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.
Cite this paper
Shaaban, M. A. , Kamel, M. M. and Milad, Y. R. (2014). Synthesis and Cytotoxicity of Heterocyclic Compounds Derived from Cyclohexane-1,3-Dione. Open Access Library Journal, 1, e1115. doi: http://dx.doi.org/10.4236/oalib.1101115.
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. http://dx.doi.org/10.1016/j.tet.2012.01.075
Antonioletti, R., Bovicelli, P.
and Malancona, S. (2002) A New Route to 2-Alkenyl-1,3-Dicarbonyl
Compounds, Inter- mediates in the Synthesis of Dihydrofurans. Tetrahedron, 58, 589-596. http://dx.doi.org/10.1016/S0040-4020(01)01173-5
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. http://dx.doi.org/10.1016/j.tet.2011.04.092
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. http://dx.doi.org/10.1016/j.jorganchem.2008.12.013
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. http://dx.doi.org/10.1016/j.ejmech.2008.07.004
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. http://dx.doi.org/10.1016/j.tetlet.2010.02.111
Mulongo, G., Mbabazi, J., Odongkara, B., Twinomuhwezi, H. and Mpango, G.B. (2011) New Biologically Active Com- pounds from 1,3-Diketones. Journal of Chemical Sciences, 1, 102-108.
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. http://dx.doi.org/10.1016/0014-5793(93)80013-K
Soeda, T. and Uchida, T. (1987) Inhibition of Pigment Synthesis by
1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxy- pyrazole, Norflurazon, and New Herbicidal
Compounds in Radish and Flatsedge Plants. Pesticide Biochemistry and Physiology, 29, 35-42.
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. http://dx.doi.org/10.1007/s10593-013-1259-4
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.
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. http://dx.doi.org/10.1016/j.steroids.2013.08.007
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. http://dx.doi.org/10.1016/j.bmc.2011.11.039
Zhang, Z.H., Zhang, P., Yang, S.H., Wang, H.J. and Deng, J. (2010) β-Cyclodextrin Mediated Synthesis of 1,8-Diox- ooctahydroxanthenes
in Water. Journal of Chemical Sciences, 122, 427-432. http://dx.doi.org/10.1007/s12039-010-0049-0
Lock, E.A., Gaskin, P., Ellis, M., Provan, W.M. and Smith, L.L. (2006) Tyrosinemia Produced
by 2-(2-nitro-4-triflu- oromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) in
Experimental Animals and Its Relationship to Corneal Injury. Toxicology and
Applied Pharmacology, 215, 9-16. http://dx.doi.org/10.1016/j.taap.2006.01.015
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. Bioorga- nic & Medicinal Chemistry Letters, 15, 1023-1025. http://dx.doi.org/10.1016/j.bmcl.2004.12.039
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. http://dx.doi.org/10.1186/1472-6750-2-17
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.