N′-(2-chloroethyl)- N′-nitrosocarbamoyl amino acid derivatives of steroid hormones

Abstract

2-Chloroethylnitrosoureas are bifunctional alkylating agents with a broad-spectrum antitumour activity in experimental systems. Their clinical value is limited, however, because of the cumulative and delayed toxic side-effects exerted by these compounds, bone-marrow toxicity being dose limiting. Recent results of structure-activity investigations have shown that analogues having both, good water-solubility and, high lipophilicity are most promising. An example is 1-(2-chloroethyl)-l-nitroso-3-(2-hydroxyethyl)urea (HECNU), a compound that is especially highly active against intracerebral tumours (3). In order to achieve a more selective cytotoxic effect of the DNA-DNA crosslinking 2Chloroethyl-N-nitrosocarbamoyl group (CNC-group) in neoplastic tissues, methods for its attachment to various carrier molecules have been developed by us. They comprise the synthesis of CNC-derivatives of amino acids and the attachment of these CNC-amino acid derivatives to various positions of steroid hormones by ester bond formation. The design of such hormone-linked antineoplastic agents follows the rationale that the attachment to the hormone carrier will provide a means to reach preferentially a hormone-receptor containing target tumour. Many human tumours have been found to contain hormone receptors, e.g. mammary carcinoma, prostatic tumours, various gastrointestinal tumours and others (5, 7, 8, 9). Attempts to use steroid hormones as carrier molecules for antineoplastic agents have already been made in the past. N-mustard derivatives linked to estradiol or prednisolone have been introduced into the clinic (1, 6). However, systematic structure-activity studies to assess the potential value of this principle are lacking up to now. We therefore synthesized a series of CNC-amino acid esters of estradiol (E2) and other estrogen-receptor affinity carriers as well as esters of androgens and corticoids. One such example is the synthesis of CNC-L-alanine-estradiol- 17-ester (CNC-ala-E2-17-ester) given in Figure 1. An important parameter for the potential value of a given steroid-linked derivative is its binding affinity to the corresponding cytosolic hormone receptor. Relative binding affinities (RBA-values) ofestradioMinked derivatives to the estrogen receptor of calf uterus cytosol are summarized in Table 1.