Design, synthesis, cytocidal activity and estrogen receptor α affinity of doxorubicin conjugates at 16α-position of estrogen for site-specific treatment of estrogen receptor positive breast cancer

Abstract

Doxorubicin (DOX) is an important medicine for the treatment of breast cancer, which is the most frequently diagnosed and the most lethal cancer in women worldwide. However, the clinical use of DOX is impeded by serious toxic effects such as cardiomyopathy and congestive heart failure. Covalently linking DOX to estrogen to selectively deliver the drug to estrogen receptor-positive (ER(+)) cancer tissues is one of the strategies under investigation for improving the efficacy and decreasing the cardiac toxicity of DOX. However, conjugation of drug performed until now was at 3- or 17-position of estrogen, which is not ideal since the hydroxyl groups at this position are important for receptor binding affinity. In this study, we designed, prepared and evaluated in vitro the first estrogen-doxorubicin conjugates at 16α-position of estradiol termed E-DOXs (8a-d). DOX was conjugated using a 3-9 carbon atoms alkylamide linking arm. E-DOXs were prepared from estrone using a seven-step procedure to afford the desired conjugates in low to moderate yields. The antiproliferative activities of the E-DOX 8a conjugate through a 3-carbon spacer chain on ER(+) MCF7 and HT-29 are in the micromolar range while inactive on M21 and the ER(-) MDA-MB-231 cells (>50 μM). Compound 8a exhibits a selectivity ratio (ER(+)/ER(-) cell lines) of >3.5. Compounds 8b-8d bearing alkylamide linking arms ranging from 5 to 9 carbon atoms were inactive at the concentrations tested (>50 μM). Interestingly, compounds 8a-8c exhibited affinity for the estrogen receptor α (ERα) in the nanomolar range (72-100 nM) whereas compound 8d exhibited no affinity at concentrations up to 215 nM. These results indicate that a short alkylamide spacer is required to maintain both antiproliferative activity toward ER(+) MCF7 and affinity for the ERα of the E-DOX conjugates. Compound 8a is potentially a promising conjugate to target ER(+) breast cancer and might be useful also for the design of more potent E-DOX conjugates.

Estrogenic activity and cytotoxicity of six anticancer drugs detected in water systems

“…CAP showed a lower effect (EC 50 value 0.48 μM) while ET and DOX EC 50 values were not found at concentrations ranging from 1.8 • 10 − 6 to 1.8 • 10 − 2 μM, indicating a low affinity for ERs at the concentrations tested. The ER is not a specific target of DOX, so that in a recent study the anti-proliferative activity and affinity of DOX towards ERα were increased covalently linking it to E 2 (Saha et al, 2012). The Relative Proliferative Effects (RPEs%) that compare the maximal proliferation induced by compounds to that induced by E 2 are shown in Fig.…”

Current research on anti-breast cancer synthetic compounds

“…4). Saha et al, 103 designed, prepared and evaluated in vitro the rst estrogen-doxorubicin conjugates at 16 aposition of estradiol termed E-DOXs. The IC 50 of E-DOX 111 (Fig.…”

Estrone-Decorated Polyion Complex Micelles for Targeted Melittin Delivery to Hormone-Responsive Breast Cancer Cells

“…Estrone is one among the major mammalian estrogens that can preferentially attach to the ERα receptors . Consequently, estrone and estrone metabolites have been extensively studied in breast carcinogenesis and drug therapy mechanisms. , The selectivity of estrone toward breast cancer cells after its conjugation to small molecular weight cytotoxic drugs has also been reported . However, most of the cytotoxic drugs require a nanocarrier to minimize their interaction with healthy cells to reach the targeted tumor site, and nowadays, research is dedicated to developing efficient nanoparticles to serve the purpose.…”