Design, synthesis and in vitro antitumor activity of 17β-estradiol-amino acid derivatives

Abstract

A total of 28 derivatives were designed and synthesized, including 18 estradiol-amino acid (17β-OH) derivatives (I-2 ∼ I-19) and 10 estradiol-amino acid (16-C) derivatives (II-2 ∼ II-11). Amino acids used in synthesis include L-phenylalanine, L-serine, L-leucine, glycine, L-proline and L-glutamine. The results showed that I-8 ∼ I-12 of 17β-OH conjugated amino acids in 17β-estradiol had good in vitro antitumor activity, indicating that the introduction of amino acids could improve the anti-proliferative effect. Among them, 3-benzyloxy-Estra-1,3,5 (10)-triene-17β-ol pyrrolidine-2-carboxylate hydrochloride (I-12) showed the best inhibitory activity against breast cancer (MDA-MB-231) cells (IC50 = 4.89 µM). Further studies on apoptosis revealed that I-12 could regulate the expression of apoptosis-related proteins in MDA-MB-231 cells. Network pharmacology and molecular docking analysis revealed that I-12 may act on targets such as mechanistic target of rapamycin kinase (mTOR), estrogen receptor 1 (ESR1), pyruvate dehydrogenase kinase (PDK2) targets and their related pathways.

Keywords

• 17β-Estradiol
• Apoptosis
• Antitumor activity
• MDA-MB-231 cells