17 Polymeric Derivatives Based on cis-Diamminedichloroplatinum(II) as Antineoplastic Agents CHARLES E. CARRAHER, JR., WILLIAM J. SCOTT, ISABEL LOPEZ, DELIE ROSELYN CERUTIS , and TUSHAR MANEK 1
Wright State University, Department of Chemistry, Dayton, OH 45435 DAVID J. GIRON Wright State University, Department of Microbiology and Immunology, Dayton, OH 45435
Platinum polyamines can be readily synthesized with good control on the chain length through reaction of salts of PtX -2 with diamines. The 4
polyamines show good antineoplastic a c t i v i t y against a wide range of tumors including mouse connective tissues, human cervical carcinoma and human amnion cancer c e l l s . Further the vast majority of the polyamines successfully altered the normal r e p l i c a t i o n cycle of the polio virus Type 1 and Encephalomyocarditic v i r u s , s t r a i n MM when the former c e l l s were treated with the v i r u s , without destruction of the cells themselves. Mice are able to tolerate large dosages of the polyamines.
Malignant neoplasms are the second leading cause of death i n the United States. In 1964 Rosenberg and coworkers discovered
1
Also affiliated with Wright State University, Department of Microbiology and Immunology, Dayton, OH 45435.
0097-6156/82/0186-0221$5.00/0 © 1982 American Chemical Society
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BIOLOGICAL ACTIVITIES OF POLYMERS
that bacteria f a i l e d to divide, but continued to grow giving filamentous c e l l s i n the presence of platinum electrodes (1). A major cause of this i n h i b i t i o n to c e l l d i v i s i o n was cis-dichlorodiamineplatinum II,c-DDP. Much work centered about the c l i n i c a l use of c-DDP leading to the licensing of i t as an antineoplast drug. I t i s currently widely used, i n conjunction with other drugs, i n the treatment of a wide variety of tumors (such as 2=5.). CI
CI Pt
I, C - DDP Most of the research involving use of platinum compounds as antitumoral agents has involved either c-DDP i t s e l f or struct u r a l l y close derivatives. Through studies (such as 6-13). i t has been observed that there generally exists a structural window for a c t i v i t y such that the most active antitumoral compounds are a. neutral, b. contain two i n e r t (NH-) and two l a b i l e (CI) ligands with c. the ligands c i s to one another. The use of c-DDP has been complicated because of negative side effects including gastrointestinal, hematopoietic, immunosuppressive, auditory and renal disfunction (such as 14-17). One method of overcoming some of these negative side effects i s to l i m i t the movement of c-DDP through inclusion of i t into a polymer thus prohibiting f i l t r a t i o n of the polymer by the kidneys, etc. Two general approaches have been taken. F i r s t , attachment of the c-DDP derivative onto a preformed polymer. This was done
CH HN
3
CH HN
3
CH
3
HN
CH^ HN
v
CH
0
K PtCl 2
4
HN
0
HN
HN
V / CI
II.
CH
\ CI
III.
HN
17.
CARRAHER ET AL. Polymeric Derivatives as Antineoplastic
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by Allcock and coworkers (such as 18-20). Poly[bis(methylamino)phosphazene] ,11, i s a water soluble polymer with coordination s i t e s on both the side group and chain nitrogen atoms (13.21). Conpound I I reacts with K-PtCl,. and l8-crown-6-ether i n organic media giving structure I I I (13.19). Compound I I I shows tumor inhibitory a c t i v i t y towards mouse P38: lymphocytic leukemia and i n the Ehrlich Ascites tumor regression test (19). Work i s continuing i n t h i s area. A second approach has the c-DDP derivative included as part of the polymer. In 1977 we i n i t i a l l y synthesized the f i r s t poly(cis-dichlorodiamineplatinum II) compound (22). Here we w i l l b r i e f l y describe the synthesis of such compounds and describe results of preliminary b i o l o g i c a l assays concentrating on tests related to their potential use as antitumoral agents.
IV. This paper presents preliminary b i o l o g i c a l assay results related to potential antineoplastic a c t i v i t y for select platinum polyamines of Form IV. Synthesis and Physical Characterization Following are t y p i c a l synthetic and structural characterization procedures more f u l l y described i n references 22 and 23. Potassium tetrachloroplatinate (£.22 x 10" moles i n 10 ml H 0) and potassium iodide (4.97 x 10" moles i n 10 ml H-O) were separately dissolved, treated for ten minutes on a ooiling water bath, mixed, heated 20 minutes longer and f i l t e r e d to remove KC1. The resulting potassium tetraiodiplatinate solution was then^ mixed with an aqueous solution of 1,6-hexanediamine (7.83 x 10" moles i n 10 ml of water) to immediately give a curdy, yellow s o l i d , poly(cis-diiodo-1,6-hexamethylenediamine platinum ( I I ) ) , DIHP, i n lk% y i e l d based on i n i t i a l potassium tetrachloroplatinate. Elemental analysis (performed by Galbraith Labs., Knoxv i l l e , Tenn.) was i n agreement with a structure of form IV; JtCfound=12.0, theory=12.8; *N-found=4.9, theory=4.9; *H-found=2.9, theory= 2.9; $Pt-found=31.3, theory=34.5; #Cl-found 0.1, theory= 0.0;
