A convergent synthesis of dibenzochrysenes and diindenochrysenes that proceeds from difluorofluorenes and acetoxyenone 15 has been used to prepare 5,6,11,12-tetrabromosemibuckminsterfullerene (31). The synthesis is highly modular and is distinguished by proceeding through an unsymmetrical intermediate. Our work will enable the straightforward preparation of semibuckminsterfullerenes from diindenochrysenes that lack bilateral symmetry using common reagents and nonpyrolytic conditions.

Dysregulated gene expression programs and redox and metabolic adaptations allow cancer cells to survive under high oxidative burden. These mechanisms also represent therapeutic vulnerabilities. Using triple-negative breast cancer (TNBC) as a model, we show that compared to normal human breast epithelial cells, the TNBC cells, MDA-MB-231 and MDA-MB-468 that harbor constitutively active STAT3 also express higher glucose-6-phosphate dehydrogenase (G6PD), thioredoxin reductase (TrxR)1, NADPH, and GSH levels for survival. Present studies discover that the natural product, R001, targets these adaptation mechanisms. Treatment of TNBC cells with R001 inhibited constitutively active STAT3, STAT3-regulated gene expression, and the functions of G6PD and TrxR1. Consequently, in the TNBC, but not normal cells, R001 suppressed GSH levels, but raised NADPH levels, reflective of a loss of mitochondrial respiration and which led to reactive oxygen species (ROS) induction, all of which led to loss of viable cells and inhibition of anchorage-dependent and independent growth. R001 treatment further led to early pyroptosis and late DNA damage, cell cycle arrest, and apoptosis only in the TNBC cells. Oral administration of 5 mg/kg R001 inhibited MDA-MB-468 xenografts growth in mice, with reduced pY705-STAT3, G6PD, TrxR1, and GSH levels. R001 serves as a therapeutic entity that targets the vulnerabilities of TNBC cells to inhibit tumor growth in vivo.

A practical synthesis of 1,8-difluorofluorenone and of its (2,7)-dibromo and (2,4,5,7)-tetrabromo derivatives has been developed. Fluorinated fluorenones are the starting materials for polyhalogenated dibenzochrysenes as well as for geodesic hydrocarbons....

Bioactive natural products have led to new drugs or been the inspiration for developing new treatments. Signal transducer and activator of transcription (STAT)3 is a an oncogene that has been implicated in many human cancers. We report that the hirsutinolide natural product, R001, blocks STAT3 DNA-binding activty in vitro. Treatment with R001 of the human triple-negative breast cancer (TNBC) cells, MDA-MB-231 and MDA-MB-468 led to the concurrent inhibition of constitutively-active STAT3 and the expression and activities of glucose-6-phosphate 1-dehydrogenase (G6PD) and thioredoxin reductase (TrxR)1, early suppression of glutathione (GSH), and the induction of reactive oxygen species (ROS), which peaked at 6-24 h post R001-treatment. In the short term, R001-treated TNBC cells showed evidence of pyroptotic cell death. Prolonged treatment of TNBC cells with R001 led to DNA damage and G2/M-phase cell cycle arrest, which are late-stage responses that were preceded by the suppression of ATM-Chk2-Cdc25c pathway, and the induction of p21 and γH2AX phosphorylation by the natural product. Accordingly, R001 suppressed the viable cell numbers, colony formation, growth in 3D-matrigel, and the migration of MDA-MB-231 and MDA-MB-468 cells in vitro. The oral administration of R001 at 5 mg/kg signficantly inhibited growth of human MDA-MB-468 xenografts in mice. Results together show that R001 inhibits STAT3, G6PD and TrxR1 functions that lead to early oxidative stress and pyroptosis and late-stage DNA damage and cell cycle arrest, which collectively cause tumor cell death and tumor growth inhibition in human TNBC models. Citation Format: Yinsong Zhu, Cody F. Dickinson, Justin Yang, Kyrstin Datanagan, Ning Zhai, Peibin Yue, Francisco Lopez-Tapia, Marcus A. Tius, James Turkson. Natural product inhibitor of Stat3, G6PD, and TrxR1 functions induces an early oxidative stress and pyroptosis, and a late-stage DNA damage and cell cycle arrest to block tumor growth in human breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5482.