2-Substituted agelasine analogs: Synthesis and biological activity, and structure and reactivity of synthetic intermediates

Abstract

2-Substituted N-methoxy-9-methyl-9H-purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9H-purines or 2-chloro-N-methoxy-9-methyl-9H-purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on 1 H NMR. The tautomers were identified by 1D and 2D 1 H, 13 C, and 15 N NMR techniques, and showed significant variation both in 13 C and 15 N shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino:imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N-methoxy-9-methyl-9H-purin-6amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines.

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products

“…The monocyclic side chain of agelasines E and F were obtained from geraniol and β-cyclocitral [ 126 ] and pulegone [ 127 ], respectively. They modified also the substitution on the purine C2 position [ 128 , 129 , 130 ]. All those analogues were evaluated for their antimicrobial, antiprotozoal, antifouling and biofilm inhibition and cytotoxicity against a panel of human cancer cell lines and it was found that the length of the terpenyl side chain is important for bioactivity and that the presence of a methyl in the purine 2-position increased the antimicrobial and antiprotozoal activity, while amino groups increase the cytotoxicity [ 40 , 130 ].…”