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Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER-positive and
Aya S Hassan1, Jannette Wober2, Günter Vollmer2
1Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, 11835, Cairo, Egypt.
Abstract:
Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) with potential clinical benefits for all stages of breast cancer. TAM is primarily metabolized to more potent metabolites via polymorphic CYP2D6. This affects the clinical outcome of TAM treatment. Herein we report novel TAM analogues that can avoid metabolism via CYP2D6. The novel analogues bear a flexible skeleton. Compounds have either an ester group on ring C or homodiaminoalkoxy groups on rings B and C. Compound 6 (E/Z-4-[1-[4-(2-diethylaminoethoxy)phenyl]-3-(4-methoxyphenyl)-2-methyl[propenyl]phenol) was found to be ten-fold more potent than TAM on MCF-7 cells (GI50 =0.15 μM). It showed fivefold greater inhibitory activity on MDA-MB-231 cells than TAM (GI50 =1.71 μM). Compound 13 (4-{3,3-bis-[4-(3-dimethylaminopropoxy)phenyl]-2-methylallyl}methoxybenzene) was the most potent among the homodiaminoalkoxy derivatives (GI50 =0.44) on both MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, the COMPARE algorithm suggested that it has different molecular targets from those of some other reported anticancer drugs.
Insights
New tamoxifen (TAM) analogues bypass CYP2D6 metabolism, offering improved potency against breast cancer cell lines. These novel selective estrogen receptor modulators (SERMs) show promise for enhanced cancer therapy.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), is a key treatment for breast cancer.
- TAM's efficacy is limited by its metabolism via the polymorphic CYP2D6 enzyme, leading to variable clinical outcomes.
- Developing TAM analogues that circumvent CYP2D6 metabolism is crucial for optimizing breast cancer treatment.
Purpose of the Study:
- To design and synthesize novel tamoxifen analogues that avoid CYP2D6 metabolism.
- To evaluate the in vitro anti-cancer activity of these novel compounds against breast cancer cell lines.
- To investigate the potential for distinct molecular targets compared to existing anticancer drugs.
Main Methods:
- Synthesis of novel tamoxifen analogues featuring flexible skeletons, ester groups on ring C, or homodiaminoalkoxy groups on rings B and C.
- In vitro evaluation of anti-proliferative activity using GI50 values on MCF-7 and MDA-MB-231 breast cancer cell lines.
- Utilized the COMPARE algorithm to predict molecular targets.
Main Results:
- Compound 6 demonstrated a ten-fold increase in potency compared to TAM on MCF-7 cells (GI50 = 0.15 μM) and five-fold greater activity on MDA-MB-231 cells (GI50 = 1.71 μM).
- Compound 13, a homodiaminoalkoxy derivative, exhibited potent activity against both cell lines (GI50 = 0.44 μM).
- The COMPARE algorithm indicated that Compound 13 may possess different molecular targets than other reported anticancer agents.
Conclusions:
- Novel tamoxifen analogues designed to bypass CYP2D6 metabolism exhibit enhanced potency against breast cancer cells.
- These compounds represent promising candidates for further development in breast cancer therapy.
- The distinct molecular target profile of Compound 13 warrants further investigation for novel therapeutic strategies.
