Peptidomimetics Based On Dehydroepiandrosterone Scaffold: Synthesis, Antiproliferation Activity, Structure-Activity Relationship, and Mechanisms

Abstract

A series of novel peptidomimetics bearing dehydroepiandrosterone moiety were designed, synthesized, and evaluated for their inhibition activities against cell proliferation. According to the preliminary studies on inhibitory activities, some of the newly prepared compounds indicated significantly inhibition activities against human hepatoma cancer (HepG2), human lung cancer (A549), human melanoma (A875) cell lines compared with the control 5-fluorouracil. Especially, compounds Ii (IC50 < 14 μM) and Ik (IC50 < 13 μM) exhibited obvious inhibition activities against all tested cell lines. The highly potential compound Ik induced apoptosis in HepG2 cells were analyzed by flow cytometry, and the apoptotic effects of compound Ik were further evaluated using Annexin V-FITC/propidium iodide dual staining assay, which revealed these highly potential compounds induced cell death in HepG2 cells at least partly by apoptosis.

Synthesis and Pharmacological Properties of Modified A- and D-Ring in Dehydroepiandrosterone (DHEA): A Review

“…On the basis of IC 50 values, it was found that compounds 45c−e and 45g, which have a fluoro-substituted -m) and 95a−l (IIa-l) at 40 μg/mL. 22 Copyright 2016, The Author(s). 5-FU: 5-Fluorouracil, used as a positive control.…”

“…Wang et al (2016) reported a series of novel peptidomimetics bearing DHEA moiety (94a−m and 95a−l) that was designed and synthesized using N-protected amino acids 91a−m and DHEA-17 hydrazone 92/DHEA-17 oxime 93 through nucleophilic substitution (Scheme 13). 22 Besides, the inhibition activity of the newly prepared compounds was evaluated against HepG2 (human hepatoma carcinoma), A549 (human lung), and A875 (human melanoma) cancer cell lines using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay compared with 5-FU (5-Fluorouracil) as a positive control. The majority of the compounds had higher inhibitory actions than 5-FU, as demonstrated in Figure 8.…”

“… Inhibition activities against cell proliferation for target compounds 94a – m (Ia-m) and 95a – l (IIa-l) at 40 μg/mL. 22 Copyright 2016, The Author(s). 5-FU: 5-Fluorouracil, used as a positive control.…”

“…Figure 8. Inhibition activities against cell proliferation for target compounds 94a−m (Ia-m) and 95a−l (IIa-l) at 40 μg/mL 22. Copyright 2016, The Author(s).…”

Peptidomimetics in cancer targeting

“…Producing peptidomimetics can be accomplished in several ways, including the following: (i) manipulating native peptide backbones, (ii) coupling unnatural amino acids derived from modifications, (iii) replacing amino groups with oxygen or sulfur by isosteric substitution (Gomes Von Borowski et al 2018 ; Wang et al 2016 ). Structure, sequence, function, and protein binding site characteristics are all factors that influence the design strategy (Lenci and Trabocchi 2020 ).…”