NOVEL MULTIPOINT MOLECULAR RECOGNITION OF NUCLEOBASES BY A NEW ZINC(II) COMPLEX OF ACRIDINE-PENDANT CYCLEN (CYCLEN=1,4,7,10-TETRAAZACYCLODODECANE)

A zinc(II) complex of acridine-pendant cyclen, 4.2ClO(4) (cyclen = 1,4,7,10-tetraazacyclododecane, 1), has been designed and synthesized as a new ''multipoint'' nucleobase receptor molecule in aqueous solution at physiological pH and compared with a Zn-II pendantless cyclen complex 2 recently discovered (ref 9) as a highly selective host for dT (deoxythymidine) and U (uridine). The strong acidity of Zn-II in 2 is retained in 4; the water at the fifth coordination site has a pK(a) value of 7.46 +/- 0.02, L-Zn-OH2 reversible arrow L-Zn-OH-. Interaction of 4 with a variety of nucleosides has been studied by potentiometric pH titration, H-1 and C-13 NMR, IR, UV-vis, and fluorescence spectroscopy. The effects of the acridine functionality in 4 are (i) an enhanced 1:1 association with N(3)-deprotonated dT (log K = 7.2 +/- 0.1 at 25 degrees C and I = 0.10 (NaNO3)) and its congeners, implying an additional acridine-thymine aromatic stacking interaction; (ii) a different interaction mode with dG (2'-deoxyguanosine) (log K = 5.0 +/- 0.1 for the N(1)-deprotonated form and 4.1 +/- 0.1 for the free form) while no interaction was observed with 2, but 4 does not interact at all with the nucleosides dA (2'-deoxyadenosine) and dC (2'-deoxycytidine); and (iii) high selectivity for dT among all of the DNA nucleosides in aqueous solution. The strong ''multipoint'' recognition of 4 with dT is proven by IR, NMR, and the X-ray analyses of an isolated 1:1 ternary complex of 4 with N(3)-deprotonated 1-methylthymine, 10.ClO4.2H(2)O. The X-ray crystal analysis of 10.ClO4.2H(2)O shows a distorted square-pyramidal N-5-coordinate structure with a strong interaction between the Zn-II and the N(3'')-deprotonated anion of the pyrimidine ring (Zn(1)-N(3'') = 1.987(4) Angstrom). The carbonyl oxygen O(2'') of the pyrimidine ring forms a hydrogen bond directly with a cyclen N(10)-H group (O(2'')-N(10) = 2.881(5) Angstrom), while the other O(4'') binds indirectly with a diagonal N(4)-H group via a water molecule. As postulated from the enhanced stability for the 4-dT complex, a strong cofacial stacking interaction is found between the acridine (at C(1'), C(2'), C(4'), C(4a'), and C(9a')) and the pyrimidine ring with the plane-to-plane separation ranging from 3.285 to 3.419 Angstrom. Crystals of 10.ClO4.2H(2)O (C28H40N7O8Cl1Zn1) are C-centered monoclinic, space group C2/c (#15) with a = 15.312(3) Angstrom, b = 21.920(3) Angstrom, c 18.774(2) Angstrom, beta = 101.68 (1)degrees, V = 6171 (1) Angstrom(3), and Z = 8. Full-matrix least-squares refinement converged at R = 0.062 and R(W) = 0.093 for 3573 independent reflections. A ternary complex 1 1 composed of 4 and the free form of dG was isolated by mixing 4 and dG in CH3CN-H2O. The X-ray crystal analysis of 11.2BF(4).2.5H(2)O shows a distorted square-pyramidal N-2-coordinate structure containing the fifth coordination from N(7'') of the dG purine ring to Zn-II (Zn(1)-N(7'') = 2.04(1) Angstrom). The carbonyl oxygen O(6'') of the purine ring forms a hydrogen bond with a cyclen N(4)-H group O(6'')-N(4), 3.01 (1) Angstrom). A strong cofacial stacking interaction between the acridine (at C(1'), C(2'), C(3', C(4'), and C(4a')) and the purine ring greatly helps to stabilize the complex. Crystals of 11.2BF(4).2.5H(2)O (C32H47N10O6.5B2F8Zn1) are monoclinic, space group P2(1) (#4) with a = 10.892(4) Angstrom, b = 21.230(2) Angstrom, c = 17.465(2) Angstrom, beta = 101.19(1)degrees, V = 3974(1) Angstrom(3), and Z = 4. Full-matrix least-squares refinement converged at R = 0.083 and R(W) = 0.104 for 4473 independent reflections.