Kiralj R., Ferreira M. M. C., “(QUANTITATIVE) STRUCTURE-SPECTROSCOPIC PROPERTY RELATIONSHIPS (Q)SSPR FOR 4,9-DIAZAPYRENIUM-NUCLEOTIDE BINDING IN AQUEOUS MEDIA”. Villeneuve d'Ascq, France, 01-06/09/2002: XXVIth  European Congress on Molecular Spectroscopy (EUCMOS XXVI), Abstracts, 371 (2002). Poster  15.13. Section: 15. NEW TECHNICS IN SPECTROSCOPY, CHEMOMETRICS.

                                                        15.13

               (QUANTITATIVE) STRUCTURE-SPECTROSCOPIC PROPERTY
          RELATIONSHIPS (Q)SSPR FOR 4,9-DIAZAPYRENIUM-NUCLEOTIDE
                                          BINDING IN AQUEOUS MEDIA

                                       R. Kiralj and M. M. C. Ferreira

Instituto de Química, Universidade Estadual de Campinas, Campinas SP, 13083-970, Brazil
                                marcia@iqm.unicamp.br, rudolf@iqm.unicamp.br

           4,9-Diazapyreniums  exhibit  anti-cancer  activity^1,2.   They  are  flat,   charged
species  soluble  in  water  and  bind  to  nucleotides  and  nucleic  acids.   The main
mechanism of interactions are p…p stacking interactions betweenaromaticsystems,
hydrogen   bonds   and   polar   interactions.   Recently,   the   binding  of   five    4,9-
diazapyreniums  and  three phenanthridinium (cations)  with  AMP, ADP,  ATP,  GMP,
CMP (anions)  in water, was studied  by  fluorimetric  titration  of  the  anions  with the
cations (quenching of  fluorescence  of  1:1  complexes),andthe  binding  constants
were calculated based on fluorescence intensities  and  concetrationsof the cations¹.
In  this  work  Principal  Component  (PCA)  andHierarchical  Cluster Analysis  (HCA)
were used to  analyze  these binding constants.  Three  Principal Components (PC’s)
describe  the data  matrix (99.0%  total variance).  HCA exihibits two clusters  of  both
anions and cations. PCA has  similar trend in clustering the molecules. PC1 and PC2
are strongly connected  to  the observed activities  (binding constants)  and  effective
contact surface area H  (they  can be rationalized  in  terms  of  structural,  electronic,
steric  and  conformational  properties  of  both  anions   and  cations).  The   binding
constants also depend  on molecular structure  of  the nucleotides.
Besides,  the  extended  set  of  16   4,9-diazapyreniums  was  studied   by  PCA  and
HCA including H and three spectroscopic descriptors based on ¹H NMR shifts of   the
diazapyrene aromatic ring³: ST – the average shift with respect  to  pyrene  analogue
values, NORM – the average shift normalized by the number of C and N atoms of the
ring,  DIFF – the maximal difference between  the shift.  ThreePC’s  describe  99.7%
total variance. Both PCA and HCA indicated that the active diazapyrenium  are  those
confirmed by experimental findings (those soluble and stable in water).  Their  activity
depends mostly on their size and substitutions   at  the  diazapyrene  ring.  There  are
high correlations between variables  ST,  NORM,  DIFF  and  H for the active cations
(correlation coefficients  greater  than  0.68).  The  binding  constants  moderately  to
highly  correlate  with  these  descriptors  (correlation  coefficients  0.38  to  0.99).  In
general,   multivariate  analysis  would  be  preferred   if  there  would  be  more  data
available.
Both  fluorescence  and  ¹H NMR  data  exhibit   the  aromaticity  and  conformational
properties of the diazapyreniums via p...p stacking interactions in  complexation  with
nucleotides. Also, chemometric analysis at qualitative and quantitative level can  help
in design of new cations with desired activity (binding to nucleotides).


                                                Fig. 1:  4,9-Diazapyrene ring
 

[1] I. Piantanida, Master Thesis, 1997, University of Zagreb, Zagreb, Croatia.
[2] I. Piantanida, V. Tomisic and M. Zinic, J. Chem. Soc. Perkin Trans. 2. 375 (2000).
[3] R. Kiralj, Doctoral Thesis, 1999, University of Zagreb, Zagreb, Croatia.
 

                                    EUCMOS XXVI - VILLENEUVE D'ASCQ  2002                 371