2-formilfenilboronik ve 3-klorofenilboronik asit türevlerinin in vitro sitotoksisite ve hücre migrasyonu açısından değerlendirilmesi

Öz

Yara tedavisi ve cildin yenilenmesi karmaşık bir proses olup, iyileşmeyen yaralar sağlık açısından büyük bir sosyoekonomik yük teşkil etmektedir. Başarılı bir yara yönetimi için etkili ve alternatif yaklaşımlara ihtiyaç bulunmaktadır. Boranik asit türevlerinin yara iyileşmesine yönelik olumlu ve güçlü etkileri rapor edilmekle beraber, fenil ikameli boranik asit türevleri iyileşmede daha rejeneratif ve etkili bileşikler olarak kullanılabilir. Bu çalışmada 2-formyl phenyl boronic acid ve 3-chloro phenyl boronic acid’in L929 fibroblast hücre hatları üzerine in vitro sitotoksik etkileri WST-8 analiziyle ve yara iyileştirici etkileri hücre göçü testi ile araştırılmıştır. Verilerimiz her iki boranik asit türevinin de konsantrasyon bağımlı etkilerini ortaya koymaktadır. 2-formyl phenyl boronic acid için 3.90-31.25 µg/ml arası doz uygulamaları % 84 ve üzerinde bir canlılık göstermiş, daha yüksek konsantrasyonlarda ise canlılık % 5-10 oranında bulunmuştur. 3-chloro phenyl boronic acid için 3.90-250 µg/ml arası doz uygulamaları sonucunda % 64-109 oranında bir canlılık gözlenirken, 500 µg/ml konsantrasyonda canlılık yüzdesi % 17’ye düşmektedir. Cell migration testi verileri, PBA türevlerinin hücre göçü açısından etkilerinin zaman arttıkça arttığını, 2-formyl phenyl boronic asitin 24. saatteki etkisinin hücre göçü açısından oldukça etkili olduğunu göstermektedir. PBA türevlerinin yara iyileştirici etkisi konsantrasyon bağımlı olduğundan, yüksek konsantrasyonların kullanımının toksik olabileceği de gözönünde bulundurulmalıdır.

Anahtar Kelimeler

• 2-formil fenil boronik asit
• 3-kloro fenil boronik asit
• in vitro sitotoksisite
• yara iyileşmesi

Evaluation of 2-formylphenylboronic and 3-chlorophenylboronic acid derivatives for in vitro cytotoxicity and cell migration

Öz

Wound treatment and skin regeneration are complex processes, and non-healing wounds pose a major socioeconomic burden in terms of health. Effective and alternative approaches are needed for successful wound management. Although boronic acid derivatives have been reported to have positive and strong effects on wound healing, phenyl-substituted boronic acid derivatives can be used as more regenerative and effective compounds in healing. In this study, the in vitro cytotoxic effects of 2-formylphenylboronic acid and 3-chlorophenylboronic acid on L929 fibroblast cell lines were investigated using WST-8 analysis, and their wound healing effects were investigated by cell migration test. Our data reveal concentration-dependent effects of both boronic acid derivatives. For 2-formylphenylboronic acid, dosage applications between 3.90-31.25 μg/ml showed a viability of 84% and above, and at higher concentrations, the viability was found to be 5-10%. For 3-chlorophenylboronic acid, a viability rate of 64-109% is observed as a result of dosage applications between 3.90-250 μg/ml, while the percentage of viability decreases to 17% at a concentration of 500 μg/ml. Cell migration test data show that the effects of phenylboronic acid (PBA) derivatives in terms of cell migration increase as time increases, and the effect of 2-formylphenylboronic acid at the 24th hour is quite effective in terms of cell migration. Since the wound healing effect of PBA derivatives is concentration dependent, it should be taken into consideration that the use of high concentrations may be toxic.

Anahtar Kelimeler

• 2-formyl phenyl boronic acid
• 3-chloro phenyl boronic acid
• in vitro cytotoxicity
• wound healing

Kaynakça

1. Türkez, H., Yıldırım, Ö. Ç., Öner, S., Kadı, A., Mete, A., Arslan, M. E., ... & Mardinoğlu, A. (2022). Lipoic acid conjugated boron hybrids enhance wound healing and antimicrobial processes. Pharmaceutics, 15(1), 149. https://doi.org/10.3390/pharmaceutics15010149
2. Lungu, R., Anisiei, A., Rosca, I., Sandu, A. I., Ailincai, D., & Marin, L. (2021). Double functionalization of chitosan based nanofibers towards biomaterials for wound healing. Reactive and Functional Polymers, 167, 105028. https://doi.org/10.1016/j.reactfunctpolym.2021.105028
3. Chebassier, N., Ouijja, E. H., Viegas, I., & Dreno, B. (2004). Stimulatory effect of boron and manganese salts on keratinocyte migration. Acta Dermato-Venereologica, 84(3), 191-194 https://doi.org/10.1080/00015550410025273
4. Demirci, S., Doğan, A., Karakuş, E., Halıcı, Z., Topçu, A., Demirci, E., & Sahin, F. (2015). Boron and poloxamer (F68 and F127) containing hydrogel formulation for burn wound healing. Biological Trace Element Research, 168, 169-180. https://doi.org/10.1007/s12011-015-0338-z
5. Hall, D. G. (2005). Structure, properties, and preparation of boronic acid derivatives. Overview of their reactions and applications. In D. G. Hall (Eds.), Boronic acids: Preparation and applications in organic synthesis and medicine (pp. 1-99). John Wiley & Sons. https://doi.org/10.1002/3527606548
6. Jeelani, A., Muthu, S., Raajaraman, B. R., & Sevvanthi, S. (2020). Spectroscopic, quantum chemical calculations, and molecular docking analysis of 3-Chlorophenyl boronic acid. Spectroscopy Letters, 53(10), 778-792. https://doi.org/10.1080/00387010.2020.1834410
7. Trippier, P. C., & McGuigan, C. (2010). Boronic acids in medicinal chemistry: Anticancer, antibacterial and antiviral applications. MedChemComm, 1(3), 183-198. https://doi.org/10.1039/C0MD00119H
8. Bayraktutan, Z. (2022). 4 hidroksi fenilboronik asidin lipopolisakkarit ile indüklenmiş karaciğer hasarı üzerine muhtemel koruyucu etkilerinin incelenmesi. Journal of Boron, 7(1), 430-439. https://doi.org/10.30728/boron.1057322

9. Lu, C., Li, H., Wang, H., & Liu, Z. (2013). Probing the interactions between boronic acids and cisdiol- containing biomolecules by affinity capillary electrophoresis. Analytical Chemistry, 85(4), 2361-2369. https://doi.org/10.1021/ac3033917
10. Yang, P., Bam, M., Pageni, P., Zhu, T., Chen, Y. P., Nagarkatti, M., ... & Tang, C. (2017). Trio act of boronolectin with antibiotic-metal complexed macromolecules toward broad-spectrum antimicrobial efficacy. ACS Infectious Diseases, 3(11), 845-853. https://doi.org/10.1021/acsinfecdis.7b00132
11. Gozdalik, J. T., Adamczyk-Woźniak, A., & Sporzyński, A. (2018). Influence of fluorine substituents on the properties of phenylboronic compounds. Pure and Applied Chemistry, 90(4), 677-702. https://doi.org/10.1515/pac-2017-1009
12. Adamczyk-Woźniak, A., Gozdalik, J. T., Wieczorek, D., Madura, I. D., Kaczorowska, E., Brzezińska, E., ... & Lipok, J. (2020). Synthesis, properties and antimicrobial activity of 5-trifluoromethyl-2-formylphenylboronic acid. Molecules, 25(4), 799. https://doi.org/10.3390/molecules25040799
13. Borys, K. M., Wieczorek, D., Pecura, K., Lipok, J., & Adamczyk-Woźniak, A. (2019). Antifungal activity and tautomeric cyclization equilibria of formylphenylboronic acids. Bioorganic Chemistry, 91, 103081. https://doi.org/10.1016/j.bioorg.2019.103081
14. Ailincai, D., Cibotaru, S., Anisiei, A., Coman, C. G., Pasca, A. S., Rosca, I., ... & Marin, L. (2023). Mesoporous chitosan nanofibers loaded with norfloxacin and coated with phenylboronic acid perform as bioabsorbable active dressings to accelerate the healing of burn wounds. Carbohydrate Polymers, 318, 121135. https://doi.org/10.1016/j.carbpol.2023.121135
15. Miao, S., Ge, Y., Yi, Z., & Feng, Q. (2020). Screening of aptamer for breast cancer biomarker calreticulin and its application to detection of serum and recognition of breast cancer cell. Chinese Journal of Analytical Chemistry, 48(5), 642-649. https://doi.org/10.1016/S1872-2040(20)60020-2
16. Simsek, F., Inan, S., & Korkmaz, M. (2019). An in vitro study in which new boron derivatives maybe an option for breast cancer treatment. Eurasian Journal of Medicine and Oncology, 3(1), 22–27. https://doi.org/10.14744/ejmo.2018.0020
17. Kahraman, E., & Göker, E. (2022). Boric acid exert anti-cancer effect in poorly differentiated hepatocellular carcinoma cells via inhibition of AKT signaling pathway. Journal of Trace Elements in Medicine and Biology, 73, 127043. https://doi.org/10.1016/j.jtemb.2022.127043
18. Sevimli, M., Bayram, D., Özgöçmen, M., Armağan, I., & Sevimli, T. S. (2022). Boric acid suppresses cell proliferation by TNF signaling pathway mediated apoptosis in SW-480 human colon cancer line. Journal of Trace Elements in Medicine and Biology, 71, 126958. https://doi.org/10.1016/j.jtemb.2022.126958
19. Sevimli, T. S., Ghorbani, A., & Sevimli, M. (2023) Investigation of the anti-proliferative and anti-apoptotic effects of boric acid on human non-small cell lung cancer cells through the tgf-β signaling pathway. Journal of Adnan Menderes University Health Sciences Faculty, 7(3), 553-564. https://doi.org/10.46237/amusbfd.1287877
20. Psurski, M., Łupicka-Słowik, A., Adamczyk-Woźniak, A., Wietrzyk, J., & Sporzyński, A. (2019). Discovering simple phenylboronic acid and benzoxaborole derivatives for experimental oncology–phase cycle-specific inducers of apoptosis in A2780 ovarian cancer cells. Investigational New Drugs, 37(1), 35-46. https://doi.org/10.1007/s10637-018-0611-z
21. Kowalska, K., Adamczyk-Woźniak, A., Gajowiec, P., Gierczyk, B., Kaczorowska, E., Popenda, Ł., ... & Sporzyński, A. (2016). Fluoro-substituted 2-formylphenylboronic acids: Structures, properties and tautomeric equilibria. Journal of Fluorine Chemistry, 187, 1-8. https://doi.org/10.1016/j.jfluchem.2016.05.001
22. Cebeci, E., Yüksel, B., & Şahin, F. (2022). Anti-cancer effect of boron derivatives on small-cell lung cancer. Journal of Trace Elements in Medicine and Biology, 70, 126923. https://doi.org/10.1016/j.jtemb.2022.126923
23. Marasovic, M., Ivankovic, S., Stojkovic, R., Djermic, D., Galic, B., & Milos, M. (2017). In vitro and in vivo antitumour effects of phenylboronic acid against mouse mammary adenocarcinoma 4T1 and squamous carcinoma SCCVII cells. Journal of Enzyme Inhibition and Medicinal Chemistry, 32(1), 1299-1304. https://doi.org/10.1080/14756366.2017.1384823
24. Wang, R., Tian, Y., Wang, J., Song, W., Cong, Y., Wei, X., ... & Chen, Y. M. (2021). Biomimetic glucose trigger-insulin release system based on hydrogel loading bidentate β-cyclodextrin. Advanced Functional Materials, 31(38), 2104488. https://doi.org/10.1002/adfm.202104488
25. Wang, Q., Wang, H., Chen, Q., Guan, Y., & Zhang, Y. (2020). Glucose-triggered micellization of poly (ethylene glycol)-b-poly (N-isopropylacrylamide-co-2-(acrylamido) phenylboronic acid) block copolymer. ACS Applied Polymer Materials, 2(9), 3966-3976. https://doi.org/10.1021/acsapm.0c00635
26. Abid, H. M. U., Hanif, M., Mahmood, K., Aziz, M., Abbas, G., & Latif, H. (2022). Wound-healing and antibacterial activity of the quercetin–4-formyl phenyl boronic acid complex against bacterial pathogens of diabetic foot ulcer. ACS Omega, 7(28), 24415-24422. https://doi.org/10.1021/acsomega.2c01819
27. Temel, H., Atlan, M., Ertas, A., Yener, I., Akdeniz, M., Yazan, Z., ... & Akyuz, E. (2022). Cream production and biological in vivo/in vitro activity assessment of a novel boron-based compound derived from quercetin and phenyl boronic acid. Journal of Trace Elements in Medicine and Biology, 74, 127073. https://doi.org/10.1016/j.jtemb.2022.127073
28. Beyranvand, S., Pourghobadi, Z., Sattari, S., Soleymani, K., Donskyi, I., Gharabaghi, M., ... & Adeli, M. (2020). Boronic acid functionalized graphene platforms for diabetic wound healing. Carbon, 158, 327-336. https://doi.org/10.1016/j.carbon.2019.10.077
29. Routray, I., & Ali, S. (2016). Boron induces lymphocyte proliferation and modulates the priming effects of lipopolysaccharide on macrophages. PLOS ONE, 11(3), e0150607. https://doi.org/10.1371/journal.pone.0150607
30. Zhao, B., Zhu, S., Liu, Y., Zhu, J., Luo, H., Li, M., ... & Cao, X. (2023). Enriching and smart releasing curcumin via phenylboronic acid-anchored bioinspired hydrogel for diabetic wound healing. Advanced NanoBiomed Research, 3(5), 2200177. https://doi.org/10.1002/anbr.202200177