Computational assessment of the platinum (II) complex of imidazolidine dioximes substituted with methoxydiglycol units: from activation to DNA binding

Abstract

To overcome the issue of toxicity inherent in the approved anticancer agents, many cisplatin derivatives continue to be designed and tested today. Recently, we have proposed a new series of platinum complexes with highly potent imidazolidine dioxime ligands, a combination of two active ligands targeting DNA, substituted with aliphatic carbon chains or aromatic moiety. Quantum mechanical calculations have revealed their potential activity, particularly highlighting the potentially enhanced activity of complexes with aliphatic substituents in DNA platination. Here, we extend our previous study with the inclusion of methoxydiglycol unit (2-(2-methoxyethoxy)ethyl substituents) into the imidazolidine dioxime ligands of our previously proposed complexes to possibly enhance the solubility and bioavailability. Our current investigation focuses on modeling the aquation and DNA binding reactions to assess the potential of this modification and the results are compared to cisplatin.

Keywords

• Platinum drugs
• anticancer agents
• cisplatin derivatives
• density functional theory

Metoksidiglikol ile sübstitüe edilmiş imidazolidin dioksimlerinin platin (II) kompleksi üzerine hesapsal bir çalışma: aktivasyondan DNA bağlanmasına

Abstract

Onaylanmış antikanser ajanlarının sahip olduğu toksisite sorunlarının üstesinden gelmek amacıyla, günümüzde birçok cisplatin türevi tasarlanmakta ve test edilmektedir. Yakın zamanda, DNA’yı hedef alan iki aktif ligand içeren, alifatik karbon zincirleri veya aromatik yapı ile sübstitüe edilmiş imidazolidin dioksim ligandlarına sahip yeni bir platin kompleks serisi önerdik. Kuantum mekanik hesaplamalar, özellikle alifatik sübstitüentlerin DNA platinasyonu üzerindeki potansiyel aktivitesini vurgulamıştır. Bu çalışmada, çözünürlük ve biyoyararlanımın artırılması amacıyla daha önce önerdiğimiz komplekslere metoksidiglikol (2-(2-metoksietoksi)etil) sübstitüenti dahil edilmiş ve bu modifikasyonun potansiyelini değerlendirmek için yeni önerilen platin kompleksinin hidroliz ve DNA bağlanma reaksiyonları hesapsal olarak çalışılmış ve sonuçlar aktif kullanımda olan cisplatin ile karşılaştırılmıştır.

Keywords

• Platin ilaçları
• antikanser ajanları
• cisplatin türevleri
• yoğunluk fonksiyoneli teorisi

References

1. Rozencweig, M., von Hoff, D.D., Slavik, M. and Muggia, F.M., Cis-diamminedichloroplatinum (II). A new anticancer drug, Annals of Internal Medicine, 86, 6, 803–812, (1977).
2. Oun, R., Moussa, Y. E. and Wheate, N. J., The side effects of platinum-based chemotherapy drugs: a review for chemists, Dalton Transactions, 47, 19, 6645–6653, (2018).
3. Stordal, B. and Davey, M., Understanding cisplatin resistance using cellular models, IUBMB Life, 59, 11, 696–699, (2007).
4. Alassadi, S., Pisani, M.J. and Wheate, N.J., A chemical perspective on the clinical use of platinum-based anticancer drugs, Dalton Transactions, 51, 29, 10835–10846, (2022).
5. Yarbro, C. H., Carboplatin: A clinical review, Seminars in Oncology Nursing, 5, 2, 63–69, (1989).
6. Stein, A. and Arnold, D., Oxaliplatin: a review of approved uses, Expert Opinion on Pharmacotherapy, 13, 1, 125–137, (2012).
7. El-Khateeb, M., Appleton, T.G., Gahan, L.R., Charles, B.G., Berners-Price, S.J. and Bolton, A.M., Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques, Journal of Inorganic Biochemistry, 77, 13–21, (1999).
8. Pinto, A. L. and Lippard, S. J., Binding of the antitumor drug c/s-diamminedichloroplatinum(II) (cisplatin) to DNA, Biochimica et Biophysica Acta, 780, 167–180, (1985).

9. Dasari, S. and Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action, European Journal of Pharmacology, 740, 364–378, (2014).
10. Schepetkin, I. A., Plotnikov, M. B., Khlebnikov, A. I., Plotnikova, T. M. and Quinn, M. T., Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential, Biomolecules, 11, 6, 777, (2021).
11. Kaya, Y., Icsel, C., Yilmaz, V. T. and Buyukgungor, O., Palladium(II) and platinum(II) complexes of a new imineoxime ligand – Structural, spectroscopic and DFT/time-dependent (TD) DFT studies, Journal of Organometallic Chemistry, 752, 83–90, (2014).
12. Sayin, K. and Karakaş, D., Computational investigations of trans‑platinum(II) oxime complexes used as anticancer drug, Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy, 188, 537–546, (2018).
13. Alinaghi, M. Karami, K., Shahpiri, A., Nasab, A.K., Momtazi-Borojeni, A.A., Abdollahi, E. and Lipkowsk, J., A Pd(II) complex derived from pyridine-2-carbaldehyde oxime ligand: Synthesis, characterization, DNA and BSA interaction studies and in vitro anticancer activity, Journal of Molecular Structure, 1219, 128479, (2020).
14. Eroğlu Gülümsek, Ö., Erciyas Baykal, E., Küçükpolat, C., Önal, E., Balcik-Ercin, P., Yagci, T., Ahsen, V., and Gürek, A.G., Bis[N,N′-bis(anilino)glioximato]platinum(II) complex: synthesis, characterization and biological activity, Journal of Coordination Chemistry, 75, 197–210, (2022).
15. Caterina, M.C., Perillo, I.A., Boiani, L., Pezaroglo, H., Cerecetto, H., González, M. and Salerno, A., Imidazolidines as new anti-Trypanosoma cruzi agents: Biological evaluation and structure–activity relationships, Bioorganic & Medicinal Chemistry, 16, 5, 2226–2234, (2008).
16. Gürses, C., Aktaş, A., Balcıoğlu, S., Fadhilah, A., Gök, Y. and Ateş, B., Synthesis, characterization, DNA binding and anticancer activities of the imidazolidine-functionalized (NHC)Ru(II) complexes, Journal of Molecular Structure, 1247, 131350, (2022).
17. Emirik, Ö.F., Şanlı, C., Ahsen, V., Gürek, A.G. and Dedeoglu, B., Theoretical investigation of the hydrolysis and DNA binding of platinum (II) complexes of imidazolidine dioximes, Molecular Physics, 121, 22, e2236244.
18. Veronese, F.M. and Mero, A., The impact of PEGylation on biological therapies, Drug Development, BioDrugs, 22, 315-329 (2008).
19. Frisch, M.J., Trucks, G.W., Fox, D.J., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery Jr., J.A., Peralta, J.E., Ogliaro, F., Bearpark, , K., Zakrzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D., Farkas, Ö., Foresman, J.B., Ortiz, J.v., Cioslowski, J. and Fox, D.J., Gaussian Inc., Wallingford, Wallingford CT, 2013.
20. Grimme, S., Antony, J., Ehrlich, S. and Krieg, H., The Journal of Chemical Physics, 132, 154104, (2010).
21. Grimme, S., Semiempirical hybrid density functional with perturbative second-order correlation, The Journal of Chemical Physics, 124, 3, 34108, (2006).
22. Marenich, A.V., Cramer, J.C. and Truhlar, D.G., Performance of SM6, SM8, and SMD on the SAMPL1 Test Set for the Prediction of Small-Molecule Solvation Free Energies, Journal of Physical Chemistry B, 113, 14, 4538–4543, (2009).
23. Reed, A.E., Weinstock, R.B. and Weinhold, F., The Journal of Chemical Physics, 83, 735–746 (1985).
24. C.Y. Legault, CYLviewsoftware [Online]. Available: http://www.cylview.org.