close

Вход

Забыли?

вход по аккаунту

?

bk-1983-0209.ch013

код для вставкиСкачать
13
Synthesis and Biological Studies of a New Class
of Antitumor Platinum Complexes
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
DAVID B. BROWN, ABDUL R. KHOKHAR, MILES P. HACKER,
JOHN J. McCORMACK, and ROBERT A. NEWMAN
University of Vermont and the Vermont Regional Cancer Center,
Departments of Chemistry and Pharmacology, Burlington, VT 05405
A series of platinum complexes having the general
formula LPtCl , where L is a ligand bearing a formal
positive charge, have been prepared and have been demonstrated to exhibit significant antitumor activity.
Complexes with this formulation satisfy the generally
accepted criteria for structural features required in
an antitumor-active platinum complex, but are expected
to possess kinetic advantages when compared to the
prototype antitumor platinum complex, cis-dichlorodiamineplatinum (II). Complexes have been prepared
where L is a monoprotonated diamine and also where L
is a protonated amino-olefin. All complexes have been
examined for cytotoxicity against L1210 leukemia in
cell culture, and selected compounds have been tested
3
for antitumor activity in vivo (L1210 leukemia in BDF
mice). One compound, where L is protonated 3-amino1
-quinuclidine, has significant in vivo activity, with
T/C approaching 150%.
More than a decade has elapsed since Rosenberg first reported
(1) the antitumor activity of cis-dichlorodiamineplatinum(II),
DDP. It would be fortuitous indeed if the first platinum complex
reported proved to be the most effective compound of its type.
Furthermore, although DDP is one of the most effective antitumor
drugs available, its use is accompanied by severe nausea and a
range of toxic effects Ç2). These factors, combined with the
rather limited range of clinical activity for DDP, have led to
the search for new antitumor platinum compounds having either
increased efficacy or decreased toxicity, or both.
A vast number of platinum compounds have now been screened
for antitumor activity, and the results of these investigations
have led to a set of empirical guidelines for the minimum structural features required for activity. Although they may be
stated in various forms, the key structure-activity relationships
(3) are:
0097-6156/83/0209-0265$06.00/0
©
1983 American Chemical Society
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
METAL CHEMOTHERAPEUTIC AGENTS
266
1.
2.
3.
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
4.
The complex must have a p a i r of c i s - a n i o n i c l i g a n d s (the
l e a v i n g groups), as the trans analogs are i n v a r i a b l y much
less active.
The a n i o n i c l i g a n d s must be moderately hard Lewis bases,
such as c h l o r i d e i o n s or oxygen donors.
The Pt complexes must be water s o l u b l e , but must a l s o be
capable of e n t e r i n g the c e l l i n t a c t . For a l l p r a c t i c a l
purposes, t h i s l i m i t s compounds to those bearing no net
charge.
The i d e n t i t y of the n e u t r a l l i g a n d s (the amines) i s
c r u c i a l to a c t i v i t y i n that there i s suggestion that only
complexes of primary (and p o s s i b l y secondary) amines are
e f f e c t i v e o n c o l y t i c agents.
Compliance w i t h these g u i d e l i n e s means that v i r t u a l l y a l l
compounds which have been examined have had the general s t r u c t u r e
I.
(Y)
I
In I , X i s an a n i o n i c l i g a n d , t y p i c a l l y c h l o r i d e , and A i s an
amine (or A^ a c h e l a t i n g diamine.) O x i d a t i o n to the f r e q u e n t l y
more s o l u b l e platinum (IV) analogs r e q u i r e s the i n c o r p o r a t i o n of
two a d d i t i o n a l a n i o n i c l i g a n d s , Y.
The general f a t e of DDP analogs i n the body seems c l e a r
(equation 1). I t i s thought that DDP enters the c e l l i n t a c t .
/0H
CI
Ptr
A/
CI
«2?
+2
2
DNA^
A
2
Pt/DNA Complex
In the c e l l , an area of low c h l o r i d e i o n c o n c e n t r a t i o n , e q u i l i b rium favors l o s s of the a n i o n i c l i g a n d s w i t h the formation of
v a r i o u s hydrated d e r i v a t i v e s . I t i s these very r e a c t i v e comp l e x e s , w i t h t h e i r l a b i l e aquo l i g a n d s , which coordinate to DNA
and lead t o the observed c y t o t o x i c i t y . Excepting c o n s i d e r a t i o n s
of s o l u b i l i t y , the broad s t r u c t u r e / a c t i v i t y observations of the
past decade are probably a r e f l e c t i o n of v a r i a t i o n s i n only the
end of t h i s process.
In p a r t i c u l a r , v a r i a t i o n s i n the amine
i d e n t i t y are l i k e l y to have only minor e f f e c t s on the k i n e t i c s
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
13.
BROWN ET AL.
New Class of Antitumor Pt Complexes
267
and theraodynamics o f the h y d r o l y s i s e q u i l i b r i u m . The amine
i d e n t i t y w i l l however have a s i g n i f i c a n t e f f e c t (due t o s t e r i c
f a c t o r s , hydrogen bonding, etc.) on the thermodynamics o f p l a t i ­
num b i n d i n g t o DNA, and hence on o n c o l y t i c a c t i v i t y .
In p r i n c i p l e , i t should be p o s s i b l e t o vary the a c t i v i t y of
platinum complexes not only by a l t e r i n g the thermodynamics o f
platinum b i n d i n g t o DNA, but a l s o by a l t e r i n g the r a t e at which
the e q u i l i b r i u m of equation 1 i s a t t a i n e d . The k i n e t i c s of t h i s
h y d r o l y s i s r e a c t i o n w i l l be d i c t a t e d by the t r a n s - e f f e c t , that i s ,
by the a b i l i t y of the l i g a n d l y i n g trans t o the c h l o r i d e t o i n ­
crease the r a t e of the c h l o r i d e i o n s u b s t i t u t i o n r e a c t i o n s .
Amines l i e low i n the t r a n s - e f f e c t s e r i e s , and consequently the
h y d r o l y s i s of a c h l o r i d e i o n l y i n g trans t o an amine i s a r a t h e r
s l u g g i s h r e a c t i o n . Our work centers on e f f o r t s t o improve a n t i ­
tumor a c t i v i t y by v a r y i n g the s u b s t i t u e n t s on platinum i n such a
f a s h i o n that the r a t e of the h y d r o l y s i s r e a c t i o n i n equation (1)
i s enhanced. We have chosen t o do t h i s by r e p l a c i n g one of the
amines by a l i g a n d l y i n g higher i n the t r a n s - e f f e c t s e r i e s .
P r a c t i c a l c o n s i d e r a t i o n s g e n e r a l l y r e s t r i c t the choice of l i g a n d
to a n i o n i c s p e c i e s , and we have focused on the use of the c h l o r ­
i d e i o n . Replacement of a n e u t r a l amine by an a n i o n i c c h l o r i d e
would lead t o a net negative charge on the complex. I n order t o
m a i n t a i n o v e r a l l complex n e u t r a l i t y (which i s presumably neces­
sary f o r c e l l u l a r p e n e t r a t i o n ) , the remaining amine must be r e ­
placed by a l i g a n d bearing a formal p o s i t i v e charge. This leads
to a complex having the general formula I I :
CI
Θ
I
L
Pt
_
CI
II
I
Such complexes can i n f a c t , as w e l l as i n p r i n c i p l e , e x h i b i t
s i g n i f i c a n t antitumor a c t i v i t y . We report here the s y n t h e s i s ,
c h a r a c t e r i z a t i o n , and antitumor a c t i v i t y o f two broad c l a s s e s of
complex having s t r u c t u r e I I , those where the p o s i t i v e l y charged
l i g a n d i s a monoprotonated (or monoalkylated) diamine and those
where i t i s a monoprotonated amino-olefin.
Complexes o f Protonated Diamines
P r i o r t o our work, there had been few r e p o r t s o f platinum
complexes bearing monoprotonated (or monoalkylated) diamines as
l i g a n d s . To our knowledge, only three complexes having t h i s
s t r u c t u r e have been c h a r a c t e r i z e d . Terζis (4) prepared and
determined the c r y s t a l s t r u c t u r e of
trichloro(9-methyladeninium)
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
268
METAL CHEMOTHERAPEUTIC AGENTS
p l a t i n u m ( I I ) , Maresca, et a l . (5) prepared t r i c h l o r o ( t e t r a methylethylenediammonium)platinijm(II),
and Adeyemo, et a l . (6)
prepared t r i c h l o r o ( 4 - a m i n o - 2 , 6 - d i m e t h y l p y r i d i n e ) p l a t i n u m ( I I ) .
We
have found a l a r g e number of such complexes can be prepared using
the two general r e a c t i o n s o u t l i n e d below.
N~N
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
N-N
+
· 2HC1
K PtCl,
+
0
+
HC1
K PtCl.
2
4
CI
+
0
+
I
HN~N
Pt
J
CI
NaOH-J
CI
Under these p r e p a r a t i v e c o n d i t i o n s , a l a r g e number of a l t e r n a t i v e
products (e.g., ( N ~ N ) P t C l , (Ν ~ N H ) P t C l ^ , etc.) are p l a u s i b l e ,
and indeed i n c e r t a i n cases were found. For the compounds r e ­
ported here, the combination of C, H, N, and CI m i c r o a n a l y t i c a l
data was adequate to demonstrate u n e q u i v o c a l l y a r a t i o of 3C1/
diamine/Pt.
Although t h i s i s supportive of the c o o r d i n a t i o n sphere of
platinum being P t C l ^ N , i t i s a more d i f f i c u l t problem to determine
which of the two n i t r o g e n s i t e s of the diamine i s coordinated to
platinum and, consequently, which n i t r o g e n s i t e i s protonated.
It
i s probable that the s p e c i f i c isomeric form which i s produced i s a
consequence of some complex i n t e r p l a y of both k i n e t i c and thermo­
dynamic f a c t o r s . In p a r t i c u l a r , i t s i d e n t i t y w i l l depend upon the
Lewis b a s i c i t y of each n i t r o g e n donor s i t e toward the Lewis a c i d
platinum i n the form P t C l ^ . Since knowledge of that Lewis b a s i c ­
i t y does not e x i s t , we have no p r e d i c t i v e a b i l i t y .
In the case of the compound d e r i v e d from 3-aminoquinuclidine
( t r i c h l o r o ( 3 - a m i n o q u i n u c l i d i n i u m ) p l a t i n u m ( I I ) , or QTP) we have
t r i e d to r e s o l v e the s t r u c t u r a l question by examination of i n f r a ­
red s p e c t r a i n the N-H s t r e t c h i n g r e g i o n . Comparisons of s p e c t r a
f o r 3-aminoquinuclidine, i t s mono- and di-protonated h y d r o c h l o r ­
i d e s , and QTP suggest that i n the platinum complex i t i s the -NH
group which i s ^ p r o t o n a t e d . S p e c i f i c a l l y , a broad and i n t e n s e band
at ca 2800 cm
which can be assigned to the protonated t e r t i a r y
amine group i n the mono- and d i - h y d r o c h l o r i d e i s absent from QTP.
I n f r a r e d s p e c t r a thus suggest s t r u c t u r e I I I f o r QTP.
2
2
2
2
CI
I
Pt
CI
III
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
13.
BROWN ET AL.
New Class of Antitumor Pt Complexes
269
B i o l o g i c a l Studies of Protonated Diamine Complexes
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
A l l of the compounds we have prepared have been evaluated as
i n h i b i t o r s of the growth of murine leukemic c e l l s (L1210) and a
DDP-resistant s u b l i n e (L1210/DDP) i n v i t r o . We have chosen a 50%
i n h i b i t o r y dose ( I D ^ Q ) of 10 jag/ml as our u p p e r - l i m i t c r i t e r i o n
f o r a s i g n i f i c a n t l e v e l of a c t i v i t y . Compounds t h a t s a t i s f y the
c r i t e r i o n are evaluated f u r t h e r f o r t h e i r a b i l i t y t o prolong the
l i f e span of mice i n o c u l a t e d w i t h L1210 c e l l s . Although we have
prepared a l a r g e number of complexes having the g e n e r a l formul a t i o n I I , most e x h i b i t r e l a t i v e l y l i t t l e a c t i v i t y a g a i n s t L1210
i n the c e l l c u l t u r e screen (Table I g i v e s s e l e c t e d I D ^ Q v a l u e s ) .
Table I .
+
Compounds (L )PtCl« Which S a t i s f y the C r i t e r i o n
f o r A c t i v i t y i n C e i l C u l t u r e Studies
I D
L
L1210
sn'
L1210/DDP
* S o l u b i l i z e d i n DMSO.
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
270
METAL CHEMOTHERAPEUTIC
AGENTS
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
The most i n t e r e s t i n g compound i n terms of b i o l o g i c a l a c t i v i t y
i s QTP, the compound w i t h 3-aminoquinuclidine as the l i g a n d , espec i a l l y i n view of i t s a b i l i t y t o produce roughly e q u i v a l e n t i n h i b i t i o n of the growth of both L1210 and L1210/DDP c e l l s . QTP i s ,
u n f o r t u n a t e l y , very p o o r l y s o l u b l e i n water. I n an attempt to
f i n d w a t e r - s o l u b l e analogs of QTP, s e v e r a l d e r i v a t i v e s were p r e pared by the routes o u t l i n e d below:
LPtCl
3
+
Ag S0
LPtCl
3
+
2H 0
LPtCl
3
+
H 0
LPtCl(S0 )
4
2
2
2
+
*LPtCl(S0 ) · H 0
4
4
I V
>LPt Cl (OH)
2
3
+
2
2HC1
Ba C H ( C 0 0 )
2
> LPt
2
2
I V
Cl
2
+ 2AgCl
+
2^0
5
+
21^0
> L P t C l CH (COO>
2
2
+
BaS0
4
These compounds, s e v e r a l having enhanced aqueous s o l u b i l i t y , were
evaluated f o r i n v i t r o a c t i v i t y . Each of the compounds (Table I I )
has a c t i v i t y a g a i n s t DDP-sensitive L1210 c e l l s comparable to that
of QTP, but i s l e s s e f f e c t i v e against L1210 c e l l s r e s i s t a n t t o
DDP.
Table I I . A c t i v i t y of 3-Aminoquinuclidinium D e r i v a t i v e s
Against L1210 C e l l s I n V i t r o
ID
Compound
L1210/0
5 Q
Oig/ml)
L1210/DDP
LPtCl
3
2
LPtCl
5
4.4
>10
4.5
>10
4.6
>10
LPtCl (OH)
3
2
LPtCl (S0.)
3
4
o
LPtCl(CH (C00) )
2
2
5
2.7
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
13.
BROWN ET AL.
New Class of Antitumor Pt Complexes
111
To evaluate the a c t i v i t y of compounds against L1210 i n v i v o ,
the f o l l o w i n g procedure was employed. L1210 c e l l s (1 χ 106
suspended i n 0.1 ml of p h y s i o l o g i c a l s a l i n e s o l u t i o n ) were i n o c u ­
l a t e d i n t r a p e r i t o n e a l l y ( i . p . ) i n t o BDF^ mice (20-22 gm) and drug
treatment ( i . p . ) was i n i t i a t e d 24 hours l a t e r . Animals that r e ­
ceived no drug treatment d i e d between 7 and 9 days a f t e r i n o c u l a ­
t i o n of L1210 c e l l s (mean s u r v i v a l time ~8.5 days). R e s u l t s ex­
press the r a t i o of the mean s u r v i v a l time of t r e a t e d animals t o
the mean s u r v i v a l time of c o n t r o l animals (%T/C).
Studies i n our l a b o r a t o r y r e v e a l that QTP has s i g n i f i c a n t
antileukemic a c t i v i t y . For example, when given as a s i n g l e dose
(10 mg/kg; day 1) the compound gave a T/C value of 125% and the
%T/C value was increased somewhat (to 138) when a more i n t e n s i v e
schedule of a d m i n i s t r a t i o n was employed (5 mg/kg; days 1, 2, 5,
6, 9). Our r e s u l t s were confirmed by independent s t u d i e s c a r r i e d
out under the auspices of the Developmental Therapeutics Program,
N a t i o n a l Cancer I n s t i t u t e (Table I I I ) .
The water s o l u b l e malonato d e r i v a t i v e of QTP e x h i b i t e d
l i m i t e d i n v i v o a c t i v i t y . Thus, at a s i n g l e dose (day 1) o f
50 mg/kg the compound gave a %T/C value of 126%.
We a l s o e v a l u ­
ated the s o l u b l e s u l f a t o d e r i v a t i v e of QTP i n v i v o but found i t
to be more t o x i c than QTP and to be i n e f f e c t i v e against murine
leukemia at a non-toxic dose (5 mg/kg). The b i o l o g i c a l a c t i v i t y
of QTP i s not shared by the l i g a n d per se s i n c e 3-aminoquinucli­
dine hydrochloride was found to e x h i b i t no c y t o t o x i c i t y i n v i t r o
under c o n d i t i o n s i n which the complex was q u i t e a c t i v e .
The a c t i v i t y of QTP i n the experimental leukemia system
prompted us to c a r r y out t o x i c o l o g i c a l s t u d i e s on t h i s complex.
When administered as a s i n g l e i . p . i n j e c t i o n , QTP caused no immed­
i a t e signs of t o x i c i t y but w i t h i n 48 hours mice became l e t h a r g i c ,
developed p i l o e r e c t i o n and d i s p l a y e d signs of tetany. The t o x i c
e f f e c t s progressed u n t i l p a r a l y s i s of the hind limbs was observed.
Deaths occurred 3 to 8 days f o l l o w i n g treatment. Gross necropsy
revealed signs of r e n a l t o x i c i t y i n c l u d i n g pale r e n a l c o r t e x ,
f r i a b i l i t y and exaggerated c o r t i c o m e d u l l a r y border. Other g r o s s l y
observable s i g n s of t o x i c i t y were s h a r p l y reduced spleen s i z e and
d i s t e n t i o n of s m a l l i n t e s t i n e . The c a l c u l a t e d L D ^ Q , L D ^ Q and
LD^Q values were 22, 42 and 83 mg/kg r e s p e c t i v e l y .
These s t u d i e s of the b i o l o g i c a l a c t i v i t y of QTP i n d i c a t e that
complexes of the type L P t C l ^ represent a new c l a s s of antitumor
platinum c o o r d i n a t i o n compounds. We are c u r r e n t l y engaged i n
s t u d i e s of the p r e p a r a t i o n and e v a l u a t i o n of new examples of t h i s
c l a s s of compound that may be more e f f e c t i v e and l e s s t o x i c than
QTP.
Complexes of Protonated Amino-Olefins
Although monoprotonated diamines are a convenient choice f o r
the p o s i t i v e l y charged l i g a n d i n s t r u c t u r e I I , other l i g a n d s L
may be considered.
We have consequently examined complexes where
+
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
272
METAL CHEMOTHERAPEUTIC
Table I I I .
AGENTS
A c t i v i t y of Trichloro(3-Aminoquinuclidinium)
P l a t i n u m ( I I ) Against L1210 C e l l s I n V i v o
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
a
(mg/kg)
Schedule
%T/C
5
10
50
5
2.50
5
10
20
2.5
5
10
20
40
1
1
1
1,2,5,6,9
1,5,9
1,5,9
1,5,9
1,5,9
1,5,9
1,5,9
1,5,9
1,5,9
1,5,9
123
125
Toxic
138
126
120
130
133
119
122
139
140
148
a. ) Because of the
from d i f f e r e n t
parable due t o
solubilization
low s o l u b i l i t y of t h i s compound, data
l a b o r a t o r i e s may not be d i r e c t l y comdifferent sonification/suspension/
procedures.
b. ) Data obtained a t the U n i v e r s i t y of Vermont.
c. ) Experiments 2 and 3 represent data obtained from the
NCI u t i l i z i n g two d i f f e r e n t screening c o n t r a c t o r s .
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
13.
BROWN ET AL.
273
New Class of Antitumor Pt Complexes
the l i g a n d L+ i s a protonated a m i n o - o l e f i n . In p a r t i c u l a r , we
have prepared a s e r i e s of compounds having s t r u c t u r e IV, i n which
a s u b s t i t u t e d a l l y l amine i s coordinated to platinum through the
H
Cl
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
IV
o l e f i n i c i r - s y s t e m . This s t r u c t u r e possesses the k i n e t i c advantages
discussed above f o r a l l compounds of type I I , but i n a d d i t i o n the
t h i r d c h l o r i d e i s h i g h l y a c t i v a t e d toward s u b s t i t u t i o n because of
the l a r g e t r a n s - e f f e c t of the coordinated o l e f i n .
S e v e r a l compounds analogous to I V have been r e p o r t e d , and
X-ray c r y s t a l l o g r a p h i c s t u d i e s have e s t a b l i s h e d t h a t i n each case
the c o o r d i n a t i o n environment a t platinum i s s i m i l a r to t h a t i n
Zeise's s a l t , e.g., square-planar platinum c o o r d i n a t i o n by three
c h l o r i d e s and the o l e f i n ff-system ( 7 ) . We have prepared complexes
having s t r u c t u r e I V by the d i r e c t r e a c t i o n of the N - s u b s t i t u t e d
a l l y l amine w i t h potassium t e t r a c h l o r o p l a t i n i t e i n a c i d i c aqueous
s o l u t i o n . A n a l y t i c a l data e s t a b l i s h the f o r m u l a t i o n , and i n f r a r e d
s p e c t r a demonstrate that the o l e f i n i s coordinated to platinum.
The s t r u c t u r e i s r e t a i n e d i n dimethylformamide s o l u t i o n , as demons t r a t e d by e x t e n s i v e nmr measurements.
B i o l o g i c a l Studies of Amino-Olefin Complexes
The compounds prepared i n t h i s study have been evaluated as
i n h i b i t o r s of L1210 growth u s i n g the c e l l c u l t u r e screen. Using
our c r i t e r i o n f o r a s i g n i f i c a n t c y t o t o x i c i t y , many of the compounds having s t r u c t u r e I V are found to be a c t i v e i n v i t r o
(Table I V ) . S e v e r a l trends are apparent from these data. F i r s t ,
most of the protonated a m i n o - o l e f i n complexes have comparable
c y t o t o x i c i t y (the exceptions w i l l be discussed s h o r t l y ) . F u r t h e r more, most are approximately e q u i t o x i c to the s e n s i t i v e and r e s i s tant c e l l l i n e s . This suggests that there may be a s i g n i f i c a n t
d i f f e r e n c e i n the mechanism of a c t i o n of these compounds compared
to DDP, s i n c e i n DDP and many of i t s analogs there i s a ca 2 0 - f o l d
d i f f e r e n c e i n a c t i v i t y toward these c e l l l i n e s . The three protonated a m i n o - o l e f i n compounds w i t h l a r g e values of I D C Q
equival e n t , and d i s t i n c t from the other complexes, i n that they are
d e r i v e d from t e r t i a r y amines. For simple DDP analogs there i s
s i g n i f i c a n t evidence t h a t complexes of primary, and p o s s i b l y
secondary, amines are much more a c t i v e than complexes of t e r t i a r y
amines (8). T h i s trend seems to be repeated here, but i n t h i s
case the amine i s not coordinated to platinum.
Consequently,
s u b s t i t u t i o n a t the amine would not be expected to have any
a
r
e
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
274
METAL CHEMOTHERAPEUTIC AGENTS
Table IV. C e l l C u l t u r e A c t i v i t y f o r Protonated and
N e u t r a l Complexes o f A l l y l a m i n e s
A l l y l Amine, L
Protonated Ligand
Complex, (LH+)PtCl
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
Compound No.
la
2a
3
N e u t r a l Ligand
Complex, L P t C l
I D f a g / m l ) Compound No.
ID
5Q
L1210
L1210/DDP
3.0
5.0
lb
L1210
5
>10
3a
2.5
4.0
3b
>10
4a
6
4.3
4b
7
5a
8
5b
>10
6a
>10
7a
>10
27
5 Q
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
2
13.
BROWN ET AL.
New Class of Antitumor Pt Complexes
275
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
s i g n i f i c a n t e f f e c t upon a c t i v i t y . The o b s e r v a t i o n that the e f f e c t
p e r s i s t s here should be accounted f o r i n any d i s c u s s i o n of the
o r i g i n of the e f f e c t of the amine s u b s t i t u t i o n upon antitumor
activity.
In the absence of p r o t o n a t i o n , the n e u t r a l a m i n o - o l e f i n i s ,
i n p r i n c i p l e , capable of c o o r d i n a t i o n as a c h e l a t e l i g a n d , u t i l z ing both the o l e f i n fr-system and the n i t r o g e n lone p a i r . This
would produce a n e u t r a l complex of type V, which should a l s o be
a c t i v a t e d toward the s u b s t i t u t i o n r e a c t i o n of equation ( 1 ) , and,
consequently, have p o t e n t i a l as an antitumor agent, Yellow s o l i d s
having the composition ( a m i n o - o l e f i n ) P t C l can be prepared by
n e u t r a l i z a t i o n of the (protonated a m i n o - o l e f i n ) P t C l ^ complexes
w i t h aqueous hydroxide, f o l l o w e d by e x t r a c t i o n i n t o chloroform.
A l t e r n a t i v e l y , at l e a s t i n c e r t a i n cases, i d e n t i c a l m a t e r i a l s can
be prepared by the d i r e c t r e a c t i o n of the a m i n o - o l e f i n w i t h
aqueous K ^ P t C l ^ . Once formed, these compounds are o n l y p o o r l y
s o l u b l e i n s o l v e n t s which do not cause decomposition, and t h i s
f a c t has made t h e i r c h a r a c t e r i z a t i o n e l u s i v e . Denning and Venanzi
(9) have reported complexes of t h i s form w i t h N - e t h y l a l l y l a m i n e
and N - o c t y l a l l y l a m i n e , which they formulate as polymeric and
d i m e r i c , r e s p e c t i v e l y . Apparently, a monomeric c h e l a t e complex
having S t r u c t u r e V cannot be formed because of the s t e r i c
problems inherent i n the formation of the 4%-memb«red c h e l a t e
r i n g . Based on t h e i r low s o l u b i l i t y , we b e l i e v e that the complexes we have prepared have o l i g o m e r i c s t r u c t u r e s as w e l l . I n f r a r e d s p e c t r a do, however, demonstrate c o n c l u s i v e l y that both
the amine and the o l e f i n are coordinated to platinum.
Although the n e u t r a l l i g a n d complexes corresponding to each
of the protonated l i g a n d complexes could not be prepared, b i o l o g i c a l data i s a v a i l a b l e f o r four such complexes. In g e n e r a l , c e l l
c u l t u r e a c t i v i t y i s comparable f o r both the protonated l i g a n d and
n e u t r a l l i g a n d complexes. Although t h i s may be f o r t u i t o u s , i t i s
a l s o p o s s i b l e that under b i o l o g i c a l c o n d i t i o n s the two types o f
compound are i n t e r c o n v e r t i b l e . Since the n e u t r a l l i g a n d complexes
are t y p i c a l l y prepared by deprotonation of the protonated l i g a n d
complexes, i t i s conceivable that t h i s deprotonation r e a c t i o n
occurs at p h y s i o l o g i c a l pH.
As r e p r e s e n t a t i v e samples, the complexes (protonated N - e t h y l a l l y l a m i n e ) P t C l ^ and ( N - e t h y l a l l y l a m i n e ) P t C ^ have been given a
p r e l i m i n a r y screening f o r antitumor a c t i v i t y i n v i v o . The complexes were administered i n t r a p e r i t o n e a l l y to mice w i t h L1210
?
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
276
METAL CHEMOTHERAPEUTIC AGENTS
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
Leukemia, At the dosages used, neither compound exhibited significant antitumor activity at less than toxic dose.
None of these compounds are particularly water soluble.
Consequently, we considered that the poor in vivo activity might
reflect poor water solubility, rather than inherent molecular inactivity. In order to test this hypothesis, we prepared the sulfate derivative of (protonated allylamine)PtCl« by reaction 4.
This sulfate complex is readily water soluble but, like its insoluble chloride analogs, appears to be inactive in vivo.
We are forced to conclude that although these compounds are
indeed cytotoxic, they do not have significant antitumor effects
at acceptable levels of host toxicity.
Conclusion
No single compound among those reported here exhibits the
combination of increased activity, decreased toxicity and desirable physical properties which would provide for a likely clinical
improvement over cis-dichlorodiamineplatinum(II). Nonetheless,
this work demonstrates clearly that activity is not restricted to
simple analogs of DDP, but may be found as well in significantly
different structural classes. In particular, at least one compound having a structure (L^PtCl^-trichloroquinuclidiniumplatinum(II)—has exhibited activity comparable to that of DDP.
Acknowledgment : This work was sponsored by the National Cancer
Institute through grants 24543 and 22435.
Literature Cited
1.
2.
3.
4.
5.
Rosenberg, B.; Van Camp, L; Trosko, J.E.; Mansour, V.H.
Nature 1969, 222, 385-386.
Schaeppi, U.; Hoyman, L.A.; Fleischman, R.W.; Rosenkrantz, H.;
Ilievski, V.; Phelan, R.; Cooney, D.; Davis, R.D. ToxicolAppl. Pharmacol. 1973, 25, 230.
Rosenberg, B. "Cisplatin: Current Status and New Developments"; A.W. Prestayko, S.T. Crooke, and S.K. Carter, eds.
Academic Press, Inc., 1980, pp. 9-20.
Terzis, A. Inorg. Chem., 1976, 15, 793.
Maresca, L.; Natile, G.; Rizzardi, G. Inorg. Chim. Acta,
1980, 38, 137.
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
13. BROWN ET AL.
New Class of Antitumor Pt Complexes111
6. Adeyemo, Α.; Teklu, Y.; Williams, T. Inorg. Chim. Acta, 1981,
51, 19.
7. Mura, P.; Spagna, R.; Zambonelli, L. J. Organometal. Chem.
1977, 142, 403.
8. Roberts, J.J. "Metal Ions in Genetic Information Transfer";
Vol.'3, G.L. Eichlorn and L.G. Marzilli, eds., 273-332
(1981).
9. Denning, R.G.; Venanzi, L.M. J. Chem. Soc. 1963, 3241.
13, 1982
Downloaded by TUFTS UNIV on October 28, 2017 | http://pubs.acs.org
Publication Date: January 26, 1983 | doi: 10.1021/bk-1983-0209.ch013
RECEIVED October
Lippard; Platinum, Gold, and Other Metal Chemotherapeutic Agents
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
Документ
Категория
Без категории
Просмотров
4
Размер файла
1 081 Кб
Теги
1983, 0209, ch013
1/--страниц
Пожаловаться на содержимое документа