6 Platinum complexes of pyridine-3-carboxamides

104'0

Biochimie.

N o u s a v o n s e n r e g i s t r d les s p e e t r e s d u DNA et R N A et o b t e n u p o u r la p r e m i 6 r e f o i s h n o t r e c o n n a i s s a n c e c e u x de l e u r s c o m p l e x e s avee le cis-Pt(NHa)..C1,_,. E n e o m p a r a n t le s p e c t r e d u DNA ou R N A l i b r e avec celui d u e o m p l e x e DNA o n R N A - P l a t i n e n o u s c o n s t a t o n s des m o d i f i c a t i o n s e n i n t e n s i t d et e n f r ~ q u e n c e de c e r t a i n e s raies, D a n s le c a s d u DNA, l a r a i e h 1486 cm-1 a t t r i b u d e h u n e v i b r a t i o n d u s q u e l e t t e de la g u a n i n e i m p l i q u a n t les a t o m e s H s - C s - N7- C6- N1 (svave like m o d e ) d i m i n u e d ' i n t e n s i t d e n p r d s e n c e d u p l a t i n e (I~se~Pt-DNA/ II~ssDNA ~ 2/3). O n o b s e r v e a u s s i u n e d i m i n u t i o n de l ' i n t e n s i t d de eette r a t e d a n s le s p e c t r e d u e o m p l e x e P t - R N A p a r r a p p o r t a u s p e c t r e d u R N A l i b r e (I~4~PtR N A / I x , u R N A ---- 0,90). Cette v a r i a t i o n e n i n t e n s i t ~ e s t m o i n s i m p o r t a n t e p o u r le c o m p l e x e P t - R N A . Ceci e s t dfi a u r a p p o r t p l u s f a i b l e P t / P = 0,03 et h u n p o u r e e n t a g e p l u s dlevd e n G-C (63 p. c e n t ) d a n s le e a s d u RNA. P e t i c o l a s et Col. [2] o n t d a n s le s p e c t r e d u DNA o h s e r v ~ a u s s i u n e d i m i n u t i o n d e l ' i n t e n s i t d de cette r a i e h 1486 cm-1 l o r s de la p r o t o n a t i o n o u de l ' a l k y l a t i o n de la g u a n i n e e n p o s i t i o n NT. L a r a i e h 672 em-1 d a n s le s p e c t r e d u DNA l i b r e p a s s e h 668 em-1 d a n s le e o m p l e x e P t - D N A et d i m i n u e d ' i n t e n s i t & Cette r a i e e s t a t t r i b u d e h la v i b r a t i o n <> de la g u a n i n e . D a n s le c o m p l e x e P t - R N A , o n e o n s t a t e u n e d i m i n u t i o n de l ' i n t e n s i t d d e la r a i e h 670 em-1, de eelle m e s u r d e h 1575 em-1 ( g u a n i n e <
c r y s t a l s of t h e c o m p l e x w e r e i s o l a t e d as t h e d i s o d i u m s a l t b y v a p o r d i f f u s i o n of t h e r e a c t i o n m i x t u r e a g a i n s t t-butanol. T h e g e o m e t r y o f t h e [Pt(en)(5'-GMP)~]2- a n i o n (figure) c o n s i s t s o f a s q u a r e p l a n a r a r r a n g e m e n t of ligands around platinum. The nucleotides are bonded to t h e m e t a l t h r o u g h t h e i m i d a z o l e r i n g n i t r o g e n a t o m s , N(7), of t h e g u a n i n e b a s e s . A v e r a g e d i s t a n c e s a n d a n g l e s i n t h e m o l e c u l e a r e : Pt-N(7) ---- 1.95 ~_, P t - N ( e n ) ---- 2.04 7~, N(7)...N(7) = 2.73 •, N(7)-Pt-N(7) _-- 88.4 ° , N ( 7 ) - P t - N ( e n ) ---- 94.8 ° , N ( e n ) - P t - N ( e n ) ----83.6 ° . Hydrogen-bonds are found between the ethylened i a m i n e n i t r o g e n a t o m s a n d c a r b o n y l o x y g e n s , O(6), of n e i g h b o r i n g m o l e c u l e s a t a n a v e r a g e d i s t a n c e of 2..85 ~ . A s e r i e s of i n t r a m o l e c u l a r a n d i n t e r m o l e c u l a r

hydrogen bonds further stabilize the structure. Cryst a l l o g r a p h i c d e t a i l s : c r y s t a l s of Na~EPt(en)(5'-GMP)~]. 3H20 a r e h e x a g o n a l (space g r o u p P6~22), w i t h a ---24.812 3~, c ---- 32.757 3~, Z ---- 12. C u r r e n t R f a c t o r 10.3 p e r c e n t f o r 1537 i n d e p e n d e n t n o n - z e r o reflections.

1. P. K. G a n g u l i ~ T , T h e o p h a n i d e s (h p a r a l t r e ) , 2. S. M a n s y a W . L. P e t i e o l a s (1976) Biochemistry, 15, 2650. 3. M. T s u b o i , S. T a k a h a s h i , S. M u r a i s h i , T. K a j i u r a S. N i s h i m u r a (1971) Science, 174, 1 1 4 2 .

Platinum complexes of pyridine-3-carboxamides. J. P. LAURENT a n d P. LEPAGE.

Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 3103,0 Toulouse Cedex- France.

Structure of [Pt(en)(5"-GMP).fi2- anion. R o b e r t BAU a n d R o b e r t W . GELLERT.

Department of Chemistry, University of Southern California, Los Angeles, Calif. 90007, U.S.A. The [Ptfethylenediamine) (5'-guanosine monophosphate)..]2- a n i o n w a s p r e p a r e d b y r e a c t i n g Na2(5'GMP) 'with Pt(en)Cl~ in 2:1 m o l e r a t i o . H e x a g o n a l

BIOCHIMIE, 1978, 60, n ° 9.

In c o n t r a s t to t h e yello'w o r c o l o r l e s s n a t u r e o f m o s t of t h e p l a t i n u m c o m p l e x e s i n v o l v i n g p y r i d i n e carb o x a m i d e s as l i g a n d s , 1 - m e t h y l n i c o t i n a m i d e y i e l d s deep b l u e c h l o r o - (A) a n d a q u o - (B) speeies. A t t e m p t s to p r e p a r e c r y s t a l l i n e s a m p l e s a r e u n s u c c e s s f u l h u t s o m e p r e l i m i n a r y c o n c l u s i o n s c a n he d r a ' w n a b o u t t h e nature of these two materials. Analytical data unequivocally establish the presence o f o n e n i c o t i n a m i d e l i g a n d p e r p l a t i n u m a t o m in both the chloro- and aquo- species although the hy-

1041

Abstracts. drogen ratio exhibits some v a r i a t i o n s f r o m sample to sample. Empirical f o r m u l a t i o n s such as PLCI~C~H~, NsO~ (A) and PLC~H~N~O= (B) give a reasonably good fit to the w h o l e analytical results. Both types of compounds (A and B) display similar spectroscopic features. In the visible region one broad absorbance peak only is observed at, respectively, 690 (A) and 710 n m (B). The solid state i n f r a r e d spectra strongly suggest t h a t deprotonated amido groups are involved in coordination to the p l a t i n u m atoms t h r o u g h their nitrogen and oxygen atoms. F u r t h e r characterization of the two species is gained from other physical (magnetic susceptibility m e a s u r e m e n t s , 1H and 1.~C NMR spectroscopy) and chemical (reactions with o x y d a n t s and reductants) studies. All the so-available data m a y be accomodated by assuming polymeric structure which 'would involve amido bridges bet~veen partially oxidized p l a t i n u m atoms. The coordination around each metal center would then be achieved by CI-, OH~ a d d / o r OH-. The interactions of (A) and (B) species with some nucleosides are currently investigated.

- - Multifunetional character of the ligands with several possibilities of metal coordination (different donor atoms ; monodentate, bridging, chelating (?) binding). --Possibility of G to act as neutral ligand and as anion. Differences in steric a r r a n g e m e n t s of the ligands (angle b e t w e e n plane(s) of ligand(s) ; r o t a t i o n of ligand). - - Variety of hydrolysis products of cis-Pt(NH3)3CL. Our efforts are aimed (1) at the X-ray structure d e t e r m i n a t i o n and the spectroscopic investigation of the isolated P t complex (2) at the investigation of the redissolved complex by spectroscopic and other analytical methods. By this method we gain i n f o r m a t i o n on the changes in the bases upon Pt coordination (aromatic character, tautomeric structure, acidity of ligand, H-bonding) as well as on the possible d i s t o r t i o n of the DNA structure (position of the rings due to h y b r i d i z a t i o n of the donor atoms, effect on H-bonding etc.). II. Results. - - We are p r e s e n t l y working on complexes of the u n s u b s t i t u t e d p y r i m i d i n e and purine bases as well as the 1-Alkylpyrimidines and the 9-Alkylpurines, respectively. F r o m the complexes investigated so far, this report will focus on a PL compound containing 1-Melhyleytosine and 9-Ethylguanine and a 1:1 complex of 1-Methylcytosine and Pt.

Mixed-liqand complexes of ~ c/s-Pt(NH3h~,, containing pyrimidine and purine bases. B e r n h a r d LIPPEnT. Anorganisch-Chemisches I n s t i t u t der Technischen Universildt MOnchen, Lichtenbergstr. ~, 8 0 ~ Garching, Federal Republic o[ Germany.

I. Concept of ,work. - - It is our concept to systematically synthesize and investigate the possible reaction products t h a t can be f o r m e d between cis-Pt(II) and the four m a j o r bases of DNA, t h y m i n e (T), cytosine (C), adenine (A), and guanine (G). They include the four 1:1 complexes as well as the ten 2:1 complexes, t h a t is a2PtG a2PtA a2PtC a2PtT a~PtG~ a~PtA~_ a~PtC~ a_.Pt% a~PtGA a~PtAC a~PtCT a2PtGC a2PtAT a~PtGT w i t h a~Pt = cis-Pt(NH3):. This n u m b e r (4 + 10) of possible c o m b i n a t i o n s is actually increased for several reasons :

(1) cis-Pt(NH~)2(1-Me-Cyto)C1 +. F r o m the 8 crystalline complexes containing cisPt(NH3)z2 + and 1-Methyteytosine (in 1:1 I:2, and 1:3 ratios) so far isolated and presently investigated, by X-ray (Colin J. L. Lock, McMaster University), and o t h e r methods, cis-[Pt(NH3)2(1-MeeCyto)C1]C1 • 1 H20 represents the simplest compound. X-ray results, 1H-NMR, 13C-NMR, UV, IR and Ramart data avill be presented. The changes in the cytosine ring upon Pt coordination 'will be discussed and compared to those of published structures. These changes are interpreted as being responsible for the f o r m a t i o n of complexes w i t h N-3, NH(4) bridged cytosine ligands. (2) cis[Pt(NHs)~(1-Me-Cyto)(9-Et-Gua) ]2+. The structure of a complex containing 1-Methylcytosine and 9-Ethylguanine has been d e t e r m i n e d (C. J. L. Lock) and its solution properties studied. X-ray results, 1H-NMR, 13C-NMR and UV spectra will be presented. The acidity of the proton at N(1) of the Gua ligand in this complex is enhanced by

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C~5 BIOCHIMIE, 1978, 60, n ° 9.

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