Solution kinetics of CC-1065 A-ring opening: substituent effects and general acid/base catalysis.
pH-rate studies were carried out on 2-substituted derivatives of the CC 1065 A-ring over the range of pH 5 to 0. The goals were to document the presence of general-acid-catalyzed cyclopropyl ring opening near neutrality and to assess the role of the 2-substituent on the rate of nucleophile trapping by the cyclopropyl ring. Our studies show that the cyclopropyl group undergoes reversible general-acid/base-catalyzed trapping of chloride nucleophiles above pH 4. This finding implies that the general-acid-catalyzed alkylation of DNA minor groove by the A-ring is feasible. pH-rate studies also showed that the 2-substituent does not influence the pKa of the protonated carbonyl of the A-ring (pKa approximately 1) and has relatively little effect on the rate of nucleophile trapping. This finding is consistent with calculations that show the fused pyrrolo ring as the source of carbonyl oxygen electron density. The 2-nitrogen, on the other hand, only releases electrons to the carbonyl of the 2-substituent and does not greatly influence trapping of nucleophiles by the A-ring cyclopropyl group.
Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
Daniel V
DV
LaBarbera
Edward B
EB
Skibo
D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D002384:Catalysis; D000080890:Duocarmycins; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D012996:Solutions
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D012996:Solutions; C018782:CC 1065