We have synthesized a series of small beta-peptidomimetics (M(w) <650) that were based on the minimal pharmacophore model for anti-Staphylococcal activity of short cationic antimicrobial peptides. All beta-peptidomimetics had a net charge of +2 and formed an amphipathic scaffold consisting of an achiral lipophilic beta(2,2)-amino acid coupled to a C-terminal l-arginine amide residue. By varying the lipophilic side-chains of the beta(2,2)-amino acids, we obtained a series of highly potent beta-peptidomimetics with high enzymatic stability against alpha-chymotrypsin and a general low toxicity against human erythrocytes. The most potent beta-peptidomimetics displayed minimal inhibitory concentrations of 2.1-7.2 muM against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and Escherichia coli. Small amphipathic beta-peptidomimetics may be a promising class of antimicrobial agents by means of having a similar range of potency and selectivity as larger cationic antimicrobial peptides in addition to improved enzymatic stability and lower costs of production.

We have prepared a series of highly potent achiral cationic β(2,2)-amino acid derivatives that fulfill the Lipinski's rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest β(2,2)-amino acid derivatives (M(w) 423.6) exhibiting a MIC of 3.8 μM against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 μM against Escherichia coli. The β(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the β(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.

The Suzuki-Miyaura cross-coupling reactions of 9-benzyl-6-chloropurine, 9-or 3-benzyl-8-bromoadenine and 2,6-dihalopurines with boronic acids gave the corresponding 6-, 8-or 2-arylor -alkenylpurines in good yields. Anhydrous conditions in toluene were superior for coupling of electron-rich boronic acids, while aqueous DME was used for electron-poor arylboronic acids as well as for alkenylboronic acids. A good regioselectivity was observed for the coupling of 2,6-dihalopurines: 9-benzyl-2,6-dichloropurine reacted with one equivalent of phenyl boronic acid to give 9-benzyl-2-chloro-6-phenylpurine, while an analogous reaction of 9-benzyl-6-chloro-2-iodopurine gave selectively 9-benzyl-6-chloro-2-phenylpurine.

We report a series of synthetic anticancer heptapeptides (H-KKWβ(2,2) WKK-NH(2)) containing eight different central lipophilic β(2,2) -amino acid building blocks, which have demonstrated high efficiency when used as scaffolds in small cationic antimicrobial peptides and peptidomimetics. The most potent peptides in the present study had IC(50) values of 9-23 µm against human Burkitt's lymphoma and murine B-cell lymphoma and were all nonhaemolytic (EC(50) > 200 µm). The most promising peptide 10e also demonstrated low toxicity against human embryonic lung fibroblast cells and peripheral blood mononuclear cells and exceptional proteolytic stability.

The Suzuki-Myiaura cross-coupling reactions of 9-benzyl-6-chloropurine with boronic acids gave 6-alkylated purines in moderate to excellent yields. The best results with electron rich arylboronic acids were obtained in toluene in the presence of anhydrous K 2 CO 3 as a base, while electron poor boronic acids and alkenyl boronic acids gave better results using aqueous K 2 CO 3 in DME. The reaction was successfully applied for the synthesis of 6-phenylpurine bases and nucleosides.Purine bases modified in the 6-position and their nucleoside and nucleotide derivatives and analogues possess a broad spectrum of biological activity. The cytotoxicity of 6-methylpurine and its nucleosides is well known, 1 while a promising cytostatic activity of 6-(aminoalkyl)purine derivatives (as cytokinines analogues) has been recently discovered. 2 Many 6-alkylaminopurine nucleosides are important adenosine receptors antagonists 3 and acyclic nucleotide analogues derived from 6-(di)alkylaminopurines are strong antivirals, antineoplastic agents and immunomodulators. 4 Recently, several 6-(arylalkynyl)-, 6-(arylalkenyl)-and 6-(arylalkyl)purines were reported 5 to exhibit cytokinine activity.In the last decade, with the development of the cross-coupling methodology, many 6-C-substituted purines have been prepared. 6 Thus 6-halopurine derivatives react with alkyl(aryl)zinc or tin reagents, 6a-e trialkylaluminum 6f or alkylcuprates 6g-i to give the 6-alkylpurine derivatives. Also another approach based on the reaction of purine-6-zinc iodide with aryl or vinyl halides has recently been described. 7 For the synthesis of 6-arylpurines, an alternative based on radical photochemical reactions of adenine derivatives with aromatic compounds was used, 8 but this method is very unselective and for substituted benzenes, mixtures of all ortho-, meta-and para-substituted derivatives were obtained. To the best of our knowledge, no successful Suzuki-Myiaura type of cross-coupling 9 of 6-halopurines with alkyl-or arylboronic acid has been described. The advantage of this reaction compared to the above mentioned methods would be the high stability of boronic acids, the low toxicity of boron compounds, easy work-up and isolation of the product along with availability of starting boronic acids (a number of boronic acids, especially the aromatic ones, is commercially available).In this communication we wish to report our results in this field.To test the Suzuki-Myiaura coupling reaction of purine derivatives we chose 6-halo-9-benzylpurines as model compounds. Thus Pd(PPh 3 ) 4 catalysed reaction of 9-benzyl-6-chloropurine (1) with phenylboronic acid in the presence of K 2 CO 3 in toluene at 100°C afforded after 24 h 9-benzyl-6-phenylpurine (2a) in excellent yield (95%) (Scheme 1). Scheme 19-Benzyl-6-iodopurine reacted faster giving similarly high yield (92%) of 2a, however, the reaction mixture was not as clean as in the case of 1. Also 9-benzyl-7-chloropurine (3) reacted smoothly with phenylboronic acid giving 70% isolated yield of 7-benzyl-6-phenylpurin...