Kapurimycin A3

Recent results on the action mechanisms of naturally occurring DNA-damaging antitumor antibiotics have been described. These antibiotics include neocarzinostatin (NCS) and DNA alkylating, duocarmycin A and kapurimycin A3. A series of duplex hexanucleotides of modified bases were prepared and their selectivity for C5' and C4' oxidation in the NCS-mediated degradation was investigated. Based on the cleavage data, a new binding model that permits competitive hydrogen abstraction from C5' and C4' of the DNA deoxyribose moiety has been described. Chemistry of alkylation of self complementary octanucleotide d(CGTATACG)2 by antitumor antibiotic duocarmycin A was described. It was demonstrated that N3 of adenine6 attacks the cyclopropane subunit of duocarmycin A to produce the covalently alkylated adduct. In contrast, antibiotic kapurimycin A3 alkylate N7 of guanine4 of d(CGCG)2 to provide the corresponding covalent adduct. Heating at 90 degrees C degraded the adduct to kapurimycin A3-guanine adduct and the respective abasic site-containing oligonucleotide. The structures of heat-induced abasic sites were unambiguously characterized.

The kapurimycin A3-guanine adduct was formed by alkylation of the antitumour antibiotic with d(CGCG)2. The site of alkylation of the guanine was confirmed by comparative NMR studies with N-7-methyl-guanine in DMSO-d6.

We synthesized kapurimycin A3 ABCD-ring analog and compared the sequence selectivity for DNA guanine alkylation with those of kapurimycin A3 and ABC-ring analog. In the binding to DNA, it was shown by DNA unwinding assay that ABCD-ring analog binds tightly to DNA by intercalation into DNA duplex. DNA alkylation by ABCD-ring analog was sequence selective with an order of G*G > G*A > G*T > G*C. ABCD-ring analog has a stronger binding ability, a higher reactivity to DNA and a higher GG sequence selectivity in DNA alkylation than those to ABC-ring analog. The aromatic ring system plays an important role in the effective GG selective alkylation.