Synthesis, Anticancer Potential and Comprehensive Toxicity Studies of Novel Brominated Derivatives of Bacterial Biopigment Prodigiosin from Serratia marcescens ATCC 27117

Abstract

Prodigiosins (prodiginines) are a class of bacterial secondary metabolites with remarkable biological activities and color. In this study, optimized production, purification, and characterization of prodigiosin (PG) from easily accessible Serratia marcescens ATCC 27117 strain has been achieved to levels of 14 mg/L of culture within 24 h. Furthermore, environmentally friendly bromination of produced PG was used to afford both novel mono- and dibrominated derivatives of PG. PG and its Br derivatives showed anticancer potential with IC50 values range 0.62–17.00 µg/mL for all tested cancer cell lines and induction of apoptosis but low selectivity against healthy cell lines. All compounds did not affect Caenorhabditiselegans at concentrations up to 50 µg/mL. However, an improved toxicity profile of Br derivatives in comparison to parent PG was observed in vivo using zebrafish (Danio rerio) model system, when 10 µg/mL applied at 6 h post fertilization caused death rate of 100%, 30% and 0% by PG, PG-Br, and PG-Br2, respectively, which is a significant finding for further structural optimizations of bacterial prodigiosins. The drug-likeness of PG and its Br derivatives was examined, and the novel Br derivatives obey the Lipinski’s “rule of five”, with an exemption of being more lipophilic than PG, which still makes them good targets for further structural optimization.

Prodigiosin from Serratia Marcescens in Cockroach Inhibits the Proliferation of Hepatocellular Carcinoma Cells through Endoplasmic Reticulum Stress-Induced Apoptosis

“…Jelena’s study showed that PG and its Br derivatives showed anticancer potential against all tumor cell lines and induced apoptosis, but their selectivity to healthy cell lines was low. The greater lipophilicity of Br derivatives of PG made them good targets for further structural optimization [ 12 ].…”

“…PG also inhibits the growth of human oral squamous cell carcinoma cells by targeting the autophagic cell death pathway. Hosseini’s research results showed that PG had a great affinity for the anti-apoptotic member MCL-1 of the BCL-2 family, and it could activate the mitochondrial apoptosis pathway by destroying the MCL-1/BAK complex to cause apoptosis in melanoma cells [ 12 ]. Therefore, it is necessary to clarify the role of different molecular phenotypes in the PG-induced apoptosis of malignant tumor cells and the molecular mechanisms underlying this process, which can reveal new and more effective targets for treating tumors.…”

Investigation of Antimicrobial, Anti‐Quorum Sensing, and Cytotoxic Activities of Flavonoids Isolated from Pulicaria armena Boiss. & Kotschy ex Boiss. (Asteraceae)

“…Chromobacterium violaceum CV026 biosensor strain was employed to assess the violacein production, [40] and the experiments were carried out according to the previously described methodology [41] . Serratia marcescens ATCC 27117, prodigiosin producer, [42] was used for the assessment of PuA compounds activity on prodigiosin production [43] …”

“…[39] Effect of Compounds on Bacterial Quorum Sensing and Pigments Production Chromobacterium violaceum CV026 biosensor strain was employed to assess the violacein production, [40] and the experiments were carried out according to the previously described methodology. [41] Serratia marcescens ATCC 27117, prodigiosin producer, [42] was used for the assessment of PuA compounds activity on prodigiosin production. [43] In Vitro Toxicity Determination Antiproliferative activity of the PuA compounds was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against human lung fibroblasts cells MRC-5, lung carcinoma epithelial cells A549, and human colorectal carcinoma cells HCT116 were used as described previously.…”

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets

“…For the 52 agents listed above, we found the structures of the compounds corresponding to 41 of them through literature search (Fig. 5 ) and analyzed them for drug likeness by using Python’s rdkit package (Goodwin et al 2017 ; Lazic et al 2022 ; Liu et al 2023a ; Liu et al 2022b ). Commonly, the drug properties of chemical molecules can be initially determined according to Lipinski’s rule V. Lipinski’s rule V is defined as a molecular weight not exceeding 500 Dalton, octanol–water partition coefficient [log P] not exceeding 5, hydrogen bond acceptor not exceeding 10, and hydrogen bond donor not exceeding 5 (Lipinski et al 2001 ).…”