Oligonucleotide modelization of DNA-platinum complexes interactions.

422

Abstracts

J003

O L I G O N U C L E O T I D E M O D E L I Z A T I O N OF DNAPLATINUM COMPLEXES INTERACTIONS. J . C . C h o t t a r d , Universit6 Rend Descartes, LIRA 400, 45 rue des SaintsPdres, 752 70 Paris Cedex 06, France. T h e talk will address the two following questions :

1. Which factors lead to the preferential binding of cisptatin to G,~ (n>2) sequences and which guanine is platinated first ? W e have previously shown by molecular mechanics that both a 5' and a 3' neighboring guanine can assist the platination of a guanine 1. However, due to their inherent inaccuracy,these calculations could not predict which of the t w o g u a n i n e s in a G G s e q u e n c e is p r e f e r e n t i a l l y platinatedo W e have d e v e l o p e d a t e c h n i q u e for m e a s u r i n g the four concentrations [A], [I1] , [1121 and [P] involved in the reaction of a G G - c o n t a i n i n g oligonucleotide with cis[Pt(NH3)2(H20)2] 2+ as a function of time :

--c

Scheme I

(~-z]

c

- ~'eI

..............

,.

9.,~.,

-

.....

/

,r~-"-,

(>~

Integration of the differential equations corresponding to Scheme I and an optimization of the fit between the experiment~ and calculated concentration c u r v e s y i e l d e d the four rate constants. This p r o c e d u r e was applied to the t r i n u c l e o t i d e d ( T G G ) . E x p e r i m e n t s with s i m p l e and d o u b l e s t r a n d e d oligonucleotides, as well as with cis-[Pt CI(NH3)2(tI20)] + are in progress. 2) What is the differettce between the DNA deformalions induced by the GG-cis-Pt(NH3)2 and AG-cis-Pt(Ntl3) 2 chelates which one might try to link to the different biological properties of the two adducts 2 ,~ W e have d e s c r i b e d in details the k i n k e d structure of the G * G * - c i s P t ( N t t 3 ) 2 c h e l a t e o f the d e c a n u c l e o t i d e d u p l e x d ( G C C G * G * A T C G C ) d ( G C G A T C C G G C ) , based on the N M R guided m o l e c u l ~ mechanics analysis of this short platinated nucleic acid fragment 3 A similar study is c o n d u c t e d w i t h the A * G * - c i s - P t ( N H 3 ) 2 c h e l a t e o f the n o n a n u c l e o t i d e d u p l e x d ( C T C A * G * C C T C ) - d ( G A G G C F G A G ) . The N M R and molecular mechanics data will be c o m p a r e d and d i s c u s s e d in the light of results o b t a i n e d with c h e m i c a l probes 4 and from the study o f the mutagev, ic properties of both adducts in E. coli 2,5. 1. Laoui, A.; Kozelka, J. ; Chottard, J.C., In0rg. Chem. 1988, 2_7_,2751-2753. 2. Burnouf, D. ; Gauthier, C. ; Chottard, J.C, ; R.P.P. Fuchs, _Pro_£_~._N~t_l~Ac~td. Sci. USA, 1990, _8_7_,6087-6091. 3. Herman, F. ; Kozelka, J. ; Stovcn, V. ; Guittet, E. ; Girault, J.P. ; ttuynh-Dinh, T. ; Igolen, J. ; Lallemand, J.Y. ; Chottard, J.C., E~lr, ,1, Bioq:hcm,. 1990, 19.L~4,119-133. 4. Schwartz, A. ; Marrot, L. ; Leng, M., Biochemistry, 1989, 2__~,7975-7979. 5. Essigman, J. , Confdrence, VIth International Symposium on Platinum and Other Metal Coordination compounds in Cancer Chimotherapy, San Diego, Jap... 23-26, 1991.