Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy.

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy. However, metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity. Herein, choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types, and a choline-modified strategy for small molecule-drug conjugates (SMDCs) design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy, instead of directly inhibiting choline metabolism. As a proof-of-concept, choline-modified SMDCs were designed, screened, and investigated for their druggability in vitro and in vivo. This strategy improved tumor targeting, preserved tumor inhibition and reduced toxicity of paclitaxel, through targeted drug delivery to tumor by highly expressed choline transporters, and site-specific release by carboxylesterase. This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

Ginsenoside 3ß-O-Glc-DM (C3DM) suppressed glioma tumor growth by downregulating the EGFR/PI3K/AKT/mTOR signaling pathway and modulating the tumor microenvironment.

Ginsenosides are the main bioactive constituents of Panax ginseng, which have been broadly studied in cancer treatment. Our previous studies have demonstrated that 3ß-O-Glc-DM (C3DM), a biosynthetic ginsenoside, exhibited antitumor effects in several cancer cell lines with anti-colon cancer activity superior to ginsenoside 20(R)-Rg3 in vivo. However, the efficacy of C3DM on glioma has not been proved yet. In this study, the antitumor activities and underlying mechanisms of C3DM on glioma were investigated in vitro and in vivo. Cell viability, apoptosis, migration, FCM, IHC, RT-qPCR, quantitative proteomics, and western blotting were conducted to evaluate the effect of C3DM on glioma cells. ADP-Glo™ kinase assay was used to validate the interaction between C3DM and EGFR. Co-cultured assays, lactic acid kit, and spatially resolved metabolomics were performed to study the function of C3DM in regulating glioma microenvironment. Both subcutaneously transplanted syngeneic models and orthotopic models of glioma were used to determine the effect of C3DM on tumor growth in vivo. We found that C3DM dose-dependently induced apoptosis, and inhibited the proliferation, migration and angiogenesis of glioma cells. C3DM significantly inhibited tumor growth in both subcutaneous and orthotopic mouse glioma models. Moreover, C3DM attenuated the acidified glioma microenvironment and enhanced T-cell function. Additionally, C3DM inhibited the kinase activity of EGFR and influenced the EGFR/PI3K/AKT/mTOR signaling pathway in glioma. Overall, C3DM might be a promising candidate for glioma prevention and treatment.

Design, synthesis and in vivo anticancer activity of novel parthenolide and micheliolide derivatives as NF-κB and STAT3 inhibitors.

Parthenolide and micheliolide have attracted great attention in anticancer research due to their unique activities. In this study, thirteen parthenolide derivatives and twenty-three micheliolide derivatives were synthesized. Most synthesized compounds showed higher cytotoxicity than parthenolide or micheliolide. The in vivo anticancer activity of several representative compounds was evaluated in mice. One micheliolide derivative, 9-oxomicheliolide (43), showed promising in vivo antitumor activity compared with clinical drugs cyclophosphamide or temozolomide. Compound 43 was particularly effective against glioblastoma, with its tumor inhibition rate in mice comparable to the drug temozolomide. The discovery of compound 43 also demonstrates the feasibility of developing anticancer micheliolide derivatives by modification at C-9 position. Anticancer mechanism studies revealed that 9-oxomicheliolide exhibited inhibition effect against NF-κB and STAT3 signaling pathways, as well as induction effects of cell apoptosis. It is postulated that 9-oxomicheliolide is likely to be a modulator of the immune system, which regulates the anticancer immune responses.

Acid-Mediated Intermolecular [3 + 2] Cycloaddition toward Pyrrolo[2,1-a]isoquinolines: Total Synthesis of the Lamellarin Core and Lamellarin G Trimethyl Ether.

A novel one-pot reaction has been developed for the efficient synthesis of pyrrolo[2,1-a]isoquinolines and 1-dearyllamellarin core from (E)-(2-nitrovinyl)benzenes and azomethine ylides generated in situ. This strategy provides a concise total synthesis of the lamellarin core and lamellarin G trimethyl ether using electrophilic substitution and palladium-catalyzed Suzuki-Miyaura cross-coupling reactions.

Transition-Metal-Free Multicomponent Benzannulation Reactions for the Construction of Polysubstituted Benzene Derivatives.

A transition-metal-free multicomponent benzannulation reaction was developed from readily available ketones, nitro-olefins, and diester acetylenedicarboxylate. This approach provides a straightforward and efficient way to construct polysubstituted benzene derivatives under mild conditions in high yields.