Stabilities of neutral and basic esters of bendamustine in plasma compared to the parent compound: Kinetic investigations by HPLC

Esters of the cytostatic bendamustine (1), previously demonstrated to be much more potent than the parent compound as antiproliferative agents in vitro, were investigated by HPLC for stability in buffer and plasma, as well as against porcine liver esterase in the presence of different amounts of albumin. The hydrolysis of the nitrogen mustard moiety was retarded (for 1: approximately 130 vs. 11 min) in the presence of plasma proteins. For the derivatives, both cleavage of ester and nitrogen mustard moieties were analyzed. Enzymatic hydrolysis was very fast in case of 2-pyrrolidino-, 2-piperidino- and 2-(4-methylpiperazino)-ethyl esters, whereas methyl, ethyl, morpholinoethyl and branched 2-pyrrolidinoethyl esters were considerably more stable (half-lives between 41 and 116 min, compared to <5 min). Inhibition by physostigmine indicated unspecific cholinesterases to be involved in the rapid ester cleavage. Due to lower protein content and higher enzymatic activity in murine compared to human plasma, reduced stability of all investigated esters in mouse plasma (t½ <2 min) has to be taken into account with respect to the design of animal studies

Different response of murine and human mammary tumour models to a series of diastereoisomeric [1,2-bis(difluorophenyl) ethylenediamine]dichloroplatinum(II) complexes

A series of isomeric [1,2-bis(difluorophenyl) ethylenediamine]dichloroplatinum(II) complexes and cisplatin were tested on the P388 leukemia and on the murine hormone-independent MXT (M3.2) OVEX and the ovarian-hormone-dependent MXT (M3.2) mammary carcinoma for evaluating antineoplastic activity against breast cancer in vivo. Although these results were heterogeneous, a trend to the 2,6-difluorosubstituted compound as the most active platinum complex was observed. For the development of a large-scale in vitro screening method on human breast cancer cell lines, cell number, [3H]thymidine incorporation, and crystal violet staining were evaluated as parameters for end-point determination. Chemosensitivity testing on the human breast cancer cell lines MDA-MB-231 and MCF-7 unambiguously identified [1,2-bis(2,4-difluorophenyl)ethylenediamine]dichloroplatinum(II) as the complex with the highest activity in the crystal violet micro-assay. In equimolar concentration this compound was superior to cisplatin on both cell lines. The analysis of the conflicting results of this study indicates that murine mammary carcinomas are most probably unrealistic and inappropriate models for the screening of cytotoxic platinum complexes with potential activity on human breast cancer

Esters of bendamustine and related compounds, and medical use thereof

The present invention relates to bendamustine derivatives and related compounds of formula (VII), (VIII) and (IX), and medical uses thereof in particular in cancer therapy

Tumor inhibiting [1,2-bis(difluorophenyl)ethylenediamine]dichloroplatinum(II) complexes. I. Synthesis

meso- And DL-[NH2CH(C6H3X2)]2 (L; X2 = 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-F2) were prepd. from meso-[NH2CH(C6H4OH)]2 and the resp. benzaldehydes by a diazo-Cope rearrangement. L reacted with K2PtX4 (X = Cl, I) to give PtLCl2 and PtLI2 (X2 = 2,4- and 2,6-F2) and PtLI reacted with Ag2SO4 to give PtL(SO4)