Benzimidazolyum Tipi Yeni NHC Molekülü ve Gümüş Kompleksinin Sentezi ve Karakterizasyonu ve Potansiyel Antikanser Aktivite için Teorik Analizi

Year 2023, Volume: 13 Issue: 2, 275 - 287, 15.06.2023

Elvan Üstün , Neslihan Şahin

https://doi.org/10.31466/kfbd.1186972

Abstract

N-heterosiklik karbenler başlangıçtan günümüzü katalitik aktiviteleri dolayısıyla kimyagerlerin ilgisini çekmektedir. Sonraki yıllarda N-heterosiklik karbenlerin ve bunların metal komplekslerinin biyoaktivite çalışmalarından olumlu sonuçlar alınmıştır. Teorik metotlar moleküllerin çeşitli aktiviteleri ile ilgili kullanışlı bilgiler sunarlar. Bu teorik yöntemlerde biri moleküllerin reaktiviteleri hakkında bilgiler sunan sınır orbital analizidir. Bir başka metot ise moleküler doking yöntemleri kullanılarak belirli makromoleküllerin kristallerine karşı moleküler aktivitenin incelenmesidir. Bu çalışmada, yeni 1-allil-3-(siklohekzillmetil)benzimidazolyumbromid ve bromo[1-allil-3-( siklohekzillmetil)benzimidazolyum-2-yliden]gümüş(I) molekülleri sentezlenerek karakterize edilmiştir. Moleküllerin karakterizasyonları ayrıca spektroskopik ve teorik yöntemlerle desteklenmiştir. Bu moleküllerin biyoaktiviteleri ile ilgili fikir sahibi olmak için, anjiyogenezi düzenleyen VEGFR-2 ve DNA ile etkileşimleri moleküler doking yöntemleri ile analiz edilmiştir.

Keywords

N-Heterosiklik Karbenler, VEGFR-2, Gümüş Molekülleri, Moleküler Doking, DFT

Synthesis and Characterization of Novel Benzimidazolium Type NHC Molecule and Its Silver Complex and Their Theoretical Analysis for Potential Anti-Cancer Activity

Abstract

N-heterocyclic carbenes have initially attracted great attention of the chemists in consequence of their catalytic activity. The favorable results were also obtained in bioactivity studies for N-heterocyclic carbenes, and their transition metal complexes in following years. Theoretical methods deliver beneficial data about the several activities of molecules. One of them is the frontier orbital analysis, which supplies data about the reactivity of molecules. Another method is investigation of the molecular activity against crystals of certain macromolecules using molecular docking methods. In this study, novel 1-allyl-3-(cyclohexylmethyl)benzimidazoliumbromide and bromo[1-allyl-3-(cyclohexylmethyl)benzimidazolium-2-ylidene]silver(I) were synthesized and characterized. The characterizations were also supported by spectroscopical and theoretical methods. In order to have foresight about the bioactivities of these molecules, molecular docking methods were used to get information about the interactions between molecules and VEGFR-2, which regulates the angiogenesis, and DNA.

Keywords

N-Heterocyclic Carbenes, VGEFR-2, Silver Molecules, Molecular Docking, DFT

References

• Aher, S. B., Muskawar, P. N., Thenmozhi, K., and Bhagat, P. R. (2014). Recent developments of metal N-heterocyclic carbenes as anticancer agents. European Journal of Medicinal Chemistry, 81, 408-419.
• Becke, A. D. (1988). Density-functional exchange-energy approximation with correct asymptotic behavior. Physical review A, 38(6), 3098.
• Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407(6801), 249-257.
• Choudhary, V., Bhatt, A., Dash, D., and Sharma, N. (2019). DFT calculations on molecular structures, HOMO–LUMO study, reactivity descriptors and spectral analyses of newly synthesized diorganotin (IV) 2‐chloridophenylacetohydroxamate complexes. Journal of Computational Chemistry, 40(27), 2354-2363.
• Dias, S., Hattori, K., Zhu, Z., Heissig, B., Choy, M., Lane, W., ... and Rafii, S. (2000). Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. The Journal of Clinical Investigation, 106(4), 511-521.
• Diez-Gonzalez, S., Marion, N., and Nolan, S. P. (2009). N-heterocyclic carbenes in late transition metal catalysis. Chemical Reviews, 109(8), 3612-3676.
• Drew, H. R., Wing, R. M., Takano, T., Broka, C., Tanaka, S., Itakura, K., and Dickerson, R. E. (1981). Structure of a B-DNA dodecamer: conformation and dynamics. Proceedings of the National Academy of Sciences, 78(4), 2179-2183.
• El-Adl, K., El-Helby, A. G. A., Sakr, H., Eissa, I. H., El-Hddad, S. S., and Shoman, F. M. (2020). Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2, 4-dione derivatives targeting VEGFR-2 enzyme. Bioorganic Chemistry, 102, 104059.
• Ferrara, N. (2004). Vascular endothelial growth factor: basic science and clinical progress. Endocrine reviews, 25(4), 581-611.
• Ferrara, N. (2009). Vascular endothelial growth factor. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(6), 789-791.
• Folkman, J. (1984). Angiogenesis. Biology of Endothelial Cells, 412-428.
• Fontes, J. V., Santos, I. A., Rosa, L. B., Lima, R. L., Jardim, A. C., Miguel, D. C., and Abbehausen, C. (2022). Antileishmanial and Anti‐Chikungunya Activity of Cu (I)‐N‐Heterocyclic Carbenes. ChemistrySelect, 7(31), e202201560.
• Ghosh, S., Sullivan, C. A., Zerkowski, M. P., Molinaro, A. M., Rimm, D. L., Camp, R. L., and Chung, G. G. (2008). High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Human Pathology, 39(12), 1835-1843.
• Golding Sheeba, G., Usha, D., Amalanathan, M., Sony Michael Mary, M., and MarshanRobert, H. (2021). Molecular structure, vibrational spectroscopic, frontier molecular orbital and natural bond orbital analysis of anti-cancer drug 6-chloro-3-pyridine carbonitrile. Spectroscopy Letters, 54(6), 419-436.
• Hamdi, N., Slimani, I., Mansour, L., Alresheedi, F., Özdemir, I., and Gürbüz, N. (2021). Rhodium (I) complexes with N-heterocyclic carbene ligands: synthesis, biological properties and catalytic activity in the hydrosilylation of aromatic ketones. Journal of Coordination Chemistry, 74(15), 2558-2579.
• Herrmann, W. A. (2002). N‐heterocyclic carbenes: a new concept in organometallic catalysis. Angewandte Chemie International Edition, 41(8), 1290-1309.
• Herrmann, W. A., and Köcher, C. (1997). N‐Heterocyclic carbenes. Angewandte Chemie International Edition in English, 36(20), 2162-2187.
• Hoeben, A. N. N., Landuyt, B., Highley, M. S., Wildiers, H., Van Oosterom, A. T., and De Bruijn, E. A. (2004). Vascular endothelial growth factor and angiogenesis. Pharmacological Reviews, 56(4), 549-580.
• Hopkinson, M. N., Richter, C., Schedler, M., and Glorius, F. (2014). An overview of N-heterocyclic carbenes. Nature, 510(7506), 485-496.
• Kar, R., Chandrakumar, K. R. S., and Pal, S. (2007). The influence of electric field on the global and local reactivity descriptors: reactivity and stability of weakly bonded complexes. The Journal of Physical Chemistry A, 111(2), 375-383.
• Karaaslan, M. G., Aktaş, A., Gürses, C., Gök, Y., and Ateş, B. (2020). Chemistry, structure, and biological roles of Au-NHC complexes as TrxR inhibitors. Bioorganic Chemistry, 95, 103552.
• Khajehzadeh, M., and Sadeghi, N. (2018). Molecular structure, the effect of solvent on UV–vis and NMR, FT–IR and FT–Raman spectra, NBO, frontier molecular orbital analysis of Mitomycin anticancer drug. Journal of Molecular Liquids, 256, 238-246.
• Koopmans, T. (1934). Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den einzelnen Elektronen eines Atoms. Physica, 1(1-6), 104-113.
• Miyazaki, Y., Matsunaga, S., Tang, J., Maeda, Y., Nakano, M., Philippe, R. J., ... and Nolte, R. T. (2005). Novel 4-amino-furo [2, 3-d] pyrimidines as Tie-2 and VEGFR2 dual inhibitors. Bioorganic & Medicinal Chemistry Letters, 15(9), 2203-2207.
• Neese, F. (2012). The ORCA program system. Wiley Interdisciplinary Reviews: Computational Molecular Science, 2(1), 73-78.
• Neese, F. (2022). Software update: The ORCA program system—Version 5.0. Wiley Interdisciplinary Reviews: Computational Molecular Science, 12(5), e1606.
• Neese, F., Wennmohs, F., Becker, U., and Riplinger, C. (2020). The ORCA quantum chemistry program package. The Journal of Chemical Physics, 152(22), 224108.
• Nishida, N., Yano, H., Nishida, T., Kamura, T., and Kojiro, M. (2006). Angiogenesis in cancer. Vascular health and risk management, 2(3), 213.
• Olofsson, B., Pajusola, K., Kaipainen, A., Von Euler, G., Joukov, V., Saksela, O., ... and Eriksson, U. (1996). Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proceedings of the National Academy of Sciences, 93(6), 2576-2581.
• Ott, I. (2017). Medicinal chemistry of metal N-heterocyclic carbene (NHC) complexes. In Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells (pp. 147-179). Academic Press.
• Parthasarathi, R., Subramanian, V., Roy, D. R., and Chattaraj, P. K. (2004). Electrophilicity index as a possible descriptor of biological activity. Bioorganic & Medicinal Chemistry, 12(21), 5533-5543.
• Perdew, J. P. (1986). Density-functional approximation for the correlation energy of the inhomogeneous electron gas. Physical Review B, 33(12), 8822.
• Rahimi, N. (2006). VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Frontiers in bioscience: a journal and virtual library, 11, 818.
• Rajkumar, P., Selvaraj, S., Suganya, R., Kesavan, M., Serdaroğlu, G., Gunasekaran, S., and Kumaresan, S. (2020). Experimental and theoretical investigations on electronic structure of 5-(hydroxymethyl)-2-furaldehyde: An antisickling agent identified from terminalia bellirica. Chemical Data Collections, 29, 100498.
• Şahin, N., Çelebi, M. S., Ayvaz, M. Ç., and Üstün, E. (2022). Antioxidant Activity, Enzyme Inhibition, Electrochemical and Theoretical Evaluation of Novel PEPPSI Type N-Heterocyclic Carbene Complexes. Inorganic Chemistry Communications, 110028.
• Şahin-Bölükbaşı, S., and Şahin, N. (2019). Novel Silver-NHC complexes: Synthesis and anticancer properties. Journal of Organometallic Chemistry, 891, 78-84.
• Sayed, A. M., Taher, F. A., Abdel-Samad, M. R., El-Gaby, M. S., El‐Adl, K., and Saleh, N. M. (2021). Design, synthesis, molecular docking, in silico ADMET profile and anticancer evaluations of sulfonamide endowed with hydrazone-coupled derivatives as VEGFR-2 inhibitors. Bioorganic Chemistry, 108, 104669.
• Schepetkin, I. A., Plotnikov, M. B., Khlebnikov, A. I., Plotnikova, T. M., and Quinn, M. T. (2021). Oximes: Novel therapeutics with anticancer and anti-inflammatory potential. Biomolecules, 11(6), 777.
• Serdaroğlu, G., Şahin, N., Üstün, E., Tahir, M. N., Arıcı, C., Gürbüz, N., and Özdemir, İ. (2021). PEPPSI type complexes: Synthesis, x-ray structures, spectral studies, molecular docking and theoretical investigations. Polyhedron, 204, 115281.
• Torres, P. H., Sodero, A. C., Jofily, P., and Silva-Jr, F. P. (2019). Key topics in molecular docking for drug design. International Journal of Molecular Sciences, 20(18), 4574.
• Tripathi, A., and Misra, K. (2017). Molecular docking: A structure-based drug designing approach. JSM Chem, 5(2), 1042-1047.
• Trott, O., and Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455-461.
• Üstün, E., and Şahin, N. Molecular Docking and DFT Analysis of Methallyl Substituted N-Heterocyclic Carbene Salts for Potential Anticancer Activity. Ordu Üniversitesi Bilim ve Teknoloji Dergisi, 11(2), 186-192.
• Üstün, E., Demir, S., Coşkun, F., Kaloğlu, M., Şahin, O., Büyükgüngör, O., and Özdemir, İ. (2016). A theoretical insight for solvent effect on myoglobin assay of W (CO) 4L2 type novel complexes with DFT/TDDFT. Journal of Molecular Structure, 1123, 433-440.
• Wei, B. Q., Baase, W. A., Weaver, L. H., Matthews, B. W., and Shoichet, B. K. (2002). A model binding site for testing scoring functions in molecular docking. Journal of Molecular Biology, 322(2), 339-355.