Synthesis and cytotoxicity studies of steroid-functionalized titanocenes as potential anticancer drugs: sex steroids as potential vectors for titanocenes

Abstract

Six titanocenyls functionalized with steroidal esters have been synthesized and characterized by infrared, 1H, and 13C NMR spectroscopy and elemental analysis. Among those steroids, dehydroepiandrosterone, trans-androsterone, and androsterone are androgens and pregnenolone is a progesterone precursor. Clionasterol is a natural steroid compound. These steroid-functionalized titanocenyls were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for in vitro cytotoxicity for MCF-7 breast cancer and HT-29 colon cancer cells. All complexes exhibited more cytotoxicity than titanocene dichloride. The titanocenyls containing androgen and progesterone derivatives as pendant groups had higher antiproliferative activities than those with cholesterol steroid compounds. Of particular significance is titanocenyl–dehydroepiandrosterone complex, which is 2 orders of magnitude more cytotoxic than titanocene dichloride and also shows much more sensitivity and selectivity for the MCF-7 cell line.

Steroid-Functionalized Titanocenes: Docking Studies with Estrogen Receptor Alpha

“…We have previously reported the synthesis and biological activity of seven steroid-functionalized titanocene dichlorides [9]. Among them, 1, 2, and 4 ( Figure 1) showed significant cytotoxic activity on MCF-7 hormone-dependent breast cancer cell line, with IC 50 values of 20, 13, and 21 µM, respectively, while the value for titanocene dichloride was 570 µM [9].…”

“…Among them, 1, 2, and 4 ( Figure 1) showed significant cytotoxic activity on MCF-7 hormone-dependent breast cancer cell line, with IC 50 values of 20, 13, and 21 µM, respectively, while the value for titanocene dichloride was 570 µM [9]. These remarkable differences between the parent compound and the steroid-functionalized titanocene motivated us to perform docking studies between the estrogen receptor alpha and titanocene compounds and the pendant vectors (steroids).…”

“…In particular, our group has functionalized titanocene by appending biologically important groups on the cyclopentadienyl (Cp) ring [9]. Our previously reported sex steroid-functionalized titanocenes showed substantial enhancement on their antiproliferative activity relative to titanocene dichloride on MCF-7 and HT-29 cancer cell lines [9].…”

“…Current chemotherapy for this type of cancer is the administration of antiestrogens (antagonist) to halt the rapid cell proliferation induced by β-estradiol. Thus, we initially speculated that the antiproliferative activity of the subject compounds were correlated to ERα recognition [9].…”

“…In particular, our group has functionalized titanocene by appending biologically important groups on the cyclopentadienyl (Cp) ring [9]. Our previously reported sex steroid-functionalized titanocenes showed substantial enhancement on their antiproliferative activity relative to titanocene dichloride on MCF-7 and HT-29 cancer cell lines [9]. MCF-7 is a hormone-dependent breast cancer cell line which overexpresses estrogen receptor alpha (ERα), and the pendant groups on these functionalized titanocenes have hormonal activity on ERα and inhibitory effects on breast cancer [10,11].…”