Lexitropsin Conjugates: Action on DNA Targets

Abstract

Lexitropsins have been combined with epipodophyllotoxin, aromatic and aliphatic phosphonated and sulfonated compounds, bithiazoles, oligodeoxy-ribonucleotides, pyridine, imidazole, decazadecabutylamine, acridines, anthraquinones, pyrene, ellipticine, oxazolopyridocarbazole, porphyrin, nitrosoureas, benzoyl mustards, nitrogen mustards, CC-1065, psoralens, bleomycin, flavins, metal chelating moieties, enediynes, and propargyl sulfones to give the corresponding lexitropsin conjugates. In most of the cases each of the individual components of the lexitropsin conjugate retain their modes of action as far as interaction with DNA is concerned. In some cases the components of the lexitropsin conjugates altered their mode of interaction towards DNA or developed new properties. Alkyl alkanesulfonate esters are major groove alkylators. After formation of lexitropsin conjugates they become minor groove alkylators. A-T specific netropsin and distamycin accept G-C sites after forming conjugates with pyridine. CI-ENU breaks DNA after alkylation at N7 of guanine whereas its lexitropsin conjugate cleaves at A and T residues associated with affinity binding sites. Benzoyl mustard changes from a major groove alkylator (N7 of guanine) to a minor groove alkylator (adenine) after formation of lexitropsin conjugates. Epipodophyllotoxin conjugates with lexitropsins have additional sites available for topoisomerase II cleavage compared with the unconjugated agent. Thermal stability of oligodeoxynucleotides is increased after formation of a lexitropsin conjugate. In the case of lexitropsin acridine conjugates the binding of one component is compatible with DNA binding of the other component. The A-T specificity of a netropsin-oxazolopyridocarbozole conjugate is much less as compared to netropsin. Lexitropsin-psoralen conjugates bind more tightly at A-T sites of DNA compared with the individual components. The relative rate of DNA cleavage is increased with increase in the number of N-methylpyrrole units in lexitropsin-bleomycin conjugates. Phosphonated-sulfonated lexitropsin conjugates are highly active against HIV and may prove valuable for the treatment of AIDS. The benzoyl mustard-lexitropsin conjugate, i.e., FCE-24517, shows broad spectrum anticancer activity and is undergoing clinical evaluation.