Fedor B. Bogdanov

Estrogen receptor α (ERα) remains the principal molecular driver of hormone-dependent breast cancer. In this study, we designed, synthesized, and biologically evaluated a new series of secosteroid–isatin hybrids as potential ERα-targeting anticancer agents. The lead compounds, (Z)-3a and (Z)-3b, inhibited MCF-7 cell growth with IC₅₀ values of 6.8 and 6.0 μM, respectively, comparable to cisplatin; they were approximately threefold less potent against epithelial cells than against the target cell model of ERα-positive breast cancer. Mechanistic studies demonstrated that both compounds induced a concentration-dependent depletion of ERα protein, accompanied by downregulation of the ERα-dependent proliferative mediator cyclin D1 and the anti-apoptotic protein Mcl-1, together with accumulation of cleaved PARP, indicating activation of apoptotic cell death. Importantly, an estrogen response element (ERE)-driven luciferase reporter assay demonstrated potent concentration-dependent suppression of 17β-estradiol-induced ERα transcriptional activity, with nearly complete inhibition achieved at higher concentrations, confirming that these compounds function as effective antagonists of ERα-dependent gene transcription. Furthermore, both lead compounds exhibited predominantly synergistic interactions with doxorubicin and heliomycin, suggesting their potential utility in combination therapy. Collectively, these findings identify secosteroid–isatin hybrids as a previously unexplored class of ERα modulators with efficient suppression of estrogen receptor α signaling and induction of apoptosis, which highlights this scaffold as a promising platform for the development of next-generation therapeutics for hormone-dependent breast cancer.

First tandem epoxidation/ring cleavage by in situ generated N -methyl-2-pyrrolidone hydroperoxide/potassium carbonate system.

Potent antiproliferative activity against diverse breast cancer subtypes was achieved with novel N -(4,5,6,7-tetrahydrobenzo[ d ]isoxazol-5-yl)carboxamides that modulate HSP90 and inhibit oncogenic kinases.

Background/Objectives: Breast cancer remains one of the most prevalent and life-threatening malignancies worldwide. This study describes the design and biological evaluation of a series of secosteroid–2-pyrazoline hybrids as novel antitumor agents against ERα-positive breast cancer cell lines MCF-7 and T47D. Methods: A simple and efficient method for synthesizing secosteroid–2-pyrazoline hybrids was developed starting from 13α-hydroxy-3-methoxy-13,17-secoestra-1,3,5(10)-triene-17-oic acid hydrazide and 1,3-diketones. The resulting secosteroid derivatives were evaluated against hormone-dependent MCF-7 and T47D breast cancer cells. Furthermore, the selectivity and effects of three lead compounds on signaling pathways in MCF-7 cells were examined. Flow cytometry was used to assess the cell-cycle distribution of MCF-7 cells treated with the lead compound. Results: Among the synthesized hybrids, compounds 3f, 3j, and 3k exhibited potent antiproliferative activity with IC₅₀ values of 0.2–0.5 μM against breast cancer cells, while demonstrating very low cytotoxicity towards normal cells (IC₅₀ > 25 μM), indicating a favorable safety profile. The antitumor activity of lead compound 3j was additionally investigated in combination with standard chemotherapeutics, docetaxel and doxorubicin, yielding synergistic effects. The lead compounds showed a dual mechanism of action by inhibiting S6 kinase and promoting Bcl-2 phosphorylation at 0.9 μM, without significantly affecting hormonal breast cancer targets such as ERα, GREB1, and AR. Compound 3j induced apoptosis accompanied by a reduction of the G1/G0 phase in MCF-7 cells. Conclusions: These findings highlight secosteroid–2-pyrazoline hybrids as promising candidates for the development of next-generation breast cancer therapeutics targeting apoptosis and S6K signaling pathways.

Estrogen receptor alpha (ERα) is an important target for the discovery of new therapeutic drugs against hormone-dependent breast cancer. A series of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) were synthesized and biologically evaluated as potent ERα inhibitors. Pho-STPYRs showed cytotoxicity against breast cancer cells with IC₅₀ values of 5.9 μM and higher. Pho-STPYRs 33 and 34 [IC₅₀ (MCF7) = 6.5 and 5.9 μM, respectively] were found to block the expression of ERα, the main driver of breast cancer growth, and modulate the ERK, cyclin D1, and CDK4 pathways. Compound 34 showed selectivity, anti-estrogenic potency and high antiproliferative efficacy in combination with the AKT inhibitor. Molecular docking was used to more accurately define the binding mode of lead compounds 33 and 34 to ERα. The selectivity analysis showed that lead compounds 33 and 34 produce no effects on cytochromes P450, including CYP7A1, CYP7B1, CYP17A1, CYP19A1, and CYP21A2. In a word, Pho-STPYRs 33 and 34 are promising ERα inhibitors for the treatment of hormone-dependent breast cancer.

Introduction: The design and development of antitumor compounds based on an isatin core led to the synthesis of 1-substituted isatin-5-sulfonamides with potent antiproliferative activity

An effective approach to 5-triazolyl-substituted 6,7-dihydrobenzo[d]isoxazol-4(5H)-ones and 4,5,6,7-tetrahydrobenzo[d]isoxazoles was developed. The approach included α-keto bromination of 6,7-dihydrobenzo[d]isoxazol-4(5H)-one followed by nucleophilic substitution of bromine with the azide group. For the preparation of 5-azido-6,7-dihydrobenzo[d]isoxazol-4(5H)-one, the carbonyl group at position 4 was reduced to a methylene group under ionic hydrogenation conditions using triethylsilane as a reducing agent. Cu(I)-catalyzed [2+3] cycloaddition of terminal alkynes to both obtained azides was used for the synthesis of two series of triazolyl derivatives. Compounds, which contain in their structures common for some Hsp90 inhibitors 2,4-dihydroxy-5-isopropylphenyl fragment, were evaluated as antiproliferative agents against two breast cancer cell lines: hormone-dependent MCF7 and HER2-positive HCC1954. The lead compound showed half-maximal inhibitory concentration (IC 50 ) values below 5 μM and induced significant changes in the Hsp90 signaling pathways in HER2-positive HCC1954 cells. It increased the expression of Hsp70 (used as a pharmacodynamic marker of Hsp90 inhibition) and inhibited the expression of HER2, p-c-Met, c-Met, and p-AKT. The combination of the selected isoxazole-triazole hybrid molecule and the earlier described apoptosis inducer LCTA-3344 demonstrated a significant antiproliferative effect against HCC1954 cells. The lead compound was revealed to be a promising candidate for future anticancer drug design, particularly against aggressive breast cancer positive for HER2.