A novel approach to preparing water soluble prodrug forms of cisplatin analogues bearing chelating diamines.

Abstract:

:A novel method for creating water soluble prodrugs of cisplatin analogues bearing chelating diamines is introduced. When 2-(amino-methyl)aniline is reacted with K2PtCl4 between a pH of 6 and 7, the neutral chelated complex [2-(aminomethyl)aniline)dichloroplatinum(II) (1) is isolated. On the other hand, when the complexation occurs under acidic conditions (i.e. pH 3), the zwitterionic, "open-ring" form [2-(ammonio-methyl)aniline-N1]trichloroplatinate(II) (2) is obtained, whereby only the aniline nitrogen is coordinated to platinum. Compound 2 has a solubility of 10 mM in acidic aqueous medium; that is ca. 20 times greater than that of 1. However, 2 rapidly converts to compound 1 at physiologic pH; thus 2 functions as a water soluble prodrug of 1. Both 1 and 2 are equally effective at halting the growth of three different human cancer cell lines in vitro, indicating that the prodrug is quantitatively converted to the parent drug in a complex, biologically relevant medium. In animal experiments, the prodrug form, when given at a dose of 25 mumol/kg three times a week for 6 weeks, significantly inhibits the growth of the MXT (M3.2) mammary tumor in BDF mice while the same dose of the parent drug has no antitumor activity.

journal_name

J Pharm Sci

authors

Köckerbauer R,Bednarski PJ

doi

10.1002/jps.2600840707

subject

Has Abstract

pub_date

1995-07-01 00:00:00

pages

819-23

issue

7

eissn

0022-3549

issn

1520-6017

pii

S0022-3549(15)49848-X

journal_volume

84

pub_type

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