Correlations of Physico-Chemical and Biological Properties with in

11

Downloaded by NORTH CAROLINA STATE UNIV on December 30, 2017 | http://pubs.acs.org Publication Date: December 22, 1980 | doi: 10.1021/bk-1980-0140.ch011

Correlations of Physico-Chemical and Biological Properties with in Vivo Biodistribution Data for Platinum-195 m-Labeled Chloroammineplatinum(II) Complexes JAMES D. HOESCHELE, THOMAS A. BUTLER, and JOHN A. ROBERTS Nuclear Medicine Technology Group, Health and Safety Research Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830

Cis-Dichlorodiammineplatinum(II), cis-[Pt(NH ) Cl ], is a unique metal-based antitumor drug which is most effective in combinational chemotherapy of cancers of genitourinary origin (1,2). Its mechanism of action is presumed to involve the inhibition of DNA synthesis (3,4). cis-[Pt(NH ) Cl ] is a member of a family of third-row transition metal complexes known collectively as the chloroammineplatinum(II) complexes. The typical square-planar structure and formulae of these complexes is illustrated in Figure 1. It is significant that cis-[Pt(NH ) Cl ] is the only complex in this series which exhibits clinically useful antitumor activity. In contrast, the structurally similar trans isomer is inactive (5,6), and the remaining complexes in this series exhibit either marginal or no antitumor activity (7). This striking contrast in biological activity for a series of related complexes, coupled with the fact that this model series of complexes ideally lends itself to the study of structure-activity relationships, prompted us to study the in vivo distribution properties of this important class of complexes. The purpose of t h i s study was to 3

3

2

2

2

2

3

2

2

o b t a i n b i o d i s t r i b u t i o n data of a systematic nature which could be c o r r e l a t e d with a v a i l a b l e physico-chemical and b i o l o g i c a l data f o r these complexes and with e x i s t i n g s t r u c t u r e - a c t i v i t y c r i t e r i a f o r platinum(II) antitumor agents. The type of data a v a i l a b l e f o r c o r r e l a t i o n i s tabulated i n Table I . C o r r e l a t i o n s of t h i s nature have the p o t e n t i a l of p r o v i d i n g a d d i t i o n a l i n s i g h t i n t o the mechanism of a c t i o n of P t ( I I ) compounds, a b e t t e r understanding of, and perhaps a b a s i s f o r p r e d i c t i n g the b i o l o g i c a l f a t e , d i s t r i b u t i o n , and p o t e n t i a l u t i l i t y of these and r e l a t e d t r a n s i t i o n metal complexes in vivo. These c o r r e l a t i o n s could a l s o s t i m u l a t e new ideas f o r the design of more e f f e c t i v e and, h o p e f u l l y , l e s s t o x i c antitumor agents. Our study of the in vivo d i s t r i b u t i o n of a l l s i x chloroammineplatinum(II) complexes has been completed and r e p r e s e n t s , to the best of our knowledge, the f i r s t b i o d i s t r i b u t i o n study of a comp l e t e s e r i e s of t r a n s i t i o n metal complexes. The purposes o f t h i s paper a r e to r e p o r t (a) a b r i e f d e s c r i p t i o n of the m i c r o s c a l e s y n t h e s i s of the ^ P t - r a d i o l a b e l e d complexes, (b) the e m p i r i c a l 1 9 5

0-8412-05 88-4/ 80/47-140-181 $07.00/0 ©

1980 American Chemical Society

Martell; Inorganic Chemistry in Biology and Medicine ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


182

INORGANIC

CHEMISTRY IN BIOLOGY A N D MEDICINE

[pt(NH ) . Cl ] 3

[PfA ] 4

2 +

4

x

x

2

, [ p t A C l ] , [ P t A C I ] ° , [ptACI ] 3

+

2

2

.[PtClJ

2

2

CIS a T R A N S Figure 1. Square-planar structure and formulae of the chloroammineplatinum(II) complexes. The series includes two cationic complex species [Pt(NH )^] and [Pt(NH ) ClY, two neutral species (cis-[Pt(NH ) Cl ], polar, and lr2Li\s-[Pt(NH ) Cl ], nonpolar), and two anionic complex species [Pt(NH )Cl y and [PtCl^] '. Counter ions are K and Cl~. A denotes NH . 3

3 3

3 2

2

2

s 2

s

+

2+

3

3


2

Chloroammineplatinum(II)

HOESCHELE E T A L .

Complexes


Table I . Physico-chemical and B i o l o g i c a l Data f o r Chloroammineplatinum(II)

Complexes

Physico-chemical P r o p e r t i e s 1.

Available

Reference

Chemical K i n e t i c and Thermodynamic Constants

16

f o r Aquation a)

Reactivity

of C l " and NH

3

Ligands

2.

Number and P o s i t i o n of Ligands (e.g., o i s

3.

Net Charge on Complex (-, 0, +)

4.

D i p o l e Moment, y Cfor c i s and

5.

Partition Coefficients, K

d

3

trans)

trans)

(organic/aqueous)

18, *

Biological Properties 1.

Antitumor A c t i v i t y

5, 7

2.

Toxicity

3.

Mutagenicity (CHO C e l l s )

5, 7

4.

B i o l o g i c a l Half-time, T!/ (B)

23, 24,

5.

DNA B i n d i n g Constants

26

27 2

* T h i s Study


Martell; Inorganic Chemistry in Biology and Medicine ACS Symposium Series; American Chemical Society: Washington, DC, 1980. 6

i 2

4

4

2

2

K C0

Reflux, 12 min

4

NH OAc

KNCO, Reflux (1 min) HCI, A

c/i-[*PtA CI ] (75)

2

Na *PtCI

2

2

4

4

2

195m

2

2

6 M HCI Reflux, 2 h

fra/7s-[*PtA CI ] (65)

4

15 M N H O H ^ [ * P t A ] C I (75) Heat

• K * P t C I (-50)

3

N H - 2 HQ

195m

S

Figure 2. Schematic of the microscale syntheses of Pt-radiolabeled chloroammineplatinum(II) complexes. Reactions are carried out at ambient temperature unless specified otherwise. Yields relative to the Pt target are enclosed in parentheses. NH and Pt are denoted by A and *Pt, respectively.

3

[*PtA CI]CI (26)^-

(19)

3

6 M HCI, P t ° ( 5 % ) , KCI K[*PtACI ]-^ Reflux, 2.5 h

2

Na *PtCI (99)

Aqua Regia, NaCI

*Pt Target


11.

HOESCHELE E T AL.

Chloroammineplatinum(II)

Complexes

185

c o r r e l a t i o n s and q u a l i t a t i v e observations discerned from these b i o d i s t r i b u t i o n s t u d i e s thus f a r , and (c) the i m p l i c a t i o n s of these observations. Experimental 19 5 m Radiolabel. 19 5 m ^ = 4.02 d) i s produced by neutron i r r a d i a t i o n (n_,y) of enriched P t (97.41%) i n the High Flux Isotope Reactor (HFIR) at the Oak Ridge N a t i o n a l Laboratory. Platinum-195m i s an i d e a l r a d i o l a b e l s i n c e i t emits penetrating r a d i a t i o n (y-photons of 99 and 129 keV) and thus provides the c a p a b i l i t y of s e n s i t i v e d e t e c t i o n of Pt at low concentrations i n b i o l o g i c a l specimens. The maximum s p e c i f i c a c t i v i t y achievable i s ^1 mCi P t / m g Pt, which i s equivalent to ^ 2 x 10 disinteg r a t i o n s /min/ng Pt. A l s o , 5Wpt i i d e a l l y s u i t e d f o r t i s s u e l o c a l i z a t i o n s t u d i e s by autoradiographic techniques s i n c e approximately three conversion e l e c t r o n s are emitted per event. pt

Pt

(

x

2


1 9 4

1 9 5 w

3

19

s

M i c r o s c a l e Syntheses. A schematic o u t l i n e of the microscale s y n t h e s i s of the * P t - l a b e l e d complexes i s i l l u s t r a t e d i n Figure 2. In general, the methods of synthesis employed were e s s e n t i a l l y adaptations and/or refinements of published procedures (8,13). Syntheses were performed at a s c a l e of 50-100 umoles Pt and overa l l y i e l d s of a given complex ranged from 40-99%. The r a d i o l a b e l e d complexes were p u r i f i e d by r e c r y s t a l l i z a t i o n from p h y s i o l o g i c a l s a l i n e and/or by techniques u t i l i z i n g ion-exchange r e s i n s . The p u r i t y of these complexes was c e r t i f i e d by comparing the u l t r a v i o l e t and v i s i b l e absorption s p e c t r a with a v a i l a b l e s p e c t r a l data (14,15,16) as w e l l as by t h i n - l a y e r and paper chromatographic techniques employing a radiochromatographic scanning device. A d e t a i l e d d e s c r i p t i o n of the methods f o r s y n t h e s i s , p u r i f i c a t i o n , and e v a l u a t i o n of the p u r i t y of these complexes w i l l be published elsewhere. At the m i c r o s c a l e l e v e l , a key stratagem which g r e a t l y f a c i l i t a t e s the synthesis of these complexes i s to a c c u r a t e l y determine the s p e c i f i c a c t i v i t y of Pt just after dissolution of the Pt t a r g e t i n aqua regia and, where necessary, a f t e r the s y n t h e s i s of

Correlations of Physico-Chemical and Biological Properties with in

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