Newly Designed and Synthesized Curcumin Analogs with in vitro Cytotoxicity and Tubulin Polymerization Activity

Novel curcumin analogs with 4‐piperidone ring were designed, synthesized, and evaluated for their cytotoxic activities against five different cancer cell lines. 3,5‐bis(4‐Hydroxy‐3‐methoxybenzylidene)‐4‐oxo‐N‐phenylpiperidine‐1‐carbothioamide (XIIe) exhibited considerable cytotoxic activity with IC50 values in 1–2.5 μm range. In silico and in vitro, studies were also performed to predict the binding affinity of the target compounds to the β‐chain of tubulin receptor (PDB code 1SA1) and their abilities to affect microtubules polymerization cycle. 3,5‐bis(3‐Iodo‐5‐methoxy‐4‐propoxybenzylidene)‐N‐acetylpiperidin‐4‐one (VIIa) was found to exert 93.3% inhibition of tubulin and destabilization of microtubules in vitro compared to vincristine while, 3,5‐bis(3,4,5‐trimethoxybenzylidene)‐N‐benzoylpiperidin‐4‐one (XIIc) showed high potency in a different way where it exerted 94.8% stabilization of microtubules in vitro compared to positive control paclitaxel.

[1]  R. Coppel,et al.  Cellular Effects of Curcumin on Plasmodium falciparum Include Disruption of Microtubules , 2013, PloS one.

[2]  A. Singh,et al.  Anti-microbial Activity of Turmeric Natural Dye against Different Bacterial Strains , 2012 .

[3]  P. Chakrabarti,et al.  Curcumin recognizes a unique binding site of tubulin. , 2011, Journal of medicinal chemistry.

[4]  Erik A. A. Wallén,et al.  Inhibitors and promoters of tubulin polymerization: synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents. , 2011, Bioorganic & medicinal chemistry.

[5]  Yan Li,et al.  Herbal Medicine and Hepatocellular Carcinoma: Applications and Challenges , 2011, Evidence-based complementary and alternative medicine : eCAM.

[6]  Wu Mei-hua.  Synthesis and antitumor activity in vitro of curcumin analogs , 2011 .

[7]  W. W. Hsiao,et al.  The Role of Traditional Chinese Herbal Medicines in Cancer Therapy – from TCM Theory to Mechanistic Insights , 2010, Planta medica.

[8]  J. Dimmock,et al.  3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy. , 2010, Bioorganic & medicinal chemistry letters.

[9]  Elin Lindhagen,et al.  The fluorometric microculture cytotoxicity assay , 2008, Nature Protocols.

[10]  E. De Clercq,et al.  Design, synthesis and cytotoxic properties of novel 1-[4-(2-alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones and related compounds. , 2007, European journal of medicinal chemistry.

[11]  V. Menon,et al.  Antioxidant and anti-inflammatory properties of curcumin. , 2007, Advances in experimental medicine and biology.

[12]  N. Kozlov,et al.  Vanillin esters in reactions with indan-1,3-dione , 2006 .

[13]  Ki Young Lee,et al.  Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin. , 2006, Journal of medicinal chemistry.

[14]  A. Chan,et al.  Curcumin Analogs as Potent Aldose Reductase Inhibitors , 2006, Archiv der Pharmazie.

[15]  N. Kozlov,et al.  Vanillal Esters in Reaction with 2-Naphthylamine and 1,3-Diketones , 2005 .

[16]  K. Gusak,et al.  Reactions of Vanillin and Vanillal Esters with 6-Quinolylamine and Phenidone , 2005 .

[17]  K. Youssef,et al.  Synthesis and Antitumor Activity of Some Curcumin Analogs , 2005, Archiv der Pharmazie.

[18]  K. Youssef,et al.  Synthesis of Curcumin Analogues as Potential Antioxidant, Cancer Chemopreventive Agents , 2004, Archiv der Pharmazie.

[19]  V. Potkin,et al.  1-Adamantanecarboxylic Acid Esters of Certain Terpenols, Sterols, and Plant Phenols , 2003, Chemistry of Natural Compounds.

[20]  T. Fukui,et al.  Enhancement of antioxidant activity of p-alkylaminophenols by alkyl chain elongation. , 2003, Bioorganic & medicinal chemistry.

[21]  R. Bloch,et al.  Enantioselective synthesis of the PAF antagonist MK-287 , 2002 .

[22]  K. Misra,et al.  Syntheses of Curcumin Bioconjugates and Study of Their Antibacterial Activities against beta-Lactamase-Producing Microorganisms. , 2001, Bioconjugate chemistry.

[23]  M M Manson,et al.  Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  Paul J Thornalley,et al.  Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro. , 2001, Biochemical pharmacology.

[25]  V. Menon,et al.  Neuroprotective role of curcumin from Curcuma longa on ethanol‐induced brain damage , 1999, Phytotherapy research : PTR.

[26]  Jen-kun Lin,et al.  Curcumin Inhibits SK-Hep-1 Hepatocellular Carcinoma Cell Invasion in vitro and Suppresses Matrix Metalloproteinase-9 Secretion , 1998, Oncology.

[27]  B. Aggarwal,et al.  Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines. , 1997, Anti-Cancer Drugs.

[28]  J. Weinstein,et al.  Inhibition of human immunodeficiency virus type-1 integrase by curcumin. , 1995, Biochemical pharmacology.

[29]  S. Hecht,et al.  Chemoprevention by isothiocyanates , 1995, Journal of cellular biochemistry. Supplement.

[30]  Peter Nygren,et al.  Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia, using a fluorometric microculture cytotoxicity assay (FMCA) , 1992, International journal of cancer.

[31]  R. Kuttan,et al.  Inhibition of chemical carcinogenesis by curcumin. , 1989, Journal of ethnopharmacology.

[32]  Y. Oshima,et al.  Antihepatotoxic Principles of Curcuma longa Rhizomes1 , 1983, Planta medica.

[33]  E. Profft,et al.  Über das Äthylvanillin II. Mitt. , 1964 .

[34]  E. Profft,et al.  [ON ETHYLVANILLIN. I]. , 1964, Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft.