SpringerLink
Log in

Unveiling the gemcitabine drug complexation with cucurbit[n]urils (n = 6–8): a computational analysis

  • Research
  • Published:
Structural Chemistry Aims and scope Submit manuscript

Abstract

In this work, we have investigated the complex formation capability of gemcitabine drug with host cucurbit[n]urils, Q[n] (n = 6, 7, and 8) using density functional theory (DFT). The DFT studies demonstrate that the most stable configuration is a fully encapsulated complex. In the encapsulated gemcitabine@Q[6] and gemcitabine@Q[7] complexes, the gemcitabine amino -NH2 and the alcoholic groups bond with the carbonyl units of Q[n]. The addition of sodium ions leads to the partial exclusion of the gemcitabine molecule and the sodium atoms lie close to the carbonyl portal of Q[7]. Thermodynamic parameters computed for the complexation process exhibit high negative Gibbs free energy change, implying that the encapsulation process is spontaneous and is an enthalpy-driven process. Frontier molecular orbitals are located mainly on the gemcitabine uracil ring, before and after encapsulation, indicating that the encapsulation occurs by pure physical adsorption. Quantitative molecular electrostatic potentials demonstrate a shift in electron density during the complex formation and are more pronounced in gemcitabine@Q[7]. Atoms-in-molecule (AIM) topological analysis illustrate that these complexes are stabilized by various non-covalent interactions including hydrogen bonding (HBs) and C···F interactions. The reduced density gradient (RDG) graph exhibits the presence of strong HBs and weak van der Waals interactions and the presence of steric repulsion. The isosurface non-covalent interactions (NCI) diagram shows predominant steric interaction in the gemcitabine@Q[6] complex. The NCI isosurface for gemcitabine encapsulated complexes with Q[7] and Q[8] host displays that the green patches are uniformly distributed in all directions. Finally, EDA results demonstrate Pauling’s repulsive energy is predominant in gemcitabine@Q[6] complex, while the orbital and dispersion energies stabilize the gemcitabine@Q[7] complex.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the author on reasonable request.

Code availability

Not applicable.

References

  1. Lee JW, Samal S, Selvapalam N, Kim HJ, Kim K (2003) Cucurbituril homologues and derivatives: new opportunities in supramolecular chemistry. Acc Chem Res 36:621–630

    Article  CAS  PubMed  Google Scholar 

  2. Barrow SJ, Kasera S, Rowland MJ, Del Barrio J, Scherman OA (2015) Cucurbituril-based molecular recognition. Chem Rev 115:12320–12406

    Article  CAS  PubMed  Google Scholar 

  3. Kim J, Jung IS, Kim SY, Lee E, Kang JK, Sakamoto S, Yamaguchi K, Kim K (2000) New cucurbituril homologues: syntheses, isolation, characterization, and X-ray crystal structures of cucurbit [n] uril (n = 5, 7, and 8). J Am Chem Soc 122:540–541

    Article  CAS  Google Scholar 

  4. Shetty D, Khedkar JK, Park KM, Kim K (2015) Can we beat the biotin–avidin pair?: Cucurbit[7]uril-based ultrahigh affinity host–guest complexes and their applications. Chem Soc Rev 44:8747–8761

    Article  CAS  PubMed  Google Scholar 

  5. Jansen K, Buschmann HJ, Wego A, Döpp D, Mayer C, Drexler HJ, Holdt HJ (2001) Schollmeyer, E.: Cucurbit[5]uril, decamethylcucurbit[5]uril and cucurbit[6]uril. Synthesis, solubility and amine complex formation. J Incl Phenom Macrocyclic Chem 39:357–363

    Article  CAS  Google Scholar 

  6. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Christine Cripps M, Portenoy RK, Storniolo AM, Tarassoff P (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413

    Article  CAS  PubMed  Google Scholar 

  7. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410

    Article  CAS  PubMed  Google Scholar 

  8. Scagliotti GV, Parikh P, Von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551

    Article  CAS  PubMed  Google Scholar 

  9. Veerman G, van Haperen VWT, Vermorken JB, Noordhuis P, Braakhuis BJ, Pinedo HM, Peters GJ (1996) Antitumor activity of prolonged as compared with bolus administration of 2′, 2′-difluorodeoxycytidine in vivo against murine colon tumors. Cancer Chemother Pharmacol 38:335–342

    Article  CAS  PubMed  Google Scholar 

  10. Veltkamp SA, Pluim D, van Eijndhoven MA, Bolijn MJ, Ong FH, Govindarajan R, Unadkat JD, Beijnen JH, Schellens JH (2008) New insights into the pharmacology and cytotoxicity of gemcitabine and 2′, 2′-difluorodeoxyuridine. Mol Cancer Ther 7:2415–2425

    Article  CAS  PubMed  Google Scholar 

  11. Laufer M, Ramalingam S, Schoenberg MP, Haisfield-Wolf ME, Zuhowski EG, Trueheart IN, Eisenberger MA, Nativ O, Egorin MJ (2003) Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study. J Clin Oncol 21:697–703

    Article  CAS  PubMed  Google Scholar 

  12. Jelovac D, Armstrong DK (2011) Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin 61:183–203

    Article  PubMed  PubMed Central  Google Scholar 

  13. Stuurman FE, Nuijen B, Beijnen JH, Schellens JH (2013) Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement. Clin Pharmacoknet 52:399–414

    Article  CAS  Google Scholar 

  14. Oun R, Floriano RS, Isaacs L, Rowan EG, Wheate NJ (2014) The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles. Toxicol Res 3:447–455

    Article  CAS  Google Scholar 

  15. Macartney DH (2011) Encapsulation of drug molecules by cucurbiturils: effects on their chemical properties in aqueous solution. Isr J Chem 51:600–615

    Article  CAS  Google Scholar 

  16. Wheate NJ, Buck DP, Day AI, Collins JG (2006) Cucurbit[n]uril binding of platinum anticancer complexes. Dalton Trans 451–458

  17. Walker S, Oun R, McInnes FJ, Wheate NJ (2011) The potential of cucurbit[n]urils in drug delivery. Isr J Chem 51:616–624

    Article  CAS  Google Scholar 

  18. Kemp S, Wheate NJ, Stootman FH, Aldrich-Wright JR (2007) The host-guest chemistry of proflavine with cucurbit[6, 7, 8]urils. Supramol Chem 19:475–484

    Article  CAS  Google Scholar 

  19. Wu X, Zhang YM, Liu Y (2016) Nanosupramolecular assembly of amphiphilic guest mediated by cucurbituril for doxorubicin delivery. RSC Adv 6:99729–99734

    Article  CAS  Google Scholar 

  20. Buczkowski A, Gorzkiewicz M, Stepniak A, Malinowska-Michalak M, Tokarz P, Urbaniak P, Ionov M, Klajnert-Maculewicz B, Palecz B (2020) Physicochemical and in vitro cytotoxicity studies of inclusion complex between gemcitabine and cucurbit[7]uril host. Bioorg Chem 99:103843

    Article  CAS  PubMed  Google Scholar 

  21. Buczkowski A, Palecz B, Schroeder G (2019) Stoichiometry and thermodynamics of gemcitabine and cucurbituril Q7 supramolecular complexes in high acidic aqueous solution. J Mol Struct 1178:554–563

    Article  CAS  Google Scholar 

  22. Buczkowski A (2022) Thermodynamic study of pH and sodium chloride impact on gemcitabine binding to cucurbit[7]uril in aqueous solutions. J Mol Liq 345:117857

    Article  CAS  Google Scholar 

  23. Sivalakshmidevi A, Om Reddy VG, Sivaram DVN, Swamy PV, Sairam RPP (2003) 2’-Deoxy-2’,2’-difluorocytidine monohydrochloride (gemcitabine hydrochloride). Acta Cryst E59:o1435–o1437

    Google Scholar 

  24. Venkataramanan NS, Suvitha A, Mizuseki H, Kawazoe Y (2015) Computational study on the interactions of mustard gas with cucurbituril macrocycles. Int J Quantum Chem 115:1515–1525

    Article  CAS  Google Scholar 

  25. Grimme S, Antony J, Ehrlich S, Krieg H (2010) DFT-D3 – a dispersion correction for density functionals, Hartee-Fock and semi-empirical quantum chemical methods DFT-D3. J Chem Phys 132:154104

    Article  PubMed  Google Scholar 

  26. Sure R, Antony J, Grimme S (2014) Blind prediction of binding affinities for charged supramolecular host-guest systems: achievements and shortcomings of DFT-D3. J Phys Chem B 118:3431–3440

    Article  CAS  PubMed  Google Scholar 

  27. Assaf KI, Florea M, Antony J, Henriksen NM, Yin J, Hansen A, Qu Z-W, Sure R, Klapstein D, Gilson MK, Grimme S, Nau WM (2017) Hydrophobe challenge: a joint experiment and computational study on the host-guest binding of hydrocarbons to cucucurbiturils, allowing explicit evaluation of guest hydration free-energy contributions. J Phys Chem B 121:11144–11162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Suvitha A, Venkataramanan NS (2017) Trap** of organophosphorus chemical nerve agents by pillar[5]arene: a DFT, AIM, NCI and EDA analysis. J Incl Phenom Macrocyclic Chem 87:207–218

    Article  CAS  Google Scholar 

  29. Klamt A (2018) The COSMO and COSMO-RS solvation models. Wiley Interdiscip Rev Comput Mol Sci 8:e1338

    Article  Google Scholar 

  30. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T. Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery, Jr JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin, RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2019) Gaussian 16, Revision C.01, Gaussian, Inc., Wallingford

  31. Imane D, Leila N, Fatiha M, Abdelkrim G, Mouna C, Ismahan L, Abdelazize B (2020) Investigation of intermolecular interactions in inclusion complexes of pyroquilon with cucurbit[n]urils (n = 7, 8) using DFT-D3 correction dispersion. J Mol Liq 309:113233

    Article  CAS  Google Scholar 

  32. Bulat FA, Toro-Labbe A, Brinck T, Murray JS, Politzer P (2010) Quantitative analysis of molecular surfaces: areas, volumes, electrostatic potentials and average local ionization energies. J Mol Model 16:1679–1691

    Article  CAS  PubMed  Google Scholar 

  33. te Velde G, Bickelhaupt FM, Baerends EJ, Fonseca Guerra C, van Gisbergen SJA, Snijders JG, Ziegler T (2001) Chemistry with ADF. J Comput Chem 22:931

    Article  Google Scholar 

  34. Ziegler T, Rauk A (1977) On the calculation of bonding energies by the Hartree Fock Slater method. I. The transition state method. Theor Chim Acta 46:1

    Article  CAS  Google Scholar 

  35. AIMAll (Version 19.10.12), Keith TA, Gristmill TK: Software, Overland Park KS, USA, 2019 (aim.tkgristmill.com)

  36. Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33:580–592

  37. Chemcraft - graphical software for visualization of quantum chemistry computations. https://www.chemcraftprog.com

  38. Bardelang D, Udachin KA, Leek DM, Margeson JC, Chan G, Ratcliffe CI, Ripmeester JA (2011) Cucurbit[n]urils (n = 5 – 8): a comprehensive solid state study. Cryst Growth Des 11:5598–5614

    Article  CAS  Google Scholar 

  39. Mecozzi S, Rebek J Jr (1998) The 55% solution: a formula for molecular recognition in the liquid state. Chem Eur J 4:1016–1022

    Article  CAS  Google Scholar 

  40. Grimm LM, Spicher S, Tkachenko B, Scheiner PR, Grimme S, Biedermann F (2022) The role of packing dispersion, electrostatics, and solvation in high-affinity complexes of cucurbit[n]urils with uncharged polar guests. Chem Eur J 28:e202200529

    Article  CAS  PubMed  Google Scholar 

  41. Athare SV, Gejji SP (2018) Confinement of 1 butyl 3 methylimidazolium in cucurbiturils. J Mol Liq 272:496–506

    Article  CAS  Google Scholar 

  42. Suvitha A, Venkataramanan NS, Sahara R, Kawazoe Y (2019) A theoretical exploration of the intermolecular interactions between resveratrol and water: a DFT and AIM analysis. J Mol Model 25:1–11

    Article  CAS  Google Scholar 

  43. Venkataramanan NS, Suvitha A, Sahara R (2019) Structure, stability, and nature of bonding between high energy water clusters confined inside cucurbituril: a computational study. Comput Theor Chem 1148:44–54

    Article  CAS  Google Scholar 

  44. Grishaeva TN, Masliy AN, Kuznetsov AM (2017) Water structuring inside the cavities of cucurbit[n]urils (n = 5 – 8): a quantum-chemical forecast. J Incl Pheom Marocyclic Chem 89:299–313

    Article  CAS  Google Scholar 

  45. Masliy AN, Grishaeva TN, Kuznetsov AM (2018) Formation of aqua and tetrammine Cu(II) complexes inside the cavities of cucurbit[6,8]urils: a DFT forecast. Int J Quantum Chem 119:e25877

    Article  Google Scholar 

  46. Biedermann F, Nau WM, Scheider H-J (2014) The hydrophobic effect revisited studies with supramolecular complexes imply high-energy water as a noncovalent driving forces. Angew Chem Int Ed 53:2–16

    Article  Google Scholar 

  47. He S, Biedermann F, Vankova N, Zhechkov L, Heine T, Hoffman R, De Simone A, Duignan TT, Nau WM (2018) Cavitation energies can outperform dispersion interactions. Nat Chem 10:1252–1257

    Article  CAS  PubMed  Google Scholar 

  48. Grishaeva TN, Masliy AN, Kuznetsov AM (2022) The role of water molecular structuring in the formation of the inclusion compounds based on cucurbit[8]uril and trans-[Co(en)2 Cl2]+, trans-[Ru(en)2 Cl2]+ complexes: a DFT examination. J Incl Phenom Macrocyclic Chem 102:653–662

    Article  CAS  Google Scholar 

  49. Venkataramanan NS, Suvitha A, Vijayaraghavan A, Thamotharan S (2017) Investigation of inclusion complexation of acetaminophen with pillar[5]arene: UV–Vis, NMR and quantum chemical study. J Mol Liq 241:782–791

    Article  CAS  Google Scholar 

  50. Ma F, Zheng X, **e L, Li Z (2021) Sequence-dependent nanomolar binding of tripeptides containing N-terminal phenylalanine by cucurbit[7]uril: a theoretical study. J Mol Liq 328:115479

    Article  CAS  Google Scholar 

  51. Aihara J-I (1999) Reduced HOMO-LUMO gap as an index of kinetic stability for polycyclic aromatic hydrocarbons. J Phys Chem A 103:7487–7495

    Article  CAS  Google Scholar 

  52. Imane D, Leila N, Fatiha M, Abdelkrim G, Mouna C, Ismahan L, Abdelazize B, Brahim H (2020) Investigation of intermolecular interactions in inclusion complexes of pyroquilon with cucurbit[n]urils (n = 7, 8) using DFT-D3 correction dispersion. J Mol Liq 309:113233

    Article  CAS  Google Scholar 

  53. Venkataramanan NS, Suvitha A, Sahara R, Kawazoe Y (2021) A computational study on the complexation of bisbenzimidazolyl derivatives with cucurbituril and cyclohexylcucurbituril. J Incl Phenom Macrocyclic Chem 100:217–231

    Article  CAS  Google Scholar 

  54. Yahiaoui K, Seridi L, Mansouri K (2021) Temozolomide binding to cucurbit[7]uril: QTAIM, NCI-RDG and NBO analyses. J Incl Phenom Macrocyclic Chem 99:61–77

    Article  CAS  Google Scholar 

  55. Bulat FA, Toro-Labbé A, Brinck T, Murray JS, Politzer P (2010) Quantitative analysis of molecular surfaces: areas, volumes, electrostatic potentials and average local ionization energies. J Mol Model 16:1679–1691

    Article  CAS  PubMed  Google Scholar 

  56. Varadwaj A, Marques HM, Varadwaj PR (2019) Is the fluorine in molecules dispersive? Is molecular electrostatic potential a valid property to explore fluorine-centered non-covalent interactions? Molecules 24:379

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sarkar R, Kundu TK (2019) Nonbonding interaction analyses on PVDF/[BMIM][BF4] complex system in gas and solution phase. J Mol Model 25:1–27

    Article  CAS  Google Scholar 

  58. Rozas I, Alkort I, Elguero J (2000) Behavior of ylides containing N, O, and C atoms as hydrogen bond acceptors. J Am Chem Soc 122:11154–11161

    Article  CAS  Google Scholar 

  59. Rozas I, Alkorta I, Elguero J (1998) Bifurcated hydrogen bonds: three-centered interactions. J Phy Chem A 102:9925–9932. https://doi.org/10.1021/jp9824813

    Article  CAS  Google Scholar 

  60. Alkorta I, Elguero J (2004) Fluorine–fluorine interactions: NMR and AIM analysis. Struct Chem 15:117–120

    Article  CAS  Google Scholar 

  61. López CS, Faza ON, Cossío FP, York DM, De Lera AR (2005) Ellipticity: a convenient tool to characterize electrocyclic reactions. Chem Eur J 11:1734–1738

    Article  PubMed  Google Scholar 

  62. Mahadevi AS, Sastry GN (2016) Cooperativity in noncovalent interactions. Chem Rev 116:2775–2825

    Article  CAS  PubMed  Google Scholar 

  63. Venkataramanan NS, Suvitha A, Kawazoe Y (2019) Unraveling the binding nature of hexane with quinone functionalized pillar[5]quinone: a computational study. J Incl Phenom Macrocyclic Chem 95:307–319

    Article  CAS  Google Scholar 

  64. Suvitha A, Venkataramanan NS, Sahara R (2022) Effect of water molecule in the structure, stability, and electronic properties of sulfur trioxide clusters: a computational analysis. Monatsh Chem 153:347–357

    Article  CAS  Google Scholar 

  65. Thellamurege N, Hirao H (2013) Water complexes of cytochrome P450: insights from energy decomposition analysis. Molecules 18:6782–6791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks the staff of the Center for Computational Materials Science, Institute for Materials Research, Tohoku University, and the supercomputer resources through the HPCI System Research Project (Project ID: hphp200040).

Author information

Authors and Affiliations

  1. Center for Computational Chemistry & Materials Science (CCC&MS), Saveetha Dental College and Hospitals, SIMATS, Saveetha University, Chennai, 602 105, Tamil Nadu, India

    Natarajan Sathiyamoorthy Venkataramanan & Ambigapathy Suvitha

  2. SHARP Substratum, Adavathur East, Trichy, 620 102, India

    Ambigapathy Suvitha

  3. Research Center for Structural Materials, NIMS, Tsukuba, Ibaraki, 305‑0047, Japan

    Ryoji Sahara

  4. NICHE, Tohoku University, Sendai, 980-8577, Japan

    Yoshiyuki Kawazoe

  5. Department of Physics, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand

    Yoshiyuki Kawazoe

  6. Department of Physics and Nanotechnology, SRM Institute of Science and Technology, Tamil Nadu, Kattankulathur, 603203, India

    Yoshiyuki Kawazoe

Authors
  1. Natarajan Sathiyamoorthy Venkataramanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ambigapathy Suvitha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryoji Sahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiyuki Kawazoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AS carried out the formal analysis, conceiving the problem, and data curation for tables. NSV designed the methodology, supervised the work done, conceptualized the study, and edited the final manuscript. RS supervised the work done, conceptualized the study, and edited the final manuscript. YK supervised the work and edited the final manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Natarajan Sathiyamoorthy Venkataramanan.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlights

• Inclusion complexes are more stable.

• MESP analysis shows an electron density delocalization in the inclusion complex.

• Atoms in molecule analysis show the presence of hydrogen bonds and C···F interactions between host and gemcitabine.

• EDA shows a high Pauling’s repulsion for the inclusion complex with Q[6] as the host.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 6962 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Venkataramanan, N.S., Suvitha, A., Sahara, R. et al. Unveiling the gemcitabine drug complexation with cucurbit[n]urils (n = 6–8): a computational analysis. Struct Chem 34, 1869–1882 (2023). https://doi.org/10.1007/s11224-023-02133-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-023-02133-z

Keywords

Search

Navigation