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Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi

Yıl 2023, Cilt: 13 Sayı: 3, 1838 - 1850, 01.09.2023
https://doi.org/10.21597/jist.1288146

Öz

Bu çalışmada nipagin’den (metil paraben, metil-4-hidroksibenzoat) hareketle yeni seçici ve düşük toksisiteye sahip potansiyel anti kanser ajanlar geliştirilmesi amacıyla arilidenhidrazid yapısında sekiz adet bileşik (4-11) sentezlendi ve bu bileşiklerin meme kanseri büyüme faktörü reseptörü olan HER2’ye karşı etkinlikleri in siliko yöntemlerle ilk defa araştırıldı. Öncelikle moleküler docking çalışmaları ile hedef bileşiklerin ilgili protein üzerindeki bağlanma skorları ve serbest bağlanma enerjileri belirlendi, daha sonra moleküler dinamik çalışmaları ile protein-ligand komplekslerinin kararlılıkları incelendi ve son olarak bileşiklerin tahmini ADME parametreleri hesaplandı. Sentezlenen bütün bileşikler 1H NMR, 13C NMR, FT-IR ve HRMS analizleri ile karakterize edildi. Moleküler doking çalışmalarının sonuçlarına göre en aktif molekülün, -10.098 kcal/mol docking skoru ve -64.97 kcal/mol serbest bağlanma enerjisine sahip bileşik Bold olduğu belirlendi. Bileşik 6-HER2 ligand-protein kompleksinin moleküler dinamik simülasyonunda simülasyon zamanının %70’i boyunca hidrojen bağı ve pi-pi staking etkileşimlerinin devam ettiği ve ligand atomlarının RMSD değerlerinin ortalamasının 2Å olduğu tespit edildi. Hedef bileşiklerin in siliko ADME parametrelerinin referans aralıklarda olduğu ve tahmini ADME sonuçlarına göre ilaç benzerliği taşıdığı görüldü. Ayrıca sonuçlar referans antikanser ilaç doksorubisinin ile karşılaştırıldı ve bazı parametrelerin doksorubisine göre daha anlamlı ve uygun olduğu tespit edildi. Sonuç olarak ilk defa bu çalışmada sentezlen bileşik Bold, meme kanserinin büyüme faktörü reseptörü olan HER2’ye karşı yapılan in siliko çalışmalara göre en iyi inhibitör adayı olabileceği belirlendi.

Kaynakça

  • Afonin, A. V., Ushakov, I. A., Pavlov, D. V., Petrova, O. V., Sobenina, L. N., Mikhaleva, A. I. ve Trofimov, B. A. (2013). Structural studies of meso-CF3-3(5)-aryl(hetaryl)- and 3,5-diaryl(dihetaryl)-BODIPY dyes by H-1, C-13 and F-19 NMR spectroscopy and DFT calculations. Journal of Fluorine Chemistry, 145, 51-57.
  • Aslanhan, Ö., Kalay, E., Tokalı, F. S., Can, Z. ve Şahin, E. (2023). Design, synthesis, antioxidant and anticholinesterase activities of novel isonicotinic hydrazide-hydrazone derivatives. Journal of Molecular Structure, 1279, 135037.
  • Cansouline, X., Lipan, B., Sizaret, D., Tallet, A., Vandier, C., Carmier, D. ve Legras, A. (2022). EGFR-Mutant Non-Small-Cell Lung Cancer at Surgical Stages: What Is the Place for Tyrosine Kinase Inhibitors? Cancers, 14 (9), 2257.
  • Cho, J. Y., Moon, J. H., Seong, K. Y. ve Park, K. H. (1998). Antimicrobial activity of 4-hydroxybenzoic acid and trans 4-hydroxycinnamic acid isolated and identified from rice hull. Bioscience Biotechnology and Biochemistry, 62 (11), 2273-2276.
  • Crampon, K., Giorkallos, A., Deldossi, M., Baud, S. ve Steffenel, L. A. (2022). Machine-learning methods for ligand-protein molecular docking. Drug Discovery Today, 27 (1), 151-164.
  • Fatriansyah, J. F., Rizqillah, R. K., Yandi, M. Y., Fadilah ve Sahlan, M. (2022). Molecular docking and dynamics studies on propolis sulabiroin-A as a potential inhibitor of SARS-CoV-2. Journal of King Saud University Science, 34 (1), 101707.
  • Giaquinto, A. N., Sung, H., Miller, K. D., Kramer, J. L., Newman, L. A., Minihan, A., Jemal, A. ve Siegel, R. L. (2022). Breast Cancer Statistics, 2022. Ca-a Cancer Journal for Clinicians, 72 (6), 524-541.
  • Gombler, W. (1981). NMR Spectroscopic Studies on Chalcogen Compounds .2. Te-125, Se-77, F-19 And C-13 Chemical-Shifts of CF3 Substituted Selenium and Tellurium Compounds. Zeitschrift Fur Naturforschung Section B-a Journal of Chemical Sciences, 36 (5), 535-543.
  • Hausman, D. M. (2019). What is cancer? Perspectives in Biology and Medicine, 62 (4), 778-784.
  • Jorgensen, W. L. ve Duffy, E. M. (2002). Prediction of drug solubility from structure. Advanced Drug Delivery Reviews, 54 (3), 355-366.
  • Kılınç, N., Açar, M., Tuncay, S. ve Karasakal, F. Ö. (2022). Potential Inhibitors Identification of Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Angiotensin-Converting Enzyme 2 and Main Protease from Anatolian Traditional Plants. Letters in Drug Design & Discovery, 19 (11), 996 - 1006.
  • Lipinski, C. A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies, 1 (4), 337-341.
  • Lipinski, C. A., Lombardo, F., Dominy, B. W. ve Feeney, P. J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23 (1), 3-25.
  • Muangsri, R., Chuysinuan, P., Thanyacharoen, T., Techasakul, S., Sukhavattanakul, P. ve Ummartyotin, S. (2022). Release Characteristic and Antioxidant Activity of 4-Hydroxybenzoic Acid (4HB) from Sodium Alginate and Polyvinyl Alcohol-based Hydrogel. Chemistryselect, 7 (34), e202202329.
  • Saikia, S. ve Bordoloi, M. (2019). Molecular Docking: Challenges, Advances and its Use in Drug Discovery Perspective. Curr Drug Targets, 20 (5), 501-521.
  • Sannino, F., Sansone, C., Galasso, C., Kildgaard, S., Tedesco, P., Fani, R., Marino, G., De Pascale, D., Ianora, A., Parrilli, E., Larsen, T. O., Romano, G. ve Tutino, M. L. (2018). Pseudoalteromonas haloplanktis TAC125 produces 4-hydroxybenzoic acid that induces pyroptosis in human A459 lung adenocarcinoma cells. Scientific Reports, 8 (1), 1190.
  • Shafique, I., Saeed, A., Ahmed, A., Shabir, G., Ul-Hamıd, A., Khan, A., Tüzün, B., Kirici, M., Taslimi, P. ve Latif, M. (2022). Exploring the multi-target enzyme inhibition potential of new sulfonamido-thiazoline derivatives; synthesis and computational studies. Results in Chemistry, 4, 100656.
  • Siegel, R. L., Miller, K. D., Fuchs, H. E. ve Jemal, A. (2022). Cancer statistics, 2022. Ca-a Cancer Journal for Clinicians, 72 (1), 7-33.
  • Şenol, H., Ağgül, A. G. ve Atasoy, S. (2023a). Synthesis, Characterization, Molecular Docking and in vitro Biological Studies of Thiazolidin-4-one Derivatives as Anti-Breast-Cancer Agents. Chemistryselect, 8 (20), e202300481.
  • Şenol, H., Ağgül, A. G., Atasoy, S. ve Güzeldemirci, N. U. (2023). Synthesis, characterization, molecular docking and in vitro anti-cancer activity studies of new and highly selective 1,2,3-triazole substituted 4-hydroxybenzohyrdazide derivatives. Journal of Molecular Structure, 1283, 135247.
  • Tokalı, F. S., Şenol, H., Bulut, Ş. ve Hacıosmanoğlu-Aldoğan, E. (2023). Synthesis, characterization and molecular docking studies of highly selective new hydrazone derivatives of anthranilic acid and their ring closure analogue Quinazolin-4(3H)-ones against lung cancer cells A549. Journal of Molecular Structure, 1282, 135176.
  • Tokalı, F. S., Taslimi, P., Demircioğlu, İ. H., Şendil, K., Tuzun, B. ve Gülçin, İ. (2022). Novel phenolic Mannich base derivatives: synthesis, bioactivity, molecular docking, and ADME-Tox Studies. Journal of the Iranian Chemical Society, 19 (2), 563-577.
  • Tokalı, F. S., Taslimi, P., Sadeghian, N., Taskin-Tok, T. ve Gülçin, İ. (2023). Synthesis, Characterization, Bioactivity Impacts of New Anthranilic Acid Hydrazones Containing Aryl Sulfonate Moiety as Fenamate Isosteres. Chemistryselect, 8 (13), e202300241.
  • Waks, A. G. ve Winer, E. P. (2019). Breast Cancer Treatment A Review. Jama-Journal of the American Medical Association, 321 (3), 288-300.
  • Winter, A. N., Brenner, M. C., Punessen, N., Snodgrass, M., Byars, C., Arora, Y. ve Linseman, D. A. (2017). Comparison of the Neuroprotective and Anti-Inflammatory Effects of the Anthocyanin Metabolites, Protocatechuic Acid and 4-Hydroxybenzoic Acid. Oxidative Medicine and Cellular Longevity, 2017:6297080.

Synthesis of New Hydrazone Derivatives of Nipagin and Determination of their in Silico Biological Activities

Yıl 2023, Cilt: 13 Sayı: 3, 1838 - 1850, 01.09.2023
https://doi.org/10.21597/jist.1288146

Öz

In this study, eight compounds (4-11) with the arylidenehydrazide structure were synthesized in order to develop new selective and low-toxicity potential anti-cancer agents based on nipagin (methyl paraben, methyl-4-hydroxybenzoate) and these compounds were synthesized and the anti-cancer potential of these compounds against HER2, the breast cancer growth factor receptor, were investigated for the first time by in silico methods. For the first time, their efficacy against the disease was investigated by in silico methods. First of all, the binding scores and free binding energies of the target compounds on the related protein were determined by molecular docking studies, then the stability of protein-ligand complexes were determined by molecular dynamics studies and finally the predicted ADME parameters were calculated. Target compounds were characterized by 1H NMR, 13C NMR, FT-IR and HRMS analyses. Based on the molecular docking studies, the target molecule with the highest inhibition potential was determined as compound Bold with a docking score of -10.098 kcal/mol and a free binding energy of -64.97 kcal/mol. In the molecular dynamics simulation of the compound 6-HER2 ligand-protein complex, it was determined that hydrogen bonding and pi-pi stacking interactions continued for 70% of the simulation time and the average RMSD values of the ligand atoms were 2Å. It was observed that in silico ADME parameters of the target compounds were within reference ranges and had drug similarity according to the estimated ADME results. In addition, the results were compared with anticancer drug doxorubicin and some parameters were found to be more significant and appropriate than doxorubicin. As a result, compound Bold, which was synthesized for the first time in this study, was determined as the best inhibitor candidate according to in silico studies against HER2, the growth factor receptor of breast cancer.

Kaynakça

  • Afonin, A. V., Ushakov, I. A., Pavlov, D. V., Petrova, O. V., Sobenina, L. N., Mikhaleva, A. I. ve Trofimov, B. A. (2013). Structural studies of meso-CF3-3(5)-aryl(hetaryl)- and 3,5-diaryl(dihetaryl)-BODIPY dyes by H-1, C-13 and F-19 NMR spectroscopy and DFT calculations. Journal of Fluorine Chemistry, 145, 51-57.
  • Aslanhan, Ö., Kalay, E., Tokalı, F. S., Can, Z. ve Şahin, E. (2023). Design, synthesis, antioxidant and anticholinesterase activities of novel isonicotinic hydrazide-hydrazone derivatives. Journal of Molecular Structure, 1279, 135037.
  • Cansouline, X., Lipan, B., Sizaret, D., Tallet, A., Vandier, C., Carmier, D. ve Legras, A. (2022). EGFR-Mutant Non-Small-Cell Lung Cancer at Surgical Stages: What Is the Place for Tyrosine Kinase Inhibitors? Cancers, 14 (9), 2257.
  • Cho, J. Y., Moon, J. H., Seong, K. Y. ve Park, K. H. (1998). Antimicrobial activity of 4-hydroxybenzoic acid and trans 4-hydroxycinnamic acid isolated and identified from rice hull. Bioscience Biotechnology and Biochemistry, 62 (11), 2273-2276.
  • Crampon, K., Giorkallos, A., Deldossi, M., Baud, S. ve Steffenel, L. A. (2022). Machine-learning methods for ligand-protein molecular docking. Drug Discovery Today, 27 (1), 151-164.
  • Fatriansyah, J. F., Rizqillah, R. K., Yandi, M. Y., Fadilah ve Sahlan, M. (2022). Molecular docking and dynamics studies on propolis sulabiroin-A as a potential inhibitor of SARS-CoV-2. Journal of King Saud University Science, 34 (1), 101707.
  • Giaquinto, A. N., Sung, H., Miller, K. D., Kramer, J. L., Newman, L. A., Minihan, A., Jemal, A. ve Siegel, R. L. (2022). Breast Cancer Statistics, 2022. Ca-a Cancer Journal for Clinicians, 72 (6), 524-541.
  • Gombler, W. (1981). NMR Spectroscopic Studies on Chalcogen Compounds .2. Te-125, Se-77, F-19 And C-13 Chemical-Shifts of CF3 Substituted Selenium and Tellurium Compounds. Zeitschrift Fur Naturforschung Section B-a Journal of Chemical Sciences, 36 (5), 535-543.
  • Hausman, D. M. (2019). What is cancer? Perspectives in Biology and Medicine, 62 (4), 778-784.
  • Jorgensen, W. L. ve Duffy, E. M. (2002). Prediction of drug solubility from structure. Advanced Drug Delivery Reviews, 54 (3), 355-366.
  • Kılınç, N., Açar, M., Tuncay, S. ve Karasakal, F. Ö. (2022). Potential Inhibitors Identification of Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Angiotensin-Converting Enzyme 2 and Main Protease from Anatolian Traditional Plants. Letters in Drug Design & Discovery, 19 (11), 996 - 1006.
  • Lipinski, C. A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies, 1 (4), 337-341.
  • Lipinski, C. A., Lombardo, F., Dominy, B. W. ve Feeney, P. J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23 (1), 3-25.
  • Muangsri, R., Chuysinuan, P., Thanyacharoen, T., Techasakul, S., Sukhavattanakul, P. ve Ummartyotin, S. (2022). Release Characteristic and Antioxidant Activity of 4-Hydroxybenzoic Acid (4HB) from Sodium Alginate and Polyvinyl Alcohol-based Hydrogel. Chemistryselect, 7 (34), e202202329.
  • Saikia, S. ve Bordoloi, M. (2019). Molecular Docking: Challenges, Advances and its Use in Drug Discovery Perspective. Curr Drug Targets, 20 (5), 501-521.
  • Sannino, F., Sansone, C., Galasso, C., Kildgaard, S., Tedesco, P., Fani, R., Marino, G., De Pascale, D., Ianora, A., Parrilli, E., Larsen, T. O., Romano, G. ve Tutino, M. L. (2018). Pseudoalteromonas haloplanktis TAC125 produces 4-hydroxybenzoic acid that induces pyroptosis in human A459 lung adenocarcinoma cells. Scientific Reports, 8 (1), 1190.
  • Shafique, I., Saeed, A., Ahmed, A., Shabir, G., Ul-Hamıd, A., Khan, A., Tüzün, B., Kirici, M., Taslimi, P. ve Latif, M. (2022). Exploring the multi-target enzyme inhibition potential of new sulfonamido-thiazoline derivatives; synthesis and computational studies. Results in Chemistry, 4, 100656.
  • Siegel, R. L., Miller, K. D., Fuchs, H. E. ve Jemal, A. (2022). Cancer statistics, 2022. Ca-a Cancer Journal for Clinicians, 72 (1), 7-33.
  • Şenol, H., Ağgül, A. G. ve Atasoy, S. (2023a). Synthesis, Characterization, Molecular Docking and in vitro Biological Studies of Thiazolidin-4-one Derivatives as Anti-Breast-Cancer Agents. Chemistryselect, 8 (20), e202300481.
  • Şenol, H., Ağgül, A. G., Atasoy, S. ve Güzeldemirci, N. U. (2023). Synthesis, characterization, molecular docking and in vitro anti-cancer activity studies of new and highly selective 1,2,3-triazole substituted 4-hydroxybenzohyrdazide derivatives. Journal of Molecular Structure, 1283, 135247.
  • Tokalı, F. S., Şenol, H., Bulut, Ş. ve Hacıosmanoğlu-Aldoğan, E. (2023). Synthesis, characterization and molecular docking studies of highly selective new hydrazone derivatives of anthranilic acid and their ring closure analogue Quinazolin-4(3H)-ones against lung cancer cells A549. Journal of Molecular Structure, 1282, 135176.
  • Tokalı, F. S., Taslimi, P., Demircioğlu, İ. H., Şendil, K., Tuzun, B. ve Gülçin, İ. (2022). Novel phenolic Mannich base derivatives: synthesis, bioactivity, molecular docking, and ADME-Tox Studies. Journal of the Iranian Chemical Society, 19 (2), 563-577.
  • Tokalı, F. S., Taslimi, P., Sadeghian, N., Taskin-Tok, T. ve Gülçin, İ. (2023). Synthesis, Characterization, Bioactivity Impacts of New Anthranilic Acid Hydrazones Containing Aryl Sulfonate Moiety as Fenamate Isosteres. Chemistryselect, 8 (13), e202300241.
  • Waks, A. G. ve Winer, E. P. (2019). Breast Cancer Treatment A Review. Jama-Journal of the American Medical Association, 321 (3), 288-300.
  • Winter, A. N., Brenner, M. C., Punessen, N., Snodgrass, M., Byars, C., Arora, Y. ve Linseman, D. A. (2017). Comparison of the Neuroprotective and Anti-Inflammatory Effects of the Anthocyanin Metabolites, Protocatechuic Acid and 4-Hydroxybenzoic Acid. Oxidative Medicine and Cellular Longevity, 2017:6297080.
Toplam 25 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Kimya Mühendisliği
Bölüm Kimya / Chemistry
Yazarlar

Halil Şenol 0000-0002-8333-035X

Erken Görünüm Tarihi 29 Ağustos 2023
Yayımlanma Tarihi 1 Eylül 2023
Gönderilme Tarihi 26 Nisan 2023
Kabul Tarihi 9 Haziran 2023
Yayımlandığı Sayı Yıl 2023 Cilt: 13 Sayı: 3

Kaynak Göster

APA Şenol, H. (2023). Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi. Journal of the Institute of Science and Technology, 13(3), 1838-1850. https://doi.org/10.21597/jist.1288146
AMA Şenol H. Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi. Iğdır Üniv. Fen Bil Enst. Der. Eylül 2023;13(3):1838-1850. doi:10.21597/jist.1288146
Chicago Şenol, Halil. “Nipagin Türevi Yeni Hidrazonların Sentezi Ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi”. Journal of the Institute of Science and Technology 13, sy. 3 (Eylül 2023): 1838-50. https://doi.org/10.21597/jist.1288146.
EndNote Şenol H (01 Eylül 2023) Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi. Journal of the Institute of Science and Technology 13 3 1838–1850.
IEEE H. Şenol, “Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi”, Iğdır Üniv. Fen Bil Enst. Der., c. 13, sy. 3, ss. 1838–1850, 2023, doi: 10.21597/jist.1288146.
ISNAD Şenol, Halil. “Nipagin Türevi Yeni Hidrazonların Sentezi Ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi”. Journal of the Institute of Science and Technology 13/3 (Eylül 2023), 1838-1850. https://doi.org/10.21597/jist.1288146.
JAMA Şenol H. Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi. Iğdır Üniv. Fen Bil Enst. Der. 2023;13:1838–1850.
MLA Şenol, Halil. “Nipagin Türevi Yeni Hidrazonların Sentezi Ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi”. Journal of the Institute of Science and Technology, c. 13, sy. 3, 2023, ss. 1838-50, doi:10.21597/jist.1288146.
Vancouver Şenol H. Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi. Iğdır Üniv. Fen Bil Enst. Der. 2023;13(3):1838-50.