Synthesis and in vitro evaluation of estrogen receptor specific tamoxifen conjugates tethered with platinum(II)

Breast cancer is one of the most terrifying diseases. Statistically every one out of eight women in the U.S.A. has a risk of developing breast cancer. The estrogen receptor is believed to mediate the estrogen signal involved in tumorigenesis. Antiestrogens inhibit the estrogen binding to the estrogen receptor-ligand binding domain (ER-LBD). Among antiestrogens, tamoxifen is the most successful drug against breast cancer. In one study, it reduced the recurrence rate by 46% compared to the placebo. Cis-diamminedichloroplatinum(II) (Cis-DDP) is a remarkable DNA targeting anticancer agent that contains the transition metal Pt(II). Carboplatin is less toxic than cis-DDP and also comparatively easier to administer the drug to patients because of enhanced water solubility.;In this study, we developed methods to synthesize conjugate dual mode hybrid molecules designed to contain analogs of an antiestrogenic homing unit in one end and the Pt(II) moiety payload unit in the other end. These drugs are expected to behave as "smart" drugs to specifically target the estrogen receptor of cancer cells and destroy them.;Three nonestrogen triphenylene-tethered (Pt-09, Pt-10, and Pt-11) and tamoxifen (TAM)-tethered (Pt-CCN) platinum(II) complexes have been synthesized from cis-DDP and appropriate Na or K salts. A sequence of selective modification and coupling reactions have been developed to prepare triphenylene-tethered and mono- and di-hydroxysubstituted triphenylene-tethered platinum(II) complexes. A novel procedure for the synthesis of tamoxifen-tethered platinum(II) has been developed. This research demonstrates the first successful synthesis of the novel conjugate composed of intact tamoxifen and carboplatin spaced by a six-carbon tether.;These tethered platinum complexes have been examined in vitro for antitumor activity in both breast and ovarian cancer cell lines. Four new conjugates responded differently to four human cancer cell lines. However, we could observe an interesting structure-activity correlation for platinum(II) complexes for both PA-1 and OVCAR-3 ovarian cancer cell lines and for the MCF-7 breast cancer cell line and the SK-OV-3 ovarian cancer cell line. 1n addition, the cytotoxicity of Pt-CCN for PA-1 surpassed that of carboplatin, however, it is less toxic than tamoxifen.