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Monoamineplatinum (II) complexes conjugated to water‐soluble carrier polymers for chemotherapeutic applications
Author(s) -
Mbonyana Carol W N,
Neuse Eberhard W,
Perlwitz Axel G
Publication year - 1993
Publication title -
applied organometallic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.53
H-Index - 71
eISSN - 1099-0739
pISSN - 0268-2605
DOI - 10.1002/aoc.590070407
Subject(s) - chemistry , platinum , aqueous solution , conjugate , amine gas treating , conjugated system , ligand (biochemistry) , metal , solubility , polymer , combinatorial chemistry , polymer chemistry , stereochemistry , organic chemistry , catalysis , mathematical analysis , biochemistry , receptor , mathematics
In the light of the observed carcinostatic activity of the monoamineplatinum complexes K[PtCl 3 (NH 3 )] and K[PtCl 3 (t‐butylamine)], it has been of interest in this laboratory to develop water‐soluble, antineoplastic conjugates in which square‐planar platinum complex structures of the monoamineplatinum type are linked to suitable carrier polymers possessing water solubility for improved pharmacokinetics. In the present paper the synthesis is described of conjugates in which each platinum atom is coordinated to a single, primary amine ligand provided by a water‐soluble polyaspartamide‐type carrier. Microanalytical data suggest the remaining three coordination sites on the metal center to be occupied on average by one aquo and two chloro ligands. The carriers, prepared by a known method from polysuccinimide by stepwise aminolytic ring‐opening, are designed so as to feature randomly placed hydrosolubilizing units and metal‐binding units in a ratio of 3:1, thus providing spatial insulation between the latter and minimize intramolecular interaction between the platinum complexes incorporated subsequently. Platination of the carriers is brought about by treatment with K 2 PtCl 4 in aqueous solution at 25–60 °C in the pH range 5–6, and the polymer–platinum conjugates are purified and isolated in 50–70% yield by aqueous‐phase dialysis and freeze‐drying. The extent of platination attained depends inter alia on the Pt/NH 2 feed ratio (equivalents of tetrachloroplatinate per carrier base unit); in optimal cases complete metal coordination to the carrier‐attached primary‐amine ligands is achieved with a feed ratio of 1.4:1. The conjugates, initially showing complete solubility in water, tend to undergo an ageing process on storage believed to involve intermolecular solid‐state interaction of the bound platinum complexes with proximate amine sites, resulting in gradual loss of solubility. In frozen aqueous solution, however, the conjugates are stable for extended periods of time.