Adamantane-Substituted Purines and Their β-Cyclodextrin Complexes: Synthesis and Biological Activity

Abstract

Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug’s solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.

A comprehensive analysis of the role of molecular docking in the development of anticancer agents against the cell cycle CDK enzyme

“…Among them, important residues for 64 were Lys89, and Ile20 with a binding energy of −7.89 kcal/mol (Mansour et al, 2021a). Rouchal et al (2021). revealed that the compounds with 2,6,9-trisubstituted purines scaffold (72) (Fig.…”

“…17) can act as good anticancer drugs. However, on the downside, they have low solubility in water, which can be improved by appropriate derivatization of the compounds with the adamantane moiety (Rouchal et al, 2021). They also performed molecular docking (AutoDock Vina) and in vitro analysis and found that purine derivatives with adamantane cages can easily bind inside the CDK2 to form complexes.…”

“…They performed a docking study to clarify the inactivity of previously published adamantylated purines. Docking studies revealed that the inactivity was not related to the presence of the bulky adamantane moiety, which was believed to prevent the entrance of the inhibitor to the active site (Rouchal et al, 2021). The most promising residues for purine core were Ile11, Leu84, His85, Asp87, and Ls90.…”

Adamantane-Substituted Purine Nucleosides: Synthesis, Host–Guest Complexes with β-Cyclodextrin and Biological Activity

“…On the other hand, introducing an adamantane motif into the structure of the considered biologically-active substances can lead to a slight decrease in the solubility of the final compound in a water environment. This limitation can be overcome using one of the most interesting properties of the adamantane moiety, i.e., its ability to form relatively stable supramolecular host–guest complexes with cyclodextrins (CDs) [ 31 , 32 ]. CDs represent non-toxic, biodegradable, and water-soluble cyclic oligosaccharides, originating via bacterial degradation of starch.…”

“…Several types of modified CDs, prepared by the transformation of hydroxyl groups with different functional motifs, have been synthesized, with the aim of improving the water solubility of natural CDs [ 33 ]. The influence of the host–guest complex formation between potential drug candidates and CDs (natural and/or modified), for example, on water solubility, biological activity, bioavailability, and/or stability, has been extensively studied [ 31 , 32 , 34 , 35 , 36 , 37 ].…”