Medicinal‐Chemistry‐Driven Approach to 2‐Substituted Benzoxazole–Estradiol Chimeras: Synthesis, Anticancer Activity, and Early ADME Profile

• Published in: ChemMedChem 2023-11, Vol.18 (22), p.e202300352-n/a
• Main Authors: Kovács, Ferenc, Huliák, Ildikó, Árva, Hédi, Kiricsi, Mónika, Erdős, Dóra, Kocsis, Marianna, Takács, Gergely, Balogh, György T., Frank, Éva
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Aminophenol; Anticancer properties; Antineoplastic Agents - chemistry; antiproliferation; Antitumor activity; Antitumor agents; Apoptosis; Benzene; benzoxazole; Benzoxazoles - pharmacology; Cancer; Cell Line, Tumor; Cell Proliferation; Chimeras; Drug Screening Assays, Antitumor; Embedding; estradiol; Estradiol - pharmacology; Functional groups; Humans; hybridization; Hybrids; Lipophilic; Molecular Structure; Oxazole; Oxazoles - pharmacology; Physicochemical properties; Sex hormones; Steroids; Structure-Activity Relationship; Synthesis; Tumor cell lines
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300352

The efficient synthesis of novel estradiol‐based A‐ring‐fused oxazole derivatives, which can be considered as benzoxazole‐steroid domain‐integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2‐aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection‐based t‐distributed stochastic neighbor embedding (t‐SNE), the novel molecules were proved to represent a new chemical space among steroid drugs. They were characterized based on critical physicochemical parameters using in silico and experimental data. The performance of the compounds to inhibit cell proliferation was tested on four human cancer cell lines and non‐cancerous cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency (LLE) values, cancer cell selectivity, and apoptosis‐triggering features. Pharmacological tests and LLE metric revealed that some derivatives, especially the 2‐(4‐ethylpiperazin‐1‐yl)oxazole derivative exhibit strong anticancer activity and trigger the apoptosis of cancer cells with relatively low promiscuity risk similarly to the structurally most closely‐related and intensively studied anticancer agent, 2‐methoxy‐estradiol. A series of diversely substituted benzoxazole–estradiol chimeras were prepared and characterized based on critical physicochemical parameters. The performance of the compounds to inhibit cell proliferation was tested on human cancer cell lines and non‐cancerous cells. Pharmacological tests (IC50 values, cancer cell selectivity, apoptosis‐triggering features) and LLE metric revealed that the anticancer activity of some derivatives was stronger than or similar to that of 2‐methoxyestradiol and cisplatin.