedron Lett 38:2673–2676CrossRefGoogle Scholar
  11. Hao C, Gao LX, Zhang YR, Wang W, Yu GL, Guan HS, Zhang LJ, Li CX (2015) Acetylated chitosan oligosaccharides act as antagonists against glutamate-induced PC12 cell death via Bcl-2/Bax signal pathway. Mar Drugs 13:1267–1289CrossRefGoogle Scholar
  12. Hu CQ, Xu DQ, Du WT, Qian SJ, Wang L, Lou JS, He QJ, Yang B, Hu YZ (2010) Novel 4β-anilino- podophyllotoxin derivatives: design synthesis and biological evaluation as potent DNA- topoisomerase II poisons and anti-MDR agents. Mol BioSyst 6:410–420CrossRefGoogle Scholar
  13. Jin ZG, Shen JF, He JY, Hu CQ (2015) Combination therapy with p53-MDM2 binding inhibitors for malignancies. Med Chem Res 24:1369–1379CrossRefGoogle Scholar
  14. Jordan MA, Thrower D, Wilson L (1992) Effects of vinblastine, podophyllotoxin and nocodazole on mitotic spindles. Implications for the role of microtubule dynamics in mitosis. J Cell Sci 102:401–416PubMedGoogle Scholar
  15. Kamal A, Arifuddin M, Dastidar SG, Kumar BA (2003a) Synthesis of 4β-amido and 4β-sulphonamido analogues of podophyllotoxin as potential antitumour agents. Bioorg Med Chem 11:5135–5142CrossRefGoogle Scholar
  16. Kamal A, Gayatri NL, Reddy DR, Mohan-Reddy PS, Arifuddin M, Dastidar SG, Kondapi AK, Rajkumar M (2005) Synthesis and biological evaluation of new 4β-anilino- and 4β-imido-substituted podophyllotoxin congeners. Bioorg Med Chem 13:6218–6225CrossRefGoogle Scholar
  17. Kamal A, Kumar BA, Arifuddin M (2003b) A one-pot, efficient and facile synthesis of 4β- arylaminopodophyllotoxins: synthesis of NPF and GL-331 as DNA topoisomerase II inhibitors. Tetrahedron Lett 44:8457–8459CrossRefGoogle Scholar
  18. Kamal A, Kumar BA, Suresh P, Juvekar A, Zingde S (2011a) Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents. Bioorg Med Chem 19:2975–2979CrossRefGoogle Scholar
  19. Kamal A, Kumar BA, Suresh P, Shankaraiah N, Kumar MS (2011b) An efficient one-pot synthesis of benzothiazolo-4β-anilino-podophyllotoxin congeners: DNA totopoisomerase-II inhibition and anticancer activity. Bioorg Med Chem Lett 21:350–353CrossRefGoogle Scholar
  20. Kamal A, Lakshmi-Gayatri N (1996) An efficient method for 4β-anilino-4′-demethylepipodophyllotoxins: synthesis of NPF and W-68. Tetrahedron Lett 37:3359–3362CrossRefGoogle Scholar
  21. Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256:42–49CrossRefGoogle Scholar
  22. Kim ND, Yoon J, Kim JH, Lee JT, Chen YS, Hwang MK, Ha L, Song W (2006) Putative therapeutic agents for the learning and memory deficits of people with Down syndrome. Bioorg Med Chem 15:3772–3776CrossRefGoogle Scholar
  23. Knudsen KE, Booth D, Naderi S, Sever-chroneos Z, Fribourg AF, Hunton IC, Feramisco JR, Wang JY, Knudsen ES (2000) RB-dependent S-phase response to DNA damage. Mol Cell Biol 20:7751–7763CrossRefGoogle Scholar
  24. Lakhani SA, Masud A, Kuida K, Porter-Jr GA, Booth CJ, Mehal WZ, Inayat I, Flavell RA (2006) Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311:847–851CrossRefGoogle Scholar
  25. 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
  26. Liu J, Li Y, Ren W, Hu WX (2006) Apoptosis of HL-60 cells induced by extracts from Narcissus tazetta var. chinensis. Cancer Lett 242:133–140CrossRefGoogle Scholar
  27. Liu YQ, Tian J, Qian K, Zhao XB, Morris-Natschke SL, Yang L, Nan X, Tian X, Lee KH (2015) Recent progress on C-4-modified podophyllotoxin analogs as potent antitumor agents. Med Res Rev 35:1–62CrossRefGoogle Scholar
  28. Liu YQ, Wei DF, Zhao YL, Cheng WD, Lu Y, Ma YQ, Li X, Han C, Wei YX, Cao HM, Zhao CY (2012) Synthesis and biological evaluation of a series of podophyllotoxin derivatives as a class of potent antitubulin agents. Bioorg Med Chem 20:6285–6295CrossRefGoogle Scholar
  29. Lu YX, Shi T, Wang Y, Yang HY, Yan XH, Luo XM, Jiang HL, Zhu WL (2009) Halogen bonding-a novel interaction for rational drug design? J Med Chem 52:2854–2862CrossRefGoogle Scholar
  30. Nitiss JL (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9:338–350CrossRefGoogle Scholar
  31. 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
  32. 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
  33. Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE (2000) Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 275:10761–10766CrossRefGoogle Scholar
  34. Qi SN, Jing YX, Dong GX, Chen Y, Yoshida A, Ueda T (2007) GP7 induces internucleosomal DNA fragmentation independent of caspase activation and DNA fragmentation factor in NB4 cells. Oncol Rep 18:273–277PubMedGoogle Scholar
  35. Reddy DM, Srinivas J, Chashoo G, Saxena AK, Sampath-Kumar HM (2011) 4β-[(4-Alkyl)-1,2,3-triazol- 1-yl] podophyllotoxins as anticancer compounds: design, synthesis and biological evaluation. Eur J Med Chem 46:1983–1991CrossRefGoogle Scholar
  36. Ren J, Wu L, Xin WQ, Chen X, Hu K (2012) Synthesis and biological evaluation of novel 4β-(1,3,4- oxadiazole-2-amino)-podophyllotoxin derivatives. Bioorg Med Chem Lett 22:4778–4782CrossRefGoogle Scholar
  37. 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
  38. Thurston LS, Imakura Y, Haruna M, Li DH, Liu ZC, Liu SY, Cheng YC, Lee KH (1989) Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and alpha-peltatin. J Med Chem 32:604–608CrossRefGoogle Scholar
  39. Van-Vilet DS, Tachibana Y, Bastow KF, Huang ES, Lee KH (2001) Antitumor agents. 207.1 design, synthesis, and biological testing of 4β-Anilino-2-fluoro-4′-demethylpodophyllotoxin analogues as cytotoxic and antiviral agents. J Med Chem 44:1422–1428CrossRefGoogle Scholar
  40. Wang H, Tang LJ, Tang YJ, Yuan ZP (2014) SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position. Bioorg Med Chem 22:6183–6192CrossRefGoogle Scholar
  41. Xiao ZY, Xiao YD, Feng J, Golbraikh A, Tropsha A, Lee KH (2002) Antitumor agents. 213. Modeling of epipodophyllotoxin derivatives using variable selection k nearest neighbor QSAR method. J Med Chem 45:2294–2309CrossRefGoogle Scholar
  42. Zhang L, Chen F, Wang J, Chen YZ, Zhang ZQ, Lin Y, Zhu XL (2015) Novel isatin derivatives of podophyllotoxin: synthesis and cytotoxic evaluation against human leukaemia cancer cells as potent anti-MDR agents. RSC Adv 5:97816–97823CrossRefGoogle Scholar
  43. 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
  44. 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
  45. Zhao Y, Hui J, Wang D, Zhu L, Fang JH, Zhao XD (2010) Synthesis, cytotoxicity and pro-apoptosis of novel benzoisoindolin hydrazones as anticancer agents. Chem Pharm Bull 58:1324–1327CrossRefGoogle Scholar
  46. Zhou XM, Wang ZQ, Chang JY, Chen HX, Cheng YC, Lee KH (1991) Antitumor agents. 120. New 4-substituted benzylamine and benzyl ether derivatives of 4′-O-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II. J Med Chem 34:3346–3350CrossRefGoogle Scholar
  47. 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
  48. Zhu XK, Guan J, Xiao ZY, Cosentino LM, Lee KH (2004) Anti-AIDS agents. Part 61: anti-HIV activity of new podophyllotoxin derivatives. Bioorg Med Chem 12:4267–4273CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.School of Public HealthNanchang UniversityNanchangPeople’s Republic of China

Personalised recommendations