KRAS mRNA G-quadruplexes (rG4s) in the 5'-untranslated region offer attractive targets for translational intervention in KRAS-driven cancers. We previously identified the quinoline-coumarin derivative 15a as a KRAS rG4 ligand that suppresses KRAS translation; however, its permanently charged quaternary ammonium center limits further optimization. Herein, we designed and synthesized a series of nonquaternary ammonium analogs to investigate whether this structural motif could be removed without compromising KRAS rG4-related activity. Q29 emerged as the most promising compound, showing high affinity for the KRAS rG4 and inhibiting KRAS translation. Q29 also exhibited potent antiproliferative activity across KRAS mutant cancer cells, improved cellular uptake and tolerability relative to 15a, and significant antitumor efficacy in a MIA PaCa-2 xenograft model. Collectively, our study establishes a viable strategy for optimizing KRAS rG4 ligands that retain activity despite removal of the permanent charge and identifies Q29 as a promising lead for further development of KRAS translation inhibitors.
Mao-Lin Li, Wen-Wei Li, Wen-Li Fu et al.· Journal of Medicinal Chemist...· 0 citations
N-Acetylglucosamine (GlcNAc)-decorated natural products represent a structurally unique class of metabolites that possess diverse biological activities. Through the genome mining of Coccidioides sp. CMB-TN39F, we identified a GlcNAc transferase-encoding terpene synthase gene cluster brc. Heterologous expression of this cluster in Aspergillus nidulans enabled the characterization of seven GlcNAc-adorned brasilane-type sesquiterpene glycosides, including six previously undocumented compounds, brasilane G−L (1−6), and one known compound, brasilane A (7). Functional characterization revealed that the cytochrome P450 BrcC functions as an epoxidase, catalyzing a stereoselective epoxidation of 7 to form 1. Compound 1 can undergo non-enzymatic conversions to generate compounds 2−5 under mildly acidic conditions. Pharmacological evaluation demonstrated that compounds 1−6 effectively downregulate the expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in LPS/IFN-γ-stimulated THP-1-derived macrophages. Notably, 1, which features an epoxide moiety, exhibits superior anti-inflammatory activity compared to its biosynthetic precursor 7, with an IC50 value of 30.4 μM against IL-6. This study expands the chemical space of GlcNAc-conjugated terpenoids and showcases a biosynthetic logic in which enzymatic tailoring is coupled with nonenzymatic reactions to amplify both structural diversity and biological properties.
Ming-Min Wu, Yao-Hui Shi, Yu-Wei Lin et al.· Journal of Natural Products· 0 citations
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