Medicinal Chemistry Research

, Volume 22, Issue 11, pp 5588–5597 | Cite as

Synthesis, cytotoxicity, and structure–activity insight of NH- and N-methyl-3,5-bis-(arylidenyl)-4-piperidones

  • Matthew Gregory
  • Armaan Dandavati
  • Megan Lee
  • Samuel Tzou
  • Mia Savagian
  • Kimberly A. Brien
  • Vijay Satam
  • Pravin Patil
  • Moses Lee
Original Research

Abstract

Twenty-one NH- and N-methyl-3,5-bis-(arylidenyl)-4-piperidone analogs of curcumin, 12 of which are novel, were synthesized and evaluated for their cytotoxicity against B16 (murine melanoma) and L1210 (murine lymphoma) cells grown in culture. These curcumin analogs are related to a known anticancer STAT3 inhibitor 3,5-bis-(4-fluorobenzyl)-4-piperidone (3). The compounds showed remarkable cytotoxicity, especially against B16 cells. The dimethoxy substituted analogs 4e and 4f and dihydroxy analog 4i emerged as the most active compounds with IC50 values in the range of 0.2–2.3 μM. 4e, f, and i were about 10-times more cytotoxic against both cell lines than 3. Analysis of the results demonstrates that the position of the hydroxyl group is crucial for cytotoxicity. Amino-containing analogs are generally less active than their halogenated and oxygen-containing analogs, and N-substitution in the 4-piperidone moiety adds value to the cytotoxicity of the compounds.

Keywords

Curcuminoids 4-Piperidones Cytotoxicity STAT3 Cancer B16 L1210 

References

  1. Abaee MS, Mojtahedi MM, Sharifi R, Zahedi MM (2007) A highly efficient method for solvent free synthesis of bis(arylmethylidene)piperidinones. J Heterocycl Chem 44:1497–1499CrossRefGoogle Scholar
  2. Adams BK, Ferstl EM, Davis MC, Herold M, Kurtkaya S, Camalier RF, Hollingshead MG, Kaur G, Sausville EA, Rickles FR, Snyder JP, Liotta DC, Shojia M (2004) Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. Bioorg Med Chem 12:3871–3883CrossRefPubMedGoogle Scholar
  3. Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421CrossRefPubMedGoogle Scholar
  4. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818CrossRefPubMedGoogle Scholar
  5. Bazzaro M, Anchoori RK, Mudiam MKR, Issaenko O, Kumar S, Karanam B, Lin Z-H, Isaksson Vogel R, Gavioli R, Destro F, Ferretti V, Roden RBS, Khan SR (2011) α,β-Unsaturated carbonyl system of chalcone-based derivatives is responsible for broad inhibition of proteasomal activity and preferential killing of human papilloma virus (HPV) positive cervical cancer cells. J Med Chem 54:449–456PubMedCentralCrossRefPubMedGoogle Scholar
  6. Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S (2009) Curcumin disrupts the mammalian target of rapamycin-raptor complex. Cancer Res 69:1000–1008PubMedCentralCrossRefPubMedGoogle Scholar
  7. Bello-Reuss E, Lee M (2009) Diferuloylmethane (Curcumin) and synthetic analogs are cytotoxic to ADPKD cyst cells in culture. J Am Soc Nephrol 20:273A–274AGoogle Scholar
  8. Choi H, Chun YS, Kim SW, Kim MS, Park JW (2006) Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Mol Pharmacol 70:1664–1671CrossRefPubMedGoogle Scholar
  9. Das U, Alcorn J, Shrivastav A, Sharma RK, De Clercq E, Balzarini J, Dimmock JR (2007) Design, synthesis and cytotoxic properties of novel 1-[4-(2-alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones and related compounds. Eur J Med Chem 42:71–80CrossRefPubMedGoogle Scholar
  10. Das S, Das U, Selvakumar P, Sharma RK, Balzarini J, De Clercq E, Molnar J, Serly J, Barath Z, Schatte G, Bandy B, Gorecki DK, Dimmock JR (2009) 3,5-Bis(benzylidene)-4-oxo-1-phosphonopiperidines and related diethyl esters: potent cytotoxins with multi-drug-resistance reverting properties. ChemMedChem 4:1831–1840PubMedCentralCrossRefPubMedGoogle Scholar
  11. Davis R, Das U, Mackay H, Brown T, Mooberry S, Dimmock J, Lee M, Pati HN (2008) Syntheses and cytotoxic properties of the curcumin analogs 2,6-bis(benzylidene)-4-phenylcyclohexanones. Arch Pharm Chem Life Sci 341:440–445CrossRefGoogle Scholar
  12. Dimmock JR, Padmanilayam MP, Puthucode RN, Nazarali AJ, Motaganahalli NL, Zello GA, Quail JW, Oloo EO, Kraatz H-B, Prisciak JS, Allen TM, Santos CL, Balzarini J, De Clercq E, Manavathu EK (2001) A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues. J Med Chem 44:586–593CrossRefPubMedGoogle Scholar
  13. Glienke W, Maute L, Wicht J, Bergmann L (2010) Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of survivin/BIRC5 gene expression. Cancer Invest 2:166–171Google Scholar
  14. Gupta KK, Bharne SS, Rathinasamy K, Naik NR, Panda D (2006) Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding. FEBS J 273:5320–5332CrossRefPubMedGoogle Scholar
  15. Kálai T, Kuppusamy ML, Balog M, Selvendiran K, Rivera BK, Kuppusamy P, Hideg K (2011) Synthesis of N-substituted 3,5-bis(arylidene)-4-piperidones with high antitumor and antioxidant activity. J Med Chem 54:5414–5421CrossRefPubMedGoogle Scholar
  16. Lagisettya P, Vilekara P, Sahooa K, Anantb S, Awasthi V (2010) CLEFMA—an anti-proliferative curcuminoid from structure activity relationship studies on 3,5-bis(benzylidene)-4-piperidones. Bioorg Med Chem 18:6109–6120CrossRefGoogle Scholar
  17. Makarov MV, Odinets IL, Lyssenko KA, Rybalkina EY, Kosilkin IV, Antipin MY, Timofeeva TV (2008) N-Alkylated 3,5-bis(arylidene)-4-piperidones. Synthetic approaches, X-ray structure and anticancer activity. J Heterocycl Chem 45:729–736CrossRefGoogle Scholar
  18. Makarov MV, Rybalkina EY, Roschenthaler G-V, Short KW, Timofeeva TV, Odinets IL (2009) Design, cytotoxic and fluorescent properties of novel N-phosphorylalkyl substituted E,E-3,5-bis(arylidene)piperid-4-ones. Eur J Med Chem 44:2135–2144CrossRefPubMedGoogle Scholar
  19. Makarov MV, Leonova ES, Rybalkina EY, Khrustalev VN, Shepel NE, Röschenthaler GV, Timofeeva TV, Odinets IL (2012) Methylenebisphosphonates with dienone pharmacophore: synthesis, structure, antitumor and fluorescent properties. Arch Pharm Chem Life Sci 345:349–359CrossRefGoogle Scholar
  20. Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang P, Khan SR (2006) Anticancer activities of novel chalcone and bis-chalcone derivatives. Bioorg Med Chem 14:3491–3495CrossRefPubMedGoogle Scholar
  21. Odinets IL, Makarov MV, Artyushin OI, Rybalkina EY, Lyssenko KA, Timofeeva TV, Antipin MY (2008) Phosphoryl substituted 3,5-bis(arylidene)-4-piperidones possessing high antitumor activity. Phosphorus Sulfur Silicon Relat Elem 183:619–620CrossRefGoogle Scholar
  22. Pati HN, Das U, Quail JW, Kawase M, Sakagami H, Dimmock JR (2008) Cytotoxic 3,5-bis(benzylidene)piperidin-4-ones and N-acyl analogs displaying selective toxicity for malignant cells. Eur J Med Chem 43:1–7PubMedCentralCrossRefPubMedGoogle Scholar
  23. Ravindran J, Prasad S, Aggarwal BB (2009) Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J 11:495–510PubMedCentralCrossRefPubMedGoogle Scholar
  24. Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, Pan J, Pei D, Ding K (2010) Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Med Chem Lett 1:454–459PubMedCentralCrossRefPubMedGoogle Scholar
  25. Selvendiran K, Tong L, Bratasz A, Kuppusamy ML, Ahmed S, Ravi Y, Trigg NJ, Rivera BK, Kálai T, Hideg K, Kuppusamy P (2010) Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts. Mol Cancer Ther 9:1169–1179PubMedCentralCrossRefPubMedGoogle Scholar
  26. Senft C, Polacin M, Priester M, Seifert V, Kögel D, Weissenberger J (2010) The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas. BMC Cancer 10:491–498PubMedCentralCrossRefPubMedGoogle Scholar
  27. Shukla PK, Khanna VK, Ali MM, Khan MY, Srimal RC (2008) Anti-ischemic effect of curcumin in rat brain. Neurochem Res 33:1036–1043CrossRefPubMedGoogle Scholar
  28. Stix G (2007) Spice healer. Sci Am 296:54–57CrossRefPubMedGoogle Scholar
  29. Ströfer M, Jelkmann W, Depping R (2011) Curcumin decreases survival of Hep3B liver and MCF-7 breast cancer cells: the role of HIF. Strahlenther Onkol 187:393–400CrossRefPubMedGoogle Scholar
  30. Tierney BJ, McCann GA, Cohn DE, Eisenhauer E, Sudhakar M, Kuppusamy P, Hideg K, Selvendiran K (2012) HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells. Cancer Biol Ther 13:766–775CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Matthew Gregory
    • 1
  • Armaan Dandavati
    • 1
  • Megan Lee
    • 1
  • Samuel Tzou
    • 1
  • Mia Savagian
    • 1
  • Kimberly A. Brien
    • 1
  • Vijay Satam
    • 1
  • Pravin Patil
    • 1
  • Moses Lee
    • 1
  1. 1.Division of Natural and Applied Sciences, Department of ChemistryHope CollegeHollandUSA

Personalised recommendations