Role of the Azinomycin Naphthoate and Central Amide in Sequence-Dependent DNA Alkylation and Cytotoxicity of Epoxide-Bearing Substructures

Abstract

Studies report a strong correlation between duplex DNA alkylation and in vitro cytotoxicity for a series of azinomycin partial structures 2-6 bearing the biologically relevant epoxide. Compounds lacking the naphthoate ester (e.g., 5 and 6) were poorly reactive toward DNA and were biologically inactive, as were compounds bearing the naphthoate but lacking the terminal carboxamide (e.g., 2). Compounds were evaluated for cytotoxicity against two breast cancer cell lines. [structure: see text]

Mode of action and biosynthesis of the azabicycle-containing natural products azinomycin and ficellomycin

“…25 Yet epoxides 15 and 16 lacking the naphthoate moiety also failed to react with DNA, and were found to be biologically inactive. 32 The result of removing the C5 0 -methyl 17, C3 0 -methyl ester 18, or a combination of the two 19 from the naphthalene ring indicated that the C5 0 -methyl substituent of an azinomycin analog is essential for DNA association and subsequent ISC. 33 Hodgkinson and coworkers found that simply substituting an ethoxy group at the methoxy position on the naphthalene ring reduces cytotoxicity by an average of 25-fold.…”

Chemical Biology of N5-Substituted Formamidopyrimidine DNA Adducts

“…Aflatoxin B1 epoxide, − N -methylnitrosamines, − dimethyl sulfate, , tobacco carcinogen 4-(methylnitrosamino)-1-(pyridyl)-1-butanone (NNK), N -methylnitrosourea, 1, 2-dimethylhydrazine, N , N -dimethylnitrosamine, − , cyclophosphamide, , mitomycin C, , and ethylenimine are some examples of alkylating agents that give rise to N 5 -substituted FAPy adducts. N 5 -substituted FAPy adducts are also induced by leinamycin, pluramycins, azinomycin, , and S -(2-haloethyl)­glutathione. , Structurally related unsubstituted FAPy adducts can be formed by a radical mechanism upon exposure to reactive oxygen species (ROS) − but are beyond the scope of this Perspective.…”

Bis-3-chloropiperidines containing bridging lysine linkers: Influence of side chain structure on DNA alkylating activity

“…Design of compounds 5 and 6 was based on the knowledge that naphthalene chromophores, present in the antitumour antibiotics neocarzinostatin and azinomycin A and B, contribute significantly to reinforce the affinity for DNA. [15][16][17] Additionally, the methoxy group in the 4-position of the naphthalene moiety 6 can participate in hydrogen bonding interactions.…”