Synthesis and Cytotoxicity of Heterocyclic Compounds Derived from Cyclohexane-1,3-Dione

DOI: 10.4236/oalib.1101115   PDF        1,671 Downloads   2,138 Views   Citations


Cyclohexane-1,3-dione (1) was used as a template to develop new anticancer compounds. The ring modification of compound 1occurred through its reaction with either aromaticaldehydes or benzenediazonium chloride to produce the corresponding products. The latter compounds underwenttheterocyclization reactions through the reaction with elemental sulfur and some active methylene reagents to produce tetrahydrobenzo[b]thiophene derivatives. The reaction of compound 1 with elemental sulfur and phenylisothiocyanategave the tetrahydrobenzo[d]thiazole derivative. The cytotoxicity of the newly synthesized products against human cancer and normal cell lines was evaluated. Some compounds showed high cytotoxicity against cancer cell lines. The results showed that compounds 3b, 5c, 7b, 10b, 12, 14b, 16, 18b, 19b, 20b, 21 and 24 showed the highest cytotoxicity. Moreover, the toxicity of twelve active compounds were measured.

Share and Cite:

Shaaban, M. , Kamel, M. and Milad, Y. (2014) Synthesis and Cytotoxicity of Heterocyclic Compounds Derived from Cyclohexane-1,3-Dione. Open Access Library Journal, 1, 1-16. doi: 10.4236/oalib.1101115.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Sevenard, D.V., Vorobyev, M., Sosnovskikh, V.Y., Wessel, H., Kazakova, O., Vogel, V., Shevchenko, N.E., Nenajdenko, V.G., Lork, E. and Röschenthaler, G.V. (2009) Halogenation of Fluorinated Cyclic 1,3-Dicarbonyl Compounds: New Aspects of Synthesis Application. Tetrahedron, 65, 7538-7552.
[2] Ohtsuka, Y., Uraguchi, D., Yamamoto, K., Tokuhisa, K. and Yamakawa, T. (2012) Synthesis of 2-(Trifluouromethyl)-1,3-Dicarbonyl Compounds through Direct Trifluoromethylation with CF3I and Their Application to Fluorinated Pyrazoles Syntheses. Tetrahedron, 68, 2636-2649.
[3] Antonioletti, R., Bovicelli, P. and Malancona, S. (2002) A New Route to 2-Alkenyl-1,3-Dicarbonyl Compounds, Intermediates in the Synthesis of Dihydrofurans. Tetrahedron, 58, 589-596.
[4] Chatterjee, P.N. and Roy, S. (2011) Alkylation of 1,3-Dicarbonyl Compounds with Benzylic and Propargylic Alcohols Using Irbimetallic Catalyst: Synthesis of Fully Decorated Furans and Pyrroles. Tetrahedron, 67, 4569-4577.
[5] Narayanaperumal, S., Silva, R.C., Feu, K.S., Torre, A.F., Corrêa, A.G. and Paixão, M.W. (2013) Basic-Functionalized Recyclable Ionic Liquid Catalyst: A Solvent-Free Approach for Michael Addition of 1,3-Dicarbonyl Compounds Tonitroalkenes under Ultrasound Irradiation. Ultrasonics Sonochemistry, 20, 793-798.
[6] Arcadi, A., Alfonsi, M., Chiarini, M. and Marinelli, F. (2009) Sequential Gold-Catalyzed Reactions of 1-Phenylprop-2-yn-1-ol with 1,3-Dicarbonyl Compounds. Journal of Organometallic Chemistry, 694, 576-582.
[7] Nadaraj, V., Thamarai Selvi, S.T. and Mohan, S. (2009) Microwave-Induced Synthesis and Anti-Microbial Activities of 7,10,11,12-Tetrahydrobenzo[c]acridin-8(9H)-One Derivatives. European Journal of Medicinal Chemistry, 44, 976-980.
[8] Goncalves, S., Nicolas, M., Wagner, A. and Baati, R. (2010) Exploring the One-Pot C-Acylation of Cyclic 1,3-Diones with Unactivated Carboxylic Acid. Tetrahedron Letters, 51, 2348-2350.
[9] Mulongo, G., Mbabazi, J., Odongkara, B., Twinomuhwezi, H. and Mpango, G.B. (2011) New Biologically Active Compounds from 1,3-Diketones. Journal of Chemical Sciences, 1, 102-108.
[10] Schulz, A., Ort, O., Beyer, P. and Kleinig, H. (1993) SC-0051, a 2-Benzoyl-Cyclohexane-1,3-Dione Bleaching Herbicide, Is a Potent Inhibitor of the Enzyme p-Hydroxyphenylpyruvate Dioxygenase. FEBS Letters, 318, 162-166.
[11] Soeda, T. and Uchida, T. (1987) Inhibition of Pigment Synthesis by 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole, Norflurazon, and New Herbicidal Compounds in Radish and Flatsedge Plants. Pesticide Biochemistry and Physiology, 29, 35-42.
[12] Kamel, M.M., El-Ansary, A.K. and Milad, Y.R. (2013) Design, Synthesis and Cytotoxicity of Pyridine, Pyrazole and Thiazole Derivatives Derived from N-alkyl-4,5,6,7-tetrahydro-1-benzothiophene. Chemistry of Heterocyclic Compounds, 49, 392-403.
[13] Mohareb, R.M. and Al-Omran, F. (2012) Reaction of Pregnenolone with Cyanoacetyl-Hydrazine: Novel Synthesis of Hydrazide-Hydrazone, Pyrazole, Pyridine, Thiazole, Thiophene Derivatives and Their Cytotoxicity Evaluations. Steroids, 77, 1551-1559.
[14] Mohareb, R.M., El-Sayed, N.E. and Abdelaziz, M.A. (2013) The Knoevenagel Reactions of Pregnenolone with Cyanomethylene Reagents: Synthesis of Thiophene, thieno[2,3-b]pyridine, thieno[3,2-d]isoxazole Derivatives of Pregnenolone and Their in Vitro Cytotoxicity towards Tumor and Normal Cell Lines. Steroids, 78, 1209-1219.
[15] Zhang, W., Benmohamed, R., Arvanites, A.C., Morimoto, R.I., Ferrante, R.J., Kirsch, D.R. and Silverman, R.B. (2012) Cyclohexane 1,3-diones and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation and Toxicity in PC12 Cells. Bioorganic & Medicinal Chemistry, 20, 1029-1045.
[16] Zhang, Z.H., Zhang, P., Yang, S.H., Wang, H.J. and Deng, J. (2010) β-Cyclodextrin Mediated Synthesis of 1,8-Dioxooctahydroxanthenes in Water. Journal of Chemical Sciences, 122, 427-432.
[17] Lock, E.A., Gaskin, P., Ellis, M., Provan, W.M. and Smith, L.L. (2006) Tyrosinemia Produced by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) in Experimental Animals and Its Relationship to Corneal Injury. Toxicology and Applied Pharmacology, 215, 9-16.
[18] Tehranchian, S., Akbarzadeh, T., Fazeli, M.R., Jamalifar, H. and Shafiee, A. (2005) Synthesis and Antibacterial Activity of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones. Bioorganic & Medicinal Chemistry Letters, 15, 1023-1025.
[19] Atta-ur-Rahman, Choudhary, M.I. and Thomsen, W.J. (2001) Bioassay Techniques for Drug Development. Harwood Academic Publishers, Newark, 9-10.
[20] Ballantyne, B., Marrs, T.C. and Syversen, T. (2009) General and Applied Toxicology. 2nd Edition, Vol. 1, 52 p.
[21] Carballo, J.L., Inda, Z.L.H., Pérez, P. and Grávalos, M.D.G. (2002) A Comparison between Two Brine Shrimp Assays to Detect in Vitro Cytotoxicity in Marine Natural Products. BMC Biotechnology, 2, 17.
[22] Calleja, M.C. and Persoone, G. (1992) The Potential of Ecotoxicological Tests for the Prediction of Acute Toxicityin Man as Evaluated on the 1st 10 Chemicals on the Meic Program. ATLA-Alternatives to Laboratory Animals, 20, 396-405.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.