The originality of adamantane structure showing also in the properties of its derivatives is the main factor governing the constant interest to the chemistry of this compound.69 The development of the adamantane chemistry makes it possible both to solve a series of theoretical problems and to design molecules of substances promising for the practical application in the fields of medicine, supramolecular chemistry, nanotechnologies, etc.70 Thus, adamantane derivatives found numerous applications in medicinal chemistry and drug development. No other singular hydrocarbon moiety (apart from the methyl group) is as successful as adamantane in improving or providing pharmacological activity for pharmaceuticals. Having the “lipophilic bullet” (adamantane is assumed to provide the critical lipophilicity) readily available as an “add-on” for known pharmacophors, it was used for example in the modification of hypoglycemic sulfonylureas,71 anabolic steroids,72 and nucleosides.73 The adamantane modifications were chosen to enhance lipophilicity and stability of the drugs, thereby improving their pharmacokinetics. Aminoadamantanes, such as Amantadine,74 Rimantadine,75 or Tromantadine,76 are anti-Influenza A agents and were among the first compounds on the pharmaceutical market containing an adamantyl moiety (Figure 1).77
Figure 1: Pharmaceutical active substances containing an adamantyl moiety.
The aminoadamantanes are synthetic drugs that have not been inspired by natural products like numerous other drugs. There are, however, also natural products that incorporate the adamantane skeleton, showing interesting biological properties (Figure 2).
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A. INTRODUCTION
Figure 2: Naturally occurring substrates bearing an adamantyl moiety.
Plukenetione A for example was first isolated from Clusia plukenetii in 199678 and displayed cytotoxicity in a panel of cell lines for different cancer entities.79 Also Sampsonione I, isolated from Hypericum sampsonii, showed cytotoxicity toward a P388 cell line.80 However, Hyperibone K, isolated from the Uzbek medicinal plant Hypericum scrabum, provided only moderate cytotoxicity in two human cancer cell lines,81 and no anti-HIV activity.
Noteworthy, the addition of adamantane moieties increases the permeability of the modified compounds through the blood-brain barrier.82 Therefore, targets of the central nervous system are today most promising both academically and commercially. With the discovery that Amantadine gives symptomatic benefits in Parkinson disease83 and the application of Memantine for the treatment of Alzheimer disease,84 two neurodegenerative diseases of increasing importance in the aging society are being addressed with structurally remarkably simple adamantane derivatives (Figure 3).
Figure 3: Simple adamantane derivativesas pharmaceuticals against Parkinson and Alzheimer
disease.
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G. E. Henry, H. Jacobs, C. M. S. Carrington, S. McLean, W. F. Reynolds, Tetrahedron Lett.1996, 37, 8663.
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A. INTRODUCTION
21 An emerging field with respect to the application of adamantane derivatives is the inhibition of enzymes using adamantane based scaffolds. Most important are the DPP-IV inhibitors Vildagliptin and Saxagliptin,85 that currently enter the multibillion dollar market of diabetes management (Figure 4).
Figure 4: Adamantane derivatives as pharmaceuticals against diabetes.
Moreover, there are three classes of adamantane derivatives of relevance in cancer research. The add-on strategy is followed by adamantane derivatives of cisplatin (e.g. LA-12) and Adaphostin. Adamantyl retinoids (e.g. CD437) however represent an alternative strategy to fight cancer cell proliferation (Figure 5).
Figure 5: Adamantane derivatives as pharmaceutically active substrates against cancer.
LA-12 was found to provide a higher degree of cytotoxicity against both cisplatin- sensitive and cisplatin-resistant ovarian cancer cells compared to other cisplatin- analogous substrates.86 Furthermore, Adaphostin is the adamantyl ester of the protein tyrosine kinase inhibitor AG957.87 Both AG957 and Adaphostin are classified as tyrphostins (tyrosine phosphorylation inhibitors) and were shown to induce chronic
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87
A. INTRODUCTION