Efficient inhibition of photo[2+2]cycloaddition of thymidilyl(3′-5′)thymidine and promotion of photosplitting of the cis-syn-cyclobutane thymine dimer by dimeric zinc(II)-cyclen complexes containing m- and p-xylyl spacers

被引:56
作者
Aoki, S [1 ]
Sugimura, C [1 ]
Kimura, E [1 ]
机构
[1] Hiroshima Univ, Sch Med, Dept Med Chem, Minami Ku, Hiroshima 7348551, Japan
关键词
D O I
10.1021/ja981788c
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Monomeric and dimeric zinc(II) complexes of cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) inhibited the photo[2 + 2]cycloaddition of thymidilyl(3'-5')thymidine (d(TpT)) at neutral PH in aqueous solution for a novel mechanism. Comparison of the initial rates and the product yields of the photodimerization of d(TpT) (in Tris buffer at pH 7.6 with I = 0.10 (NaNO3)) at 3-5 degrees C by high-pressure mercury lamp indicates that the dimeric zinc(II) complexes, p- and m-xylyl-bis(Zn2+-cyclen) (Zn2L2 and Zn2L3), are effective inhibitors (70-85% inhibition compared with the control reaction at [d(TpT)] = [bis(Zn2+-cyclen)] = 0.2 mM after 20 min irradiation). This inhibition is due to the extremely strong 1:1 complexation of two deprotonated thymidine (dT(-)) moieties with two Zn2+-cyclen moieties (apparent complexation constants, log K-app (K-app = [Zn2L2 (or Zn2L3)-d(T(-)pT(-))]/[Zn2Lfree2 (or Zn2Lfree3)][d(TPT)(free)] (M-1)), of 6.4 +/- 0.1 at PH 7.6 (50 mM HEPES, I = 0.1 (NaNO3)) and 25 degrees C, as determined by the isothermal calorimetric titration). A major product, cis-syn-cyclobutane thymine dimer (T[c,s]T), was also found to form complexes with Zn2+-cyclens. The apparent affinity constants for 1:1 complexes of one of the imide sites of T[c,s]T with a monomeric Zn2+-benzylcyclen (ZnL1) and with each Zn2+-cyclen unit (ZnL) of m-xylyl-bis(Zn2+-cyclen), log K-app (K-app = [ZnL1 (or ZnL)-(T[c,s]T)(-)]/[ZnLfree1 (or ZnLfree)][T[c,s]T-free] (M-1)), were 3.7 +/- 0.1 and 3.8 +/- 0.1, respectively, at pH 7.6 (50 mM HEPES, I = 0.1 (NaNO3)) and 25 degrees C. The photosplitting of T[c,s]T, a reverse reaction of the photodimerization, at pH 7.6 (5 mM Tris buffer with I = 0.1 (NaNO3)) was kinetically and thermodynamically promoted by m-xylyl-bis(Zn2+-cyclen). The H-1 NMR measurement showed that 78% of the cyclobutane of T[c,s]T (1 mM) was split after 1 h of UV exposure in the presence of an equivalent amount of m-xylyl-bis(Zn2+-cyclen), whereas the control reaction showed 54% splitting. The kinetic and thermodynamic stability of the 1:1 m-xylyl-bis(Zn2+-cyclen)- d(T-pT-) complex also accounts for the acceleration of photosplitting of T[c,s]T. The inhibitory effect of m-xylyl-bis(Zn2+-cyclen) on the photoreaction of poly(dT) was also revealed.
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页码:10094 / 10102
页数:9
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共 82 条
  • [51] UV AND SKIN-CANCER - SPECIFIC P53 GENE MUTATION IN NORMAL SKIN AS A BIOLOGICALLY RELEVANT EXPOSURE MEASUREMENT
    NAKAZAWA, H
    ENGLISH, D
    RANDELL, PL
    NAKAZAWA, K
    MARTEL, N
    ARMSTRONG, BK
    YAMASAKI, H
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (01) : 360 - 364
  • [52] NUMAO N, 1977, TETRAHEDRON LETT, P1661
  • [53] CHLORANIL-PHOTOSENSITIZED MONOMERIZATION OF DIMETHYLTHYMINE CYCLOBUTANE DIMERS AND EFFECT OF MAGNESIUM PERCHLORATE
    PAC, CJ
    MIYAMOTO, I
    MASAKI, Y
    FURUSHO, S
    YANAGIDA, S
    OHNO, T
    YOSHIMURA, A
    [J]. PHOTOCHEMISTRY AND PHOTOBIOLOGY, 1990, 52 (05) : 973 - 979
  • [54] CRYSTAL-STRUCTURE OF DNA PHOTOLYASE FROM ESCHERICHIA-COLI
    PARK, HW
    KIM, ST
    SANCAR, A
    DEISENHOFER, J
    [J]. SCIENCE, 1995, 268 (5219) : 1866 - 1872
  • [55] PROPERTIES OF TOPICAL SUNSCREEN FORMULATIONS - A REVIEW
    PATEL, NP
    HIGHTON, A
    MOY, RL
    [J]. JOURNAL OF DERMATOLOGIC SURGERY AND ONCOLOGY, 1992, 18 (04): : 316 - 320
  • [56] STUDIES ON THYMINE-DERIVED UV PHOTO-PRODUCTS IN DNA .2. COMPARATIVE ANALYSIS OF DAMAGE CAUSED BY 254 NM IRRADIATION AND TRIPLET-STATE PHOTOSENSITIZATION
    PATRICK, MH
    SNOW, JM
    [J]. PHOTOCHEMISTRY AND PHOTOBIOLOGY, 1977, 25 (04) : 373 - 384
  • [57] The ozone layer: The road not taken
    Prather, M
    Midgley, P
    Rowland, FS
    Stolarski, R
    [J]. NATURE, 1996, 381 (6583) : 551 - 554
  • [58] INFLUENCE OF MERCURIC IONS ON PHOSPHORESCENCE AND PHOTOCHEMISTRY OF DNA
    RAHN, RO
    BATTISTA, MD
    LANDRY, LC
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1970, 67 (03) : 1390 - &
  • [59] Tight binding of a dimeric derivative of vancomycin with dimeric L-Lys-D-Ala-D-Ala
    Rao, JH
    Whitesides, GM
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1997, 119 (43) : 10286 - 10290
  • [60] ULTRAVIOLET-IRRADIATION OF NUCLEIC-ACIDS - FORMATION, PURIFICATION, AND SOLUTION CONFORMATIONAL-ANALYSES OF OLIGOTHYMIDYLATES CONTAINING CIS-SYN PHOTODIMERS
    RYCYNA, RE
    WALLACE, JC
    SHARMA, M
    ALDERFER, JL
    [J]. BIOCHEMISTRY, 1988, 27 (09) : 3152 - 3163