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

Yıl 2024, Cilt: 9 Sayı: 4, 173 - 180, 31.12.2024
https://doi.org/10.30728/boron.1493431

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.

Etik Beyan

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Teşekkür

This work was studied at Eskisehir Osmangazi University Central Research Laboratory Application and Research Center (ARUM).

Kaynakça

  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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

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

Yıl 2024, Cilt: 9 Sayı: 4, 173 - 180, 31.12.2024
https://doi.org/10.30728/boron.1493431

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.

Kaynakça

  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
Toplam 30 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Malzeme Mühendisliği (Diğer)
Bölüm Research Makaleler
Yazarlar

Bükay Yenice Gürsu 0000-0002-6822-3484

Betül Yılmaz Öztürk 0000-0002-1817-8240

İlknur Dağ 0000-0002-7352-8653

Yayımlanma Tarihi 31 Aralık 2024
Gönderilme Tarihi 31 Mayıs 2024
Kabul Tarihi 13 Kasım 2024
Yayımlandığı Sayı Yıl 2024 Cilt: 9 Sayı: 4

Kaynak Göster

APA Yenice Gürsu, B., Yılmaz Öztürk, B., & Dağ, İ. (2024). Evaluation of 2-formylphenylboronic and 3-chlorophenylboronic acid derivatives for in vitro cytotoxicity and cell migration. Journal of Boron, 9(4), 173-180. https://doi.org/10.30728/boron.1493431