The outstanding evidence of phthalimide pharmacophore in securing enhanced biological activities had encouraged further research and development into phthalimide-based derivatives as potential new drugs. In this study, phthalimide core was hybridized with aldehydes giving integrated imines displaying different types of functionalities and at alternating positions. The resulting compounds, therefore, provide an innovative window to explore possible differential biological effects as antioxidants and anticancer agents. A total of sixteen compounds were synthesized, and each was verified by FT-IR, H NMR, C NMR, and MS characterization. Herein, a facile single-step synthesis method was employed substituting the conventional two-step chemical production routes. Among the sixteen tested compounds, the H7 compound with hydroxyl phenolic group has shown an eminent antioxidant activity with a 19.52% decrease to the IC50 value compared to that of the control standard BHT antioxidant. On the other hand, the halogenated H6 Schiff base structure was successful in securing effective cancer inhibition to both colon and breast cancer cell lines, while maintaining selective action toward normal tissues. Results have collectively indicated the importance and impactful effects of functional groups position and types within similar basic structures, in directing different biological outcomes.

New multipotent antioxidants (MPAOs), namely semicarbazides and thiosemicarbazides bearing thiolated butylated hydroxytoluene (BHT), were synthesized.

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancy (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 was shown to regulate inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte–monocyte progenitors (GMPs) to epigenetically repress two inflammatory signaling pathways in neutrophils: Toll-like receptor 4 (TLR4) and type I interferon (IFN) signaling. RUNX1 loss in GMPs augments neutrophils’ inflammatory response to the TLR4 ligand lipopolysaccharide through increased expression of the TLR4 coreceptor CD14. RUNX1 bindsCd14and other genes encoding proteins in the TLR4 and type I IFN signaling pathways whose chromatin accessibility increases when RUNX1 is deleted. Transcription factor footprints for the effectors of type I IFN signaling—the signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRFs)—were enriched in chromatin that gained accessibility in both GMPs and neutrophils when RUNX1 was lost. STAT1::STAT2 and IRF motifs were also enriched in the chromatin of retrotransposons that were derepressed in RUNX1-deficient GMPs and neutrophils. We conclude that a major direct effect of RUNX1 loss in GMPs is the derepression of type I IFN and TLR4 signaling, resulting in a state of fixed maladaptive innate immunity.

In the present study, a series of multipotent antioxidants (MPAOs), namely sulfur-containing BHT (S-BHT), derivatives were rationally designed and synthesized, and their inhibitory activities against free radicals and human cancer cell lines, HT29 (colon cancer) and MCF7 (breast cancer) were further evaluated. The experimental results showed that the Six out-of-eight S-BHT compounds had excellent antioxidant activity against DPPH radical with major enhancement compared to BHT. Among them, compounds 2b, 2a and 3b attained over 45% lower IC 50 values than BHT. In vitro cytotoxicity, MTT assay was carried out using two human cancer cell lines, HT29 (colon cancer) and MCF7 (breast cancer) in addition to their non-tumorigenic counterparts to explore selectivity. In line with antioxidant activity, compounds 2a and 2b displayed the highest cytotoxicity effect on both cancer types. Interestingly, 2b not only exhibited superior cancer inhibition but also scored high selectivity index (SI = 5.2, 12.5) in colon and breast tissues, respectively, exceeding that of the standard chemotherapeutic drugs used 5-Fluorouracil (5-FU) and Tamoxifen (Tmx), with lower IC 50 values. The results indicated that the symmetric S-BHT derivatives were significantly enhanced by the antioxidant potency and their ability as useful and promising selective anticancer agents.