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

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.

Homoadamantane and Adamantane Acylphloroglucinols from Hypericum hirsutum

1H NMR-guided fractionation of the petroleum ether extract of the aerial parts from Hypericum hirsutum yielded to the isolation of 19 polyprenylated polycyclic acylphloroglucinols. Structure elucidation based on 1D and 2D NMR spectroscopy together with high-resolution electrospray ionization mass spectroscopy revealed 14 acylphloroglucinols with a homoadamantane scaffold (1–14), while 5 further compounds showed an adamantane skeleton (15–19). Except for hookerione C (15), all isolated metabolites are hitherto unknown. While structurally-related metabolites have been isolated from other Hypericum species, it is the first report of admantan and homoadamantan type acylphloroglucinols in section Taeniocarpium Jaub. & Spach (Hypericaceae). The isolated compounds have been tested in a crystal violet-based in vitro assay on their properties to reduce the proliferation of human microvascular endothelial cells compared to hyperforin as the positive control. They showed a moderate reduction of proliferation with IC50 values in the range ~ 3 – 22 µM, with the homoadamantane-based compounds 2 and 4 being the most active. In addition, inhibition of the TNF-α-induced ICAM-1 expression was determined for 1 – 5, 7, and 10 – 12. Substances 3 and 12 reduced the ICAM-1 expression significantly (to 46.7% of control for 3, 62.3% for 12, at 50 µM).

Deformation of the Adamantane Skeleton by Substitution: Crystal Structure of 1-Methylsulfonyladamantane

The crystals of 1-methylsulfonyladamantane are monoclinic, space group P21/a, with a = 11.094(3), b = 7.668(2), c = 13.161(3) Å, β = 101.74(2)0, V = 1 096.1(5) Å3, Z = 4, Dx = 1.29 g cm -3, MoKα, λ = 0.71069 Å, μ = 2.65 cm-1, F(000) = 456, T = 291 K, the final R value is 0.036 for 1 834 observed reflections. For this compound and from literature data, the bond angles of adamantane derivatives are briefly discussed: the angle on the substituted C(1) atom depends clearly on the substituent but the available figures are still rather imprecise.