Calix[n]arene-based drug carriers: A DFT study of their electronic interactions with a chemotherapeutic agent used against leukemia

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Highlights

  • Calix[n]arenes were found suitable macrocyclic hosts for GTP.

  • Hydrogen bonding and dispersion forces from π–π overlap stabilize these complexes.

  • Large hosts wrap themselves around GTP maximizing their interaction.

  • Calix[n]arene sulfonic acid (n = 6, 8) are the most promising carriers.

  • Highly coordinating substituents yield the most stable complexes.

Abstract

The suitability of eight differently substituted calix[n]arenes (with R = -OEt; SO3H and n = 4, 5, 6, 8) as drug delivery agents for 3-phenyl-1H-[1]benzofuro[3,2-c]pyrazole (henceforth referred to as GTP), a promising new tyrosine kinase inhibitor drug, has been analyzed by means of DFT theoretical calculations at the B97D/6-31G(d,p) level of theory. Geometries and interaction energies for all inclusion complexes were calculated with NBO, as well as NBO deletion calculations in order to evaluate the energetics of the interactions between GTP and the inner walls of the calix[n]arene cavities. Second order perturbation theory analysis of the charge transfer based on the NBO population analysis was also performed to assess the energetics of the intramolecular bonding in the host guest complexes. Bond indexes suggest the formation of hydrogen-bonds as part of the stabilizing forces of the complex. Two possible insertion modes were explored for the insertion of GTP in the macrocyclic cavity yielding a total of 16 inclusion complexes studied. Interaction energies were higher for R = SO3H. Hosts (8) and (6) (n = 8 and 6, respectively) are the most promising candidates for becoming GTP delivery agents within the chemical space under exploration herein.

Introduction

One of the ongoing challenges in the pharmaceutical industry is increasing the specificity with which a drug reaches a specific tissue [1] because of the direct impact this specificity has on the amount of drug administered to a patient. Drug targeting techniques ultimately overcome, among other effects, uneven drug biodistribution and low specific affinity towards a pathological site, thus reducing the dosages of drugs to be supplied to a patient in order to achieve the required concentrations on the target zone [2], [3]. Encapsulation by polymer or micelle formulations has already proven to be effective in commercial products [4], [5]; yet, inclusion of a drug molecule by a single delivering host on a 1:1 stoichiometry remains an open challenge, one which could yield larger bioavailability within a specific tissue. However, carriers with large molecular weights exhibit some diffusion inconveniences, thus macromolecular carriers pose an efficient alternative to overcome both issues, molecular weight and specificity [6]. The use of monomolecular drug carriers could help solve these issues even further by providing each drug molecule of a higher retention rate without hindering too much their diffusion between cells within a pathological tissue. Particularly calix[n]arenes, are a promising kind of macrocyclic hosts to this goal.

Calix[n]arenes are a family of bowl or cone shaped macrocycles synthesized through the condensation of p-substituted phenol derivatives with an aldehyde [7], [8]. In recent times there has been a growing interest in their properties as host molecules, particularly as agents in molecular recognition [9], [10], [11], [12], [13], which can be used in selective extraction processes [14], [15]. The study of calixarenes as drug delivery agents is an ongoing and promising area of research [16], [17]. Due to the flexibility of the macrocyclic backbone, which becomes larger with the number of units involved in its formation, several conformations are possible; in the specific case of a generic calix[4]arene, four major distinct conformers are observed, namely cone, partial cone, 1,2-alternate and 1,3-alternate [18]. The number of available conformers increases with the size of the macrocycle, providing a larger flexibility towards guests of various sizes, which in turn may serve as scaffolds or templates to stabilize the host in a given conformation according to the major interactions in role. As opposed to other macrocycles such as cyclodextrines, calix[n]arenes can adjust their cavities to better fit the guest inside which makes them more versatile hosts [19]. According to recent literature, calix[n]arenes show little to null toxicity [20], [21], [22], which is the first requirement to be complied by any suitable drug carrier or drug delivery agent together with chemical stability and both improved pharmacokinetics, and controlled release kinetics of its pharmaceutical payload [23], [24]. When linked to molecules with biological activity they have been used as lipophilic carriers and prodrugs [25].

According to recent literature, calix[n]arenes show little to null toxicity [26], [27], [28], which is the first requirement to be complied by any suitable drug carrier or drug delivery agent together with chemical stability and both improved pharmacokinetics, and controlled release kinetics of its pharmaceutical payload [29], [30].

The compound 3-phenyl-1H-[1]benzofuro[3,2-c]pyrazole known also as GTP-141564 (hereafter referred to as GTP) and which structure is illustrated in Fig. 1 has been reported to have a positive activity as a tyrosine kinase inhibitor in leukemia cells [31], [32]. GTP exhibits a dipole moment of 3.098 D, which could make it not readily available through a lipid layer of a much lower polarity, despite the presence of hydrophobic groups on both ends. Thus, calix[n]arenes may be employed as carriers for GTP by encapsulating it within their cavities through carefully designed structures that maximize the host–guest interaction.

Herein we report the various energetic, bonding and structural features of GTP – calix[n]arene complexes in various orientations, thus shedding some light on the main interactions present between the two species in order to design a suitable monomolecular drug carrier for GTP.

Section snippets

Quantum mechanics study

All calculations were performed with the Gaussian09 Rev. B.02 [33] suite of programs. Vibrational frequencies were calculated from analytic second derivatives to confirm the structures as local minima on their respective potential energy surfaces. NBO deletion calculations were carried out as a mean to estimate the interaction energy, Eint, between host and guest; these calculations were performed with the NBO3.1 [34] program implemented also in the aforementioned suite. The NBO deletion

Results and discussion

Two variables were considered in the design of our host systems: n = {4, 5, 6, 8} and R = {OEt; SO3H}, yielding a chemical space of 8 different hosts which become 16 complex structures when we take the insertion modes of GTP into consideration (vide infra). Fig. 2 shows the initial structures for the free calix[n]arenes, as viewed along their main symmetry axis, inwards from the upper rim side. This image is shown only as to illustrate the structures of the hosts employed throughout the study and

Conclusions

The relationship between relative energy values between insertion modes is Erel(b) > Erel(a) for n = 4, 5, 6 but exhibits the opposite behavior for n = 8. Insertion mode (a) maximizes the overlap between the aromatic cavity and the benzofuropyrazole group which has a larger π delocalized electron system than the phenyl group that is inserted in mode (b). However, this higher stability of (b) insertion is not to be mistaken with a larger interaction between host and guest, since from Table 1 we can

Acknowledgements

We wish to acknowledge the work of Dr. Eng. Attila Kun at UBB for maintenance of our computational facilities. PMP is grateful to CNCSIS-UEFISCSU for financial support (project number PNII – ID_PCCE_129/2008). JBF is grateful to DGTIC – UNAM for the access granted to their supercomputing facilities; also to DGAPA – UNAM for financial support under project number IB200313. This work was partly supported by the TÁMOP-4.2.2.A-11/1/KONV-2012-0065 project.

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