Design, Synthesis, and Biological Evaluation of Curcumin--sitosterol Conjugate a Potential Candidate for Breast Cancer Therapy

Year 2022, , 866 - 880, 31.12.2022

Sevinç İlkar Erdağı

https://doi.org/10.35193/bseufbd.1097088

Abstract

In this study, a novel steroidal conjugate was prepared via a convenient click chemistry technique. -sitosterol (BS), a widely distributed phytosterol throughout the plant kingdom, was chosen as a steroidal component. It is known that BS uses in the stabilization of cell membranes and has beneficial effects in different diseases. On the other hand, curcumin (CUR), a phenolic compound, was used as a phytochemical agent with a variety of biological activities. The steroidal conjugate (BS-CUR) was achieved in high yield using azide-alkyne cyclization reaction. The structure of BS-CUR was elucidated by using FTIR, NMR, HRMS, and fluorescence spectroscopy techniques. In vitro cytotoxicity assays of the BS-CUR conjugate were evaluated against human breast cancer (MDA-MB-231) and healthy mouse fibroblast cell line (L929), respectively. The preliminary evaluation indicated that BS conjugate exhibited good cytotoxicity compare with the native compounds, CUR and BS. The BS-CUR conjugate could be considered a potential compound for further design and synthesis of highly effective anticancer agents.

Keywords

Curcumin, Cytotoxicity, Steroidal conjugate, -Sitosterol

Thanks

The author would like to thank Prof. Dr. Ufuk YILDIZ (Kocaeli University, Chemistry Department) for his suggestions and for allowing the use of facilities at the Chemistry Research Laboratory to be used in this study.

Meme Kanseri Tedavisi için Potansiyel Bir Aday Olan Kurkumin--Sitosterol Konjugatının Tasarımı, Sentezi ve Biyolojik Değerlendirmesi

Abstract

Bu çalışmada, klik kimyası tekniği ile yeni bir steroidal konjugat hazırlandı. Bitki dünyasında yaygın olarak kullanılan bir fitosterol olan -sitosterol (BS) steroidal bir bileşen olarak seçildi. BS'nin hücre zarlarının stabilizasyonunda kullanıldığı ve farklı hastalıklarda faydalı etkileri olduğu bilinmektedir. Fenolik bir bileşik olan kurkumin (CUR) ise çeşitli biyolojik aktivitelere sahip bir fitokimyasal ajan olarak kullanıldı. Steroidal konjugat (BS-CUR), azid-alkin halkalaşma reaksiyonu kullanılarak yüksek verimle elde edildi. BS-CUR'nin yapısı FTIR, NMR, HRMS ve floresans spektroskopi teknikleri kullanılarak aydınlatıldı. BS-CUR konjugatının anti-kanser ve biyouyumluluk analizleri, sırasıyla insan meme kanseri (MDA-MB-231) ve sağlıklı fare fibroblast (L929) hücre hatlarına karşı değerlendirildi. Ön değerlendirme, BS konjugatının, doğal bileşikler CUR ve BS ile karşılaştırıldığında iyi sitotoksisite sergilediğini gösterdi. BS konjugat, yüksek potansiyele sahip anti-kanser ajanlarının daha ileri tasarımı ve sentezi için umut verici bir ajan olarak düşünülebilir.

Keywords

Kurkumin, Steroid, Steroidal Konjugat, -Sitosterol

References

• Singla, P., Salunke, D. B. (2020). Recent advances in steroid amino acid conjugates: Old scaffolds with new dimensions. European Journal of Medicinal Chemistry, 187, 111909.
• Ke, S., Zhang, Z., Liu, M., Fang, W., Huang, D., Wan, Z., Zhou, R., Wang, K., Shi, L. (2019). Synthesis and bioevaluation of novel steroidal isatin conjugates derived from epiandrosterone/androsterone. Journal of Enzyme Inhibition and Medicinal Chemistry. 34(1), 1607-1614.
• Awad, A., Chinnam, M., Fink, C., Bradford, P. (2007). β-Sitosterol activates Fas signaling in human breast cancer cells. Phytomedicine, 14(11), 747-754.
• Rashed, K. (2020). Beta-Sitosterol Medicinal Properties: A Review Article. International Journal of Science Inventions Today, 9(4), 208-212.
• Lin, Y. T., Wu, S. S., Wu, H. L. (2007). Highly sensitive analysis of cholesterol and sitosterol in foods and human biosamples by liquid chromatography with fluorescence detection. Journal of Chromatography A, 1156(1-2), 280-287.
• Yuan, J. W., Qu, L. B. (2017). Efficient synthesis of novel β-sitosterol scaffolds containing 1, 2, 3-triazole via copper (I)-catalyzed click reaction under microwave irradiation. Zeitschrift für Naturforschung B, 72(10) 717-724.
• Paniagua Pérez, R., Madrigal Bujaidar, E., Reyes Cadena, S., Molina Jasso, D., Gallaga, J.P., Silva Miranda, A., Velazco, O., Hernández, N., Chamorro, G. (2005). Genotoxic and cytotoxic studies of beta-sitosterol and pteropodine in mouse. Journal of Biomedicine and Biotechnology, 3, 242-247.
• Li, R., Jia, C. S., Yue, L., Zhang, X. M., Xia, Q. Y., Zhao, S. L., Feng, B., Zhong, F., Chen, W. J. (2010). Lipase-catalyzed synthesis of conjugated linoleyl β-sitosterol and its cholesterol-lowering properties in mice. Journal of Agricultural and Food Chemistry, 58(3), 1898-1902.
• Bin Sayeed, M. S., Ameen, S. S. (2015). Beta-sitosterol: a promising but orphan nutraceutical to fight against cancer. Nutrition and Cancer, 67(8), 1216-1222.
• Zolottsev, V. A., Latysheva, A. S., Pokrovsky, V. S., Khan, I. I., Misharin, A. Y. (2021). Promising applications of steroid сonjugates for cancer research and treatment. European Journal of Medicinal Chemistry, 210, 113089.
• Ulu, A., Ates, B. (2017). Immobilization of L-asparaginase on carrier materials: a comprehensive review. Bioconjugate Chemistry, 28(6), 1598-1610.
• Lesma, G., Luraghi, A., Bavaro, T., Bortolozzi, R., Rainoldi, G., Roda, G., Viola, G., Ubiali, D., Silvani, A. (2018). Phytosterol and γ-oryzanol conjugates: synthesis and evaluation of their antioxidant, antiproliferative, and anticholesterol activities. Journal of Natural Products, 81(10), 2212-2221.
• Ke, S., Shi, L., Yang, Z. (2015). Discovery of novel isatin–dehydroepiandrosterone conjugates as potential anticancer agents. Bioorganic & Medicinal Chemistry Letters, 25(20), 4628-4631.
• Yuyun, Y., Ratnatilaka Na Bhuket, P., Supasena, W., Suwattananuruk, P., Praengam, K., Vajragupta, O., Muangnoi, C., Rojsitthisak, P. (2021). A novel curcumin-mycophenolic acid conjugate inhibited hyperproliferation of tumor necrosis factor-alpha-induced human keratinocyte cells. Pharmaceutics, 13(7), 956.
• El Khoury, E., Abiad, M., Kassaify, Z. G., Patra, D. (2015). Green synthesis of curcumin conjugated nanosilver for the applications in nucleic acid sensing and anti-bacterial activity. Colloids and Surfaces B: Biointerfaces, 127, 274-280.
• Jain, S., Gill, M., Pawar, H., Suresh, S. (2014). Novel curcumin diclofenac conjugate enhanced curcumin bioavailability and efficacy in streptococcal cell wall-induced arthritis. Indian Journal of Pharmaceutical Sciences, 76(5), 415.
• Ilkar Erdagi, S., Uyanik, C. (2020). Biological evaluation of bioavailable amphiphilic polymeric conjugate based-on natural products: Diosgenin and curcumin. International Journal of Polymeric Materials and Polymeric Biomaterials, 69(2), 73-84.
• Ilkar Erdagi, S., Doganci, E., Uyanik, C., Yilmaz, F. (2016). Heterobifunctional poly (ε-caprolactone): Synthesis of α-cholesterol-ω-pyrene PCL via combination of ring-opening polymerization and “click” chemistry. Reactive and Functional Polymers, 99, 49-58.
• Lenhart, J. A., Ling, X., Gandhi, R., Guo, T. L., Gerk, P. M., Brunzell, D. H., Zhang, S. (2010). “Clicked” bivalent ligands containing curcumin and cholesterol as multifunctional Aβ oligomerization inhibitors: Design, synthesis, and biological characterization. Journal of Medicinal Chemistry, 53(16), 6198-6209.
• Gogoi, B., Sen Sarma, N. (2015). Curcumin–cysteine and curcumin–tryptophan conjugate as fluorescence turn on sensors for picric acid in aqueous media. ACS Applied Materials & Interfaces, 7(21), 11195-11202.
• Dey, S., Sreenivasan, K. (2014). Conjugation of curcumin onto alginate enhances aqueous solubility and stability of curcumin. Carbohydrate Polymers, 99, 499-507.
• Yang, R., Zhang, S., Kong, D., Gao, X., Zhao, Y., Wang, Z. (2012). Biodegradable polymer-curcumin conjugate micelles enhance the loading and delivery of low-potency curcumin. Pharmaceutical Research, 29(12), 3512-3525.
• Youssef, K. M., El‐Sherbeny, M. A. (2005). Synthesis and antitumor activity of some curcumin analogs. Archiv der Pharmazie: An International Journal Pharmaceutical and Medicinal Chemistry, 338(4), 181-189.
• Saeidnia, S., Manayi, A., Gohari, A. R., Abdollahi, M. (2014). The story of beta-sitosterol-a review. European Journal of Medicinal Plants, 4(5), 590.
• Vo, T. K., Ta, Q. T. H., Chu, Q. T., Nguyen, T. T., Vo, V. G. (2020). Anti-hepatocellular-cancer activity exerted by β-Sitosterol and β-Sitosterol-glucoside from Indigofera zollingeriana Miq. Molecules, 25(13), 3021.
• Trafalis, D., Geromichalou, E., Dalezis, P., Nikoleousakos, N., Sarli, V. (2016). Synthesis and evaluation of new steroidal lactam conjugates with aniline mustards as potential antileukemic therapeutics. Steroids, 115, 1-8.
• Karpagam, S., Mamindla, A., Sali, V. K., Niranjana, R. S., Periasamy, V. S., Alshatwi, A. A., Akbarsha, M. A., Rajendiran, V. (2022). Folic acid-conjugated mixed-ligand copper(II) complexes as promising cytotoxic agents for triple-negative breast cancers: A case study using MDA-MB-231 cell. Inorganica Chimica Acta 531, 120729.
• Ozdemi̇r, F., Sever, A., Kececi̇, Y. O., Incesu, Z. (2021). Resveratrol increases the sensitivity of breast cancer MDAMB-231 cell line to cisplatin by regulating intrinsic apoptosis. Iranian Journal of Basic Medical Sciences, 24(1), 66.
• Michalak, M., Lach, M. S., Antoszczak, M., Huczynski, A., Suchorska, W. M. (2020). Overcoming Resistance to Platinum-Based Drugs in Ovarian Cancer by Salinomycin and Its Derivatives-An In Vitro Study. Molecules, 25(3), 537.
• Haribabu, J., Sabapathi, G., Tamizh, M. M., Balachandran, C., Bhuvanesh, N. S. P., Venuvanalingam, P., Karvembu, R. (2018). Water-Soluble Mono- and Binuclear Ru(η6-p-cymene) Complexes Containing Indole Thiosemicarbazones: Synthesis, DFT Modeling, Biomolecular Interactions, and In Vitro Anticancer Activity through Apoptosis. Organometallics, 37(8), 1242–1257.
• 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.
• Yuan, L., Zhang, F., Shen, M., Jia, S., Xie, J. (2019). Phytosterols suppress phagocytosis and inhibit inflammatory mediators via ERK pathway on LPS-triggered inflammatory responses in RAW264. 7 macrophages and the correlation with their structure. Foods, 8(11), 582.
• Yuan, L., Zhang, F., Jia, S., Xie, J., Shen, M. (2020). Differences between phytosterols with different structures in regulating cholesterol synthesis, transport and metabolism in Caco-2 cells. Journal of Functional Foods, 65, 103715.
• Elmegeed, G. A., Yahya, S. M., Abd-Elhalim, M. M., Mohamed, M. S., Mohareb, R. M., Elsayed, G. H. (2016). Evaluation of heterocyclic steroids and curcumin derivatives as anti-breast cancer agents: Studying the effect on apoptosis in MCF-7 breast cancer cells. Steroids, 115, 80-89.
• Elmegeed, G. A., Ahmed, H. H., Hashash, M. A., Abd Elhalim, M. M., El Kady, D. S. (2015). Synthesis of novel steroidal curcumin derivatives as anti-Alzheimer’s disease candidates: Evidences-based on in vivo study. Steroids, 101, 78-89.