Synthesis and in vitro biological evaluation of new triphenylethylene platinum (II) complexes

Bioorganic & Medicinal Chemistry Letters
1995.0

Abstract

In our search for a chemotherapeutic agent with a better therapeutic index and selectivity for the treatment of breast cancer, we have synthesized cytotoxic triphenylethylene derivatives. The synthesis of this type of compound is straightforward and efficient. The biological activity of these compounds was evaluated in vitro on ER+ and ER- human breast tumor cell lines: MCF-7 and MDA-MB-231. Several platinum coordination complexes such as cis-diamminedichloroplatinum (II) (cisplatin) and carboplatin are currently used in chemotherapy of neoplastic diseases. 1 These complexes of a non-essential heavy metal exhibit a remarkable antitumor effectiveness and a broad spectrum of activity. It is widely believed that the antitumor activity of platinum drugs is a consequence of their interaction with DNA. 2,3 Cisplatin binds readily to guanine residues of DNA molecules. 3 Cisplatin has proved very successful in the treatment of a variety of human solid tumors such as genitourinary and gynecologic tumors as well as head, neck and lung tumors. 1 Unfortunately, the development of cellular resistance to cisplatin in mammalian cells is common 4-6 and is believed to occur via four main mechanisms: (a) increased efficiency of repair of platinum-DNA lesions, 7-10 (b) increased inactivation of drug by elevated levels of cellular low-molecular weight thiols, particularly glutathione, 11-13 (c) metallothionein, 14-16 and (d) decreased cellular uptake of drug. 17-21 The clinical utility of the drug is also limited by its toxic effects, particularly kidney toxicity. 2 The search for platinum complexes with a broader spectrum of activity, less toxicity, improved clinical effectiveness against tumors characterized by intrinsic or acquired resistance to cisplatin is ongoing. In order to improve the low activity of platinum (II) complexes against breast cancer, 22 we investigated the covalent attachment of dichloroplatinum to diamino analogs of triphenylethylene. These derivatives could be considered cytotoxic analogs of tamoxifen, the latter being an efficient drug for the treatment 23 and prevention 24 of breast cancer. Therefore, considering the fact that hormonal therapy will be ultimately followed by chemotherapy or a combination of both, we synthesised a number of non-steroidal cytotoxic estrogens hoping to obtain products with dual activity ie. antiestrogenic and cytotoxic. Moreover, these compounds might also be multidrug resistance (MDR) modulators (chemosensitizers) as per their lipophilic character.25, 26 The present communication describes the synthesis and in vitro biological activity of eleven members of this new family of cytotoxic triphenylethylenes.

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