Novel Curcumin Inspired Antineoplastic 1-Sulfonyl-4-Piperidones: Design, Synthesis and Molecular Modeling Studies

Author(s): Nehmedo G. Fawzy, Siva S. Panda, Walid Fayad, May A. El-Manawaty, Aladdin M. Srour, Adel S. Girgis*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 8 , 2019

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Abstract:

Background: Curcumin is a well-known example of plant origin exhibiting promising diverse biological properties such as, anti-inflammatory and antitumor as well as poor pharmacokinetic/pharmacodynamic properties. This is why effective agents based on its chemical scaffold were explored.

Methods: A set of 3,5-bis(ylidene)-1-(alkylsulfonyl)piperidin-4-ones were synthesized in excellent yield (80- 96%) through dehydrohalogenation reaction of 3,5-bis(ylidene)-4-piperidinones with the corresponding alkane sulfonyl chloride in the presence of triethylamine. Antiproliferative properties of the synthesized compounds (dienone/curcumin inspired analogues) were studied by the standard MTT technique.

Results: Most of the synthesized compounds revealed antiproliferative properties against HCT116 (colon) and A431 (skin/squamous) cancer cell lines with IC50 values at sub-micromolar level. Compound 36 also exhibited potency against MCF7 (breast) and A549 (lung) cancer cell lines (IC50 = 2.23, 4.27µM, respectively) higher than that of the reference standards (IC50 = 3.15, 5.93µM for 5-fluorouracil and doxorubicin against MCF7 and A549 cell lines, respectively). Cytotoxic properties of the synthesized compounds against non-cancer RPE1 cell line supported the safety profile of the effective agents against normal cells. Molecular modeling (3Dpharmacophore and 2D-QSAR) studies validated the observed bio-properties and explained the parameters governing activity. Inhibitory properties of compounds 27 and 29 (representative examples of the promising antiproliferative agents synthesized) supported their mode of action against topoisomerase IIα.

Conclusion: The synthesized scaffold is a promising antitumor agent (with special selectivity against colon and skin/squamous cancer cell lines) so, it can be considered for further investigation and development of highly effective hits/leads based on the computational models obtained.

Keywords: Piperidone, sulfonyl, antitumor, molecular modeling, computational models, 3D-pharmacophore, 2D-QSAR.

[1]
Hermawana, A.; Putri, H. Current report of natural product development against breast cancer stem cells. Int. J. Biochem. Cell Biol., 2018, 104, 114-132.
[2]
Guo, Z. The modification of natural products for medical use. Acta Pharm. Sin. B, 2017, 7, 119-136.
[3]
Ferrari, E.; Pignedoli, F.; Imbriano, C.; Marverti, G.; Basile, V.; Venturi, E.; Saladini, M. Newly synthesized curcumin derivatives: Crosstalk between chemico-physical properties and biological activity. J. Med. Chem., 2011, 54, 8066-8077.
[4]
Zhang, L.; Zong, H.; Lu, H.; Gong, J.; Fenfen, M. Discovery of novel anti-tumor curcumin analogues from the optimization of curcumin scaffold. Med. Chem. Res., 2017, 26, 2468-2476.
[5]
Nelson, K.M.; Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli, G.F.; Walters, M.A. The essential medicinal chemistry of curcumin. J. Med. Chem., 2017, 60, 1620-1637.
[6]
Okuda, M.; Hijikuro, I.; Fujita, Y.; Teruya, T.; Kawakami, H.; Takahashi, T.; Sugimoto, H. Design and synthesis of curcumin derivatives as Tau and amyloid β dual aggregation inhibitors. Bioorg. Med. Chem. Lett., 2016, 26, 5024-5028.
[7]
Wang, Z.; Zou, P.; Li, C.; He, W.; Xiao, B.; Fang, Q.; Chen, W.; Zheng, S.; Zhao, Y.; Cai, Y.; Liang, G. Synthesis and biological evaluation of novel semiconservative monocarbonyl analogs of curcumin as anti-inflammatory agents. MedChemComm, 2015, 6, 1328-1339.
[8]
Thakur, A.; Manohar, S.; Vélez Gerena, C.E.; Zayas, B.; Kumar, V.; Malhotra, S.V.; Rawat, D.S. Novel 3,5-bis(arylidiene)-4-piperidone based monocarbonyl analogs of curcumin: anticancer activity evaluation and mode of action study. MedChemComm, 2014, 5, 576-586.
[9]
Schmitt, F.; Gold, M.; Begemann, G.; Andronache, I.; Biersack, B.; Schobert, R. Fluoro and pentafluorothio analogs of the antitumoral curcuminoid EF24 with superior antiangiogenic and vascular-disruptive effects. Bioorg. Med. Chem., 2017, 25, 4894-4903.
[10]
Addala, E.; Rafiei, H.; Das, S.; Bandy, B.; Das, U.; Karki, S.S.; Dimmock, J.R. 3,5-Bis(3-dimethylaminomethyl-4-hydroxybenzylidene)-4-piperidone and related compounds induce glutathione oxidation and mitochondria-mediated cell death in HCT-116 colon cancer cells. Bioorg. Med. Chem. Lett., 2017, 27, 3669-3673.
[11]
Hossain, M.; Das, U.; Umemura, N.; Sakagami, H.; Balzarini, J.; De Clercq, E.; Kawase, M.; Dimmock, J.R. Tumour-specific cytotoxicity and structure-activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones. Bioorg. Med. Chem., 2016, 24, 2206-2214.
[12]
Potter, E.; Jha, M.; Bhullar, K.S.; Rupasinghe, H.P.V.; Balzarini, J.; Jha, A. Investigation of fatty acid conjugates of 3,5-bisarylmethylene-4-piperidone derivatives as antitumor agents and human topoisomerase-IIα inhibitors. Bioorg. Med. Chem., 2015, 23, 411-421.
[23]
Choudhary, S.; Singh, P.K.; Verma, H.; Singh, H.; Silakari, O. Success stories of natural product-based hybrid molecules for multifactorial diseases. Eur. J. Med. Chem., 2018, 151, 62-97.
[24]
Dimmock, J.R.; Padmanilayam, M.P.; Puthucode, R.N.; Nazarali, A.J.; Motaganahalli, N.L.; Zello, G.A.; Quail, J.W.; Oloo, E.O.; Kraatz, H-B.; Prisciak, J.S.; Allen, T.M.; Santos, C.L.; Balzarini, J.; De Clercq, E.; Manavathu, E.K. A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues. J. Med. Chem., 2001, 44, 586-593.
[25]
Katsori, A-M.; Chatzopoulou, M.; Dimas, K.; Kontogiorgis, C.; Patsilinakos, A.; Trangas, T.; Hadjipavlou-Litina, D. Curcumin analogues as possible anti-proliferative & anti-inflammatory agents. Eur. J. Med. Chem., 2011, 46, 2722-2735.
[26]
Ismail, N.S.M.; George, R.F.; Serya, R.A.T.; Baselious, F.N.; El-Manawaty, M.; Shalaby, E.M.; Girgis, A.S. Rational design, synthesis and 2D-QSAR studies of antiproliferative tropane-based compounds. RSC Advances, 2016, 6, 101911-101923.
[27]
George, R.F.; Panda, S.S.; Shalaby, E.M.; Srour, A.M. Ahmed, Farag, I.S.; Girgis, A.S. Synthesis and molecular modeling studies of indole-based antitumor agents. RSC Advances, 2016, 6, 45434-45451.
[28]
Girgis, A.S.; Panda, S.S.; Aziz, M.N.; Steel, P.J.; Hall, C.D.; Katritzky, A.R. Rational design, synthesis, and 2D-QSAR study of anti-oncological alkaloids against hepatoma and cervical carcinoma. RSC Advances, 2015, 5, 28554-28569.
[31]
Srour, A.M.; Panda, S.S.; Salman, A.M.M.; El-Manawaty, M.A.; George, R.F.; Shalaby, E.M.; Fitch, A.N.; Fawzy, N.G.; Girgis, A.S. Synthesis & molecular modeling studies of bronchodilatory active indole-pyridine conjugates. Future Med. Chem., 2018, 10, 1787-1804.
[32]
Soliman, E.A.; Panda, S.S.; Aziz, M.N.; Shalaby, E.M.; Mishriky, N.; Asaad, F.M.; Girgis, A.S. Synthesis, molecular modeling studies and bronchodilation properties of nicotinonitrile containing-compounds. Eur. J. Med. Chem., 2017, 138, 920-931.
[33]
Faidallah, H.M.; Girgis, A.S.; Tiwari, A.D.; Honkanadavar, H.H.; Thomas, S.J.; Samir, A.; Kalmouch, A.; Alamry, K.A.; Khan, K.A.; Ibrahim, T.S.; Al-Mahmoudy, A.M.M.; Asiri, A.M.; Panda, S.S. Synthesis, antibacterial properties and 2D-QSAR studies of quinolone-triazole conjugates. Eur. J. Med. Chem., 2018, 143, 1524-1534.
[34]
Yamashita, M.; Tahara, T.; Hayakawa, S.; Matsumoto, H.; Wada, S-I.; Tomioka, K.; Iida, A. Synthesis and biological evaluation of histone deacetylase and DNA topoisomerase II-Targeted inhibitors. Bioorg. Med. Chem., 2018, 26, 1920-1928.
[35]
Matsumoto, H.; Yamashita, M.; Tahara, T.; Hayakawa, S.; Wada, S-I.; Tomioka, K.; Iida, A. Design, synthesis, and evaluation of DNA topoisomerase II-targeted nucleosides. Bioorg. Med. Chem., 2017, 25, 4133-4144.
[36]
Li, D.; Yuan, Z.; Chen, S.; Zhang, C.; Song, L.; Gao, C.; Chen, Y.; Tan, C.; Jiang, Y. Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors. Bioorg. Med. Chem., 2017, 25, 3437-3446.
[37]
Jha, A.; Duffield, K.M.; Ness, M.R.; Ravoori, S.; Andrews, G.; Bhullar, K.S.; Vasantha Rupasinghe, H.P.; Balzarini, J. Curcumin-inspired cytotoxic 3,5-bis(arylmethylene)-1-(N-(orthosubstituted aryl)maleamoyl)-4-piperidones: A novel group of topoisomerase II alpha inhibitors. Bioorg. Med. Chem., 2015, 23, 6404-6417.


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Article Details

VOLUME: 19
ISSUE: 8
Year: 2019
Page: [1069 - 1078]
Pages: 10
DOI: 10.2174/1871520619666190408131639
Price: $58

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