M. Shionoya et al., NOVEL MULTIPOINT MOLECULAR RECOGNITION OF NUCLEOBASES BY A NEW ZINC(II) COMPLEX OF ACRIDINE-PENDANT CYCLEN (CYCLEN=1,4,7,10-TETRAAZACYCLODODECANE), Journal of the American Chemical Society, 116(9), 1994, pp. 3848-3859
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 compl
ex 2 recently discovered (ref 9) as a highly selective host for dT (de
oxythymidine) and U (uridine). The strong acidity of Zn-II in 2 is ret
ained 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 de
grees C and I = 0.10 (NaNO3)) and its congeners, implying an additiona
l acridine-thymine aromatic stacking interaction; (ii) a different int
eraction 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 in
teraction was observed with 2, but 4 does not interact at all with the
nucleosides dA (2'-deoxyadenosine) and dC (2'-deoxycytidine); and (ii
i) high selectivity for dT among all of the DNA nucleosides in aqueous
solution. The strong ''multipoint'' recognition of 4 with dT is prove
n by IR, NMR, and the X-ray analyses of an isolated 1:1 ternary comple
x of 4 with N(3)-deprotonated 1-methylthymine, 10.ClO4.2H(2)O. The X-r
ay crystal analysis of 10.ClO4.2H(2)O shows a distorted square-pyramid
al N-5-coordinate structure with a strong interaction between the Zn-I
I 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 stackin
g 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 sep
aration 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) Ang
strom, 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 compose
d of 4 and the free form of dG was isolated by mixing 4 and dG in CH3C
N-H2O. The X-ray crystal analysis of 11.2BF(4).2.5H(2)O shows a distor
ted square-pyramidal N-2-coordinate structure containing the fifth coo
rdination 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) Angst
rom). 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 hel
ps to stabilize the complex. Crystals of 11.2BF(4).2.5H(2)O (C32H47N10
O6.5B2F8Zn1) 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-sq
uares refinement converged at R = 0.083 and R(W) = 0.104 for 4473 inde
pendent reflections.