Di- and trinuclear copper(II) complexes of [12]aneN3 macrocycles anchored at the upper rim of cone calix[4]arenes in 1,2-, 1,3-, and 1,2,3-positions were investigated as cleaving agents of 6-, 7-, and 17-meric oligoribonucleotides. A kinetic investigation of the cleavage reactions was carried out using gel electrophoresis to separate and analyze reactants and products having a radioactive phosphate label in the terminal 5'-position. The degree of cooperation was assessed on the basis of a comparison with rates of cleavage by mononuclear controls. A remarkable selectivity of cleavage of the CpA phosphodiester bond was observed for all metal complexes, in sharp contrast with the UpU and UpG selectivity previously observed in the cleavage of diribonucleoside monophosphates by the same metal complexes. The highest rate acceleration, brought about in the cleavage of the 5'-pCpA bond in hexanucleotide 9 by 50,uM trinuclear complex 5-CU3 (water solution, pH 7.4, 50 degrees C), amounts to 5 x 10(5)-fold, as based on the estimated background reactivity of the CpA dimer. Selectivity in the cleavage of oligoribonucleotides by copper(II) complexes closely resembles that experienced by ribonuclease A and by a number of metal-independent RNase A mimicks. The possible role of the dianionic phosphate at the 5'-terminal positions as a primary anchoring site for the metal catalyst is discussed.