Synthesis of b-Carboline Derivatives and Their Interaction with Duplex-DNA

Abstract

3-Amino-9-N-(2-aminoethyl)carhamoylethyl--carboline (3) was synthesized from 3-methoxycarbonyl-P-carboline through successivecyanoethylation, Curtius rearrangement, and addition reaction of ethylenediamine in 45 % overall yield.The terminal aliphatic amino group of 3 was transformed to a N-methylureido group with succinimidyl N-methylcarbarnate to afford a compound 4 in 80 % yield.Affinity of 3, 4, P-carboline (I), and 3-amino-P-carholine (2) to a DNA oligomer or calf thymus DNA was spectrophotometrically studied.Optical spectroscopy of these Pcarbolines showed 25 -65 nm hathochromic shifts of the light absorption hands upon binding to the nucleic acids, which suggests binding by intercalation.Scatchard plots, obtained by fluorescence titration, gave the corresponding binding constants K, to the DNA oligomer; 7.45 x lo3, 5.13 x lo5, 7.34 x lo5, and 7.01 x lo5, respectively.The terminal aliphatic amino group considerably decreases the intercalating ability of 3 to DNA.N-Alkyl-N-nitrosoureas alkylate DNA via an aliphatic diazonium ion or a solvent-separated ion pair, and this modification of DNA is associated with the mutagenic, carcinogenic, and antineoplastic activities of the drugs.'>The yield and the selectivity of this alkylation, however, are extremely low.This is particularly frustrating to elucidate the mechanism of alkylation and sequence specificity.On the other hand, it has been reported that N-heterocyclic compounds possessing an aromatic condensed ring, such as acridines, proflavins, ellipticines, have high affinity for G-C rich sites or specific sequences of the duplex-DNA?Therefore, if an alkylnitrosourea is linked to one of these intercalators, the yields and specificity of the alkylation should he accelerated by delivery of the alkylater.On the basis of this concept, we have reported a synthesis of an alkylnitrosourea linked to a DNA intercalating methidium structure, and its reaction with DNA.'As an extension of this study, preparation of a new intercalating molecule, 3-amino-9-N-(2-N'-methylureido-