SYNTHESIS, PHYSICOCHEMICAL AND SPECTROPHOTOMETRIC ANALYSIS OF CURCUMIN ANALOGS WITH CYCLOHEXANONE CORE
Keywords:
synthesis, analogs of curcumin, cyclohexanone core, conjugated carbonyl groupAbstract
Due to the presence of specific functional groups in its structure, curcumin has demonstrated a wide range of therapeutic properties for which it has garnered significant interest over the past twenty years. Despite this, curcumin's low chemical stability owing to keto-enol tautomerism and poor water solubility results in low bioavailability, limit its use in therapy. In this study were synthetized seven curcumin analogs with cyclohexanone core: Ia, Ib, Ic, IF5NO2, Id, Ie and If. Analogs were prepared by Claisen-Schmidt condensation reaction between corresponding benzaldehyde and arylaldehyde. Several spectroscopic techniques were used to confirm the structure of the obtained analogs. The effective synthesis and the presence of a conjugated dienone system can be inferred from the infrared spectra. The analogs color, which range from light yellow to orange and their UV-Vis spectra, which have λmax values above 300 nm, further substantiate the extended conjugation indicating that there are several double bonds adjacent, and their bonding orbitals can interact and form one huge delocalized system. From the infrared spectra it can be seen that analogs exhibited an absorption band below 1700 cm–1, which is likewise consistent with the literature and suggests the existence of a conjugated carbonyl group. As part of this paper, chromatographic methods (HPLC-DAD-MS) were applied to determine the purity of the synthesized curcumin analogues with cyclohexanone core. These analogues can further be tested and analyzed in terms of their cytotoxicity or therapeutic potency.
References
Aggarwal, B. B., & Harikumar, K. B. (2009). Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. The international journal of biochemistry & cell biology, 41(1), 40–59. https://doi.org/10.1016/j.biocel.2008.06.010.
Amoozadeh, A., Rahmani, S., Dutkiewicz, G. (2011). Novel Synthesis and Crystal Structures of Two α, α′-bis-Substituted Benzylidene Cyclohexanones: 2,6-Bis-2-nitro(benzylidene)cyclohexanone and 2,6-Bis-4-methyl(benzylidene)cyclohexanone. Journal of Chemical Crystallography, 41,(2), 1305–1309. https://doi.org/10.1007/s10870-011-0094-7.
Anand, P., Kunnumakkara, A. B., Newman, R. A., & Aggarwal, B. B. (2007). Bioavailability of curcumin: problems and promises. Molecular pharmaceutics, 4(6), 807–818. https://doi.org/10.1021/mp700113r
Baliga, M. S., Joseph, N., Venkataranganna, M. V., Saxena, A., Ponemone, V., & Fayad, R. (2012). Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: preclinical and clinical observations. Food & function, 3(11), 1109–1117. https://doi.org/10.1039/c2fo30097d.
Fomina, M. V., Vatsadze, S. Z., Freidzon, A. Y., Kuz'mina, L. G., Moiseeva, A. A., Starostin, R. O., Nuriev, V. N., & Gromov, S. P. (2022). Structure-Property Relationships of Dibenzylidenecyclohexanones. ACS omega, 7(12), 10087–10099. https://doi.org/10.1021/acsomega.1c06129.
Fuchs, J. R., Pandit, B., Bhasin, D., Etter, J. P., Regan, N., Abdelhamid, D., Li, C., Lin, J., & Li, P. K. (2009). Structure-activity relationship studies of curcumin analogues. Bioorganic & medicinal chemistry letters, 19(7), 2065–2069. https://doi.org/10.1016/j.bmcl.2009.01.104.
Gupta, S. C., Prasad, S., Kim, J. H., Patchva, S., Webb, L. J., Priyadarsini, I. K., & Aggarwal, B. B. (2011). Multitargeting by curcumin as revealed by molecular interaction studies. Natural product reports, 28(12), 1937–1955. https://doi.org/10.1039/c1np00051a.
Jankun, J., Wyganowska-Świątkowska, M., Dettlaff, K., Jelińska, A., Surdacka, A., Wątróbska-Świetlikowska, D., & Skrzypczak-Jankun, E. (2016). Determining whether curcumin degradation/condensation is actually bioactivation (Review). International Journal of Molecular Medicine, 37, 1151-1158. https://doi.org/10.3892/ijmm.2016.2524.
Kannappan, R., Gupta, S. C., Kim, J. H., Reuter, S., & Aggarwal, B. B. (2011). Neuroprotection by spice-derived nutraceuticals: you are what you eat!. Molecular neurobiology, 44(2), 142–159. https://doi.org/10.1007/s12035-011-8168-2.
Kar, S.; Ramamoorthy, G.; Sinha, S.; Ramanan, M.; Pola, J.K.; Golakoti, N.R.; Nanubolu, J.B.; Sahoo, S.K.; Dandamudi, R.B.; Doble, M. (2019). Synthesis of Diarylidenecyclohexanone Derivatives as Potential Anti-Inflammatory Leads against COX-2/MPGES1 and 5-LOX. New Journal of Chemistry, 43, 9012–9020. https://doi.org/10.1039/C9NJ00726A.
Liang, G., Shao, L., Wang, Y., Zhao, C., Chu, Y., Xiao, J., Zhao, Y., Li, X., & Yang, S. (2009). Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents. Bioorganic & medicinal chemistry, 17(6), 2623–2631. https://doi.org/10.1016/j.bmc.2008.10.044.
Liu, Guo-Yun, Cong-Cong Jia, Pu-Ren Han, and Jie Yang. (2018). 3,5-Bis(2-Fluorobenzylidene)-4-Piperidone Induce Reactive Oxygen Species-Mediated Apoptosis in A549 Cells. Medicinal Chemistry Research: An International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents 27(1): 128–36. https://doi.org/10.1007/s00044-017-2056-x.
Lozanovski, Z., Petreska Stanoeva, J., & Bogdanov, J. (2023). Development of a spectrophotometric method for assessment of the relative reactivity of monocarbonyl analogs of curcumin with 2-(dimethylamino)ethanethiol. Macedonian Journal of Chemistry and Chemical Engineering, 42(1), 13–24. https://doi.org/10.20450/mjcce.2023.2638.
Prasad, S., Gupta, S. C., Tyagi, A. K., & Aggarwal, B. B. (2014). Curcumin, a component of golden spice: from bedside to bench and back. Biotechnology advances, 32(6), 1053–1064. https://doi.org/10.1016/j.biotechadv.2014.04.004.
Priyadarsini K. I. (2013). Chemical and structural features influencing the biological activity of curcumin. Current pharmaceutical design, 19(11), 2093–2100. https://doi.org/10.2174/138161213805289228.
Qian, Y., Zhong, P., Liang, D., Xu, Z., Skibba, M., Zeng, C., Li, X., Wei, T., Wu, L., & Liang, G. (2015). A newly designed curcumin analog Y20 mitigates cardiac injury via anti-inflammatory and anti-oxidant actions in obese rats. PloS one, 10(3), e0120215. https://doi.org/10.1371/journal.pone.0120215.
Robinson, Thomas Philip, Richard B. Hubbard 4th, Tedman J. Ehlers, Jack L. Arbiser, David J. Goldsmith, and J. Phillip Bowen. (2005). Synthesis and Biological Evaluation of Aromatic Enones Related to Curcumin. Bioorganic & Medicinal Chemistry 13(12): 4007–13. https://doi.org/10.1016/j.bmc.2005.03.054.
Shehzad, A., and Y. S. Lee. (2010). Curcumin: Multiple Molecular Targets Mediate Multiple Pharmacological Actions: A Review. Drugs of the Future 35(2): 113. DOI:10.1358/dof.2010.035.02.1426640.
Tomren, M. A., Másson, M., Loftsson, T., & Tønnesen, H. H. (2007). Studies on curcumin and curcuminoids XXXI. Symmetric and asymmetric curcuminoids: stability, activity and complexation with cyclodextrin. International journal of pharmaceutics, 338(1-2), 27–34. https://doi.org/10.1016/j.ijpharm.2007.01.013.
