4-(1-Adamantyl)phenylalkylamines with Potential Antiproliferative Activity

Background: In our previous publications we have described the synthesis of amino-substituded diaryl adamantanes and their pharmacological evaluation in vitro and in vivo against many cancer cell lines. More recently, we have reported the synthesis of mono C2-aryl substituted aminoadamantane derivatives that have moderate antiproliferative activity at low micromolar IC50 against a panel of four tumor cell lines. Methods: The synthesis and the pharmacological evaluation of 4-(1-adamantyl)phenylalkylamines 1-4 is described in this work. The new derivatives present an aryl substitution at C-1 adamantane position and diverge from the methylene spacer between the phenyl ring and the amine heterocycle moiety. Results: Piperazines 1a (R:N-H) and 1b (R:N-Me) are more active than piperidine 1c. This difference indicates the importance of the presence of this nitrogen atom in 1a and 1b, which is at a distance of 3 atoms (two carbons and the piperazine nitrogen included) from the benzene ring. Adducts 2a,b are less active than the rest of the products, because neither the R: N-H nitrogen atom (compound 2a) nor the R: N-Me nitrogen (compound 2b) are in an optimum distance from the benzene ring. Derivatives 3a-c are almost as potent as the piperazines 1a and 1b, which means that also in this case, the distance of 2 atoms (Ph beta CH2 alpha CH2N) is sufficient for antiproliferative activity. Products 4a-c have also significant activity, possibly due to the fact that the benzene moiety is attached to the nitrogen atom via a three methylene linker. Piperidine 4c is the most potent compound, showing that the nitrogen atom of these cyclic amines, which is near to benzene ring, is important for the pharmacological action. Conclusion: The comparison of the pharmacological results of the present work in relation to our previous publication shows that C-1 substitution in adamantane skeleton with aminoaryl or aminoalkyl groups enhances the antiproliferative activity towards to C-2 substitution. Our approach shows that the optimization of the antiproliferative activity is the incorporation of the p-aminoalkylphenyl side chain at C-1 adamantane position.