Design, synthesis, and potent anticancer activity of novel indole-based Bcl-2 inhibitors

The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1–6, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives

The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies

The Anti-Candida Activity of Tephrosia apollinea Is More Superiorly Attributed to a Novel Steroidal Compound with Selective Targeting

Tephrosia is widely distributed throughout tropical, subtropical, and arid regions. This genus is known for several biological activities, including its anti-Candida activity, which is mainly attributed to prenylated flavonoids. The biological activities of most Tephrosia species have been studied, except T. apollinea. This study was conducted to investigate the underlying anti-Candida activity of T. apollinea, wildly grown in the United Arab Emirates (UAE). The T. apollinea plant was collected, dried, and the leaves were separated. The leaves were ground and extracted. The dried extract was subjected to successive chromatography to identify unique phytochemicals with a special pharmacological activity. The activity of the compound was validated by homology modeling and molecular docking studies. A novel steroidal compound (ergosta-6, 8(14), 22, 24(28)-tetraen-3-one) was isolated and named TNS. In silico target identification of TNS revealed a high structural similarity with the Candida 14-α-demethylase enzyme substrate. The compound exhibited a significant anti-Candida activity, specifically against the multi-drug-resistant Candida auris at MIC50, 16 times less than the previously reported prenylated flavonoids and 5 times less than the methanol extract of the plant. These findings were supported by homology modeling and molecular docking studies. TNS may represent a new class of Candida 14-α-demethylase inhibitors

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives

Summary: The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies