Stereoisomeric Dichloro[1‐(hydroxyphenyl)‐2‐phenyl‐1,2‐ethanediamine]platinum(II) Complexes, Part I: Synthesis

Abstract

Various erythro-and threo-configurated dichloro[l-(hydroxyphenyl)-2-phenyl-l,2-ethanediamine]platinum(II) complexes were synthesized with the hydroxy group located in either the 2-, 3-, or 4-position of the phenyl ring (38-40). The diastereoisomeric 1-(3-hydroxyphenyl)-2-phenyl-1,2-ethanediamines (31, 32) and threo-l-(2-hydroxyphenyl)-2-phenyl-1,2-ethanediamine (30) were obtained by reduction of the 1,2-diazidoethanes and subsequent ether cleavage. The configuration of the threo-1,2-diazido-l-(2-methoxyphenyl)-2-phenylethane (5) was elucidated by X-ray analysis. The reduction of the erythro-1,2-diaryl-l,2-diazidoethanes, substituted with a methoxy group in ortho or para position, results in elimination reactions with formation of side products. The desired 1,2-diaryl-l,2-ethanediamines were finally synthesized via either an aziridine derivative 21 or by reduction of the respective dioximes 27, 28. The diamine ligands were converted into the corresponding dichloroplatinum(II) complexes 38 -40.The antitumor activity') of cisplatin [cis-diamminedichloroplatinum(II)] is well established for the treatment of a variety of tumors such as cancers of the ovaries and testes as well as solid tumors of the head and neck2). In spite of the high response rate of 63% of the ovarian carcinoma the overall survival times remain short ' ). In many cases a relapse occurs within two years. The regrowing tumor usually responds poorly to another therapy with cisplatin4). A variety of mechanisms is discussed to explain the incidence of resistance. A P-glycoprotein which accelerates the drug efflux from the cell is responsible for the multidrug resistance against many lipophilic anticancer compounds 'I. Drugs forming adducts with the DNA like alkylating agents or platinum complexes are not affected by this multidrug resistance6). The current literature contains discussions of several characteristic properties of tumor cells resistant to cisplatin. For example, increased intracellular levels of peptides and proteins containing thiol or thioether groups can deactivate platinum compounds. Furthermore, an increased DNA-repair activity or a lowered uptake of the drug into the cell may be responsible for the resistance (for references see Canon et al.')). Much effort has been made in developing platinum compounds with a specific action in cisplatin-resistant tumor models. The results indicate that a chelating diamine ligand is essential for the antitumor action [e.g. 1,2-diaminocyclohexane, 1,1 -bis(aminomethyl)cyclohexane] *). In earlier publications we described the synthesis and testing of a series of (1,2-diaryl-l,2-ethanediamine)platinum(II) complexes in various cisplatin-resistant tumor modelsy-").( )-Dichloro( 1,2-diphenyl-1,2-ethanediamine)platinum(II) as well as compounds which were hydroxy-substituted in both phenyl rings showed antitumor action in these models. ( )-[ 1,2-Bis(2-hydroxyphenyl)-1,2-ethanediamine]dichloro-platinum(I1) produced marked inhibitory effects on the cisplatin-resistant Ehrlich ascites tumor (70% of the tumorbe...