Distinguishing G-Quadruplexes Stabilizer and Chaperone for c-MYC Promoter G-Quadruplexes through Single-Molecule Manipulation.

G-quadruplex (G4) selective stabilizing ligands can regulate c-MYC gene expression, but the kinetic basis remains unclear. Determining the effects of ligands on c-MYC promoter G4s' folding/unfolding kinetics is challenging due to the polymorphic nature of G4s and the high energy barrier to unfold c-MYC promoter G4s. Here, we used single-molecule magnetic tweezers to manipulate a duplex hairpin containing a c-MYC promoter sequence to mimic the transiently denatured duplex during transcription. We measured the effects of six commonly used G4s binding ligands on the competition between quadruplex and duplex structures, as well as the folding/unfolding kinetics of G4s. Our results revealed two distinct roles for G4s selective stabilization: CX-5461 is mainly acting as c-MYC G4s stabilizer, reducing the unfolding rate (ku) of c-MYC G4s, whereas PDS and 360A also act as G4s chaperone, accelerating the folding rates (kf) of c-MYC G4s. qRT-PCR results obtained from CA46 and Raji cell lines demonstrated that G4s stabilizing ligands can downregulate c-MYC expression, while G4s stabilizer CX-5461 exhibited the strongest c-MYC gene suppression. These results shed light on the potential of manipulating G4s' folding/unfolding kinetics by ligands for precise regulation of promoter G4-associated biological activities.

Hyalangiumruber sp. nov, characterization of a novel myxobacterium strain s54d21 and their secondary metabolites.

Myxobacteria are special bacteria with wide adaptability, which are rich sources of structurally diverse natural products with intriguing biological properties. Here, a gram-negative myxobacterium strain s54d21T was isolated from the sediment of a wetland park in China using the Escherichia coli baiting method. Based on 16S rRNA gene sequence and genomic data, the strain was demonstrated to be a novel species of a rare genus Hyalangium, designated Hyalangium ruber sp. nov (type strain s54d21T = GDMCC 1.1945T = JCM 39263T). The subsequent chemical investigation of the strain s54d21T led to the isolation of three rare 3,5,6-trisubstituted 2(1H)-pyrazinones, namely, hyalanones A-C (1-3), together with a known macrolactin A (4). Those new structures and their absolute configurations were unambiguously assigned by extensive analyses of spectroscopic data and density functional theory (DFT) calculations. In biological assays, compound 4 exhibited moderate cytotoxic activities against human cell lines RKO, A549, and NCM460 with IC50 values ranging from 27.21 to 32.14 µM.

Bipoladien A, a Sesterterpenoid Containing an Undescribed 5/8/5/7 Carbon Skeleton from Bipolaris maydis.

Bipoladiens A-E (1-5), five new ophiobolin-derived sesterterpenoids, and a known compound 6 (bipolaricin R) were isolated from the cultures of the phytopathogenic fungus Bipolaris maydis. Their structures and absolute configurations were elucidated based on comprehensive spectroscopic analyses, HRESIMS, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analyses. Notably, compound 1 has an undescribed tetracyclic 5/8/5/7 fused carbon skeleton, and compound 2 possesses a rare multicyclic caged ring system. The biosynthetic pathway of 1 was proposed starting from 6 via a series of oxidation and cyclization reactions. Compound 6 showed excellent antiproliferation and apoptosis induction effects against A549 cell line. Additionally, compounds 5 and 6 exhibited noticeable antimicrobial ability against Bacillus cereus, Staphylococcus aureus, and Staphylococcus epidermidis. These findings not only developed the chemical and bioactivities diversities of ophiobolin-sesterterpenoid but also provided an idea to boost the application of natural products in the control of food pathogens.