Synthesis of a celastrol derivative as a cancer stem cell inhibitor through regulation of the STAT3 pathway for treatment of ovarian cancer.

Accumulating evidence suggests that the root of drug chemoresistance in ovarian cancer is tightly associated with subpopulations of cancer stem cells (CSCs), whose activation is largely associated with signal transducer and activator of transcription 3 (STAT3) signaling. Recently, celastrol has shown a significant anti-cancer effect on ovarian cancer, but its clinical translation is very challenging due to its oral bioavailability and high organ toxicity. In this study, a celastrol derivative (Cel-N) was synthesized to augment the overall efficacy, and its underlying mechanisms were also explored. Different ovarian cancer cells, SKOV3 and A2780, were used to evaluate and compare the anticancer effects. Cel-N displayed potent activities against all the tested ovarian cancer cells, with the lowest IC50 value of 0.14-0.25 µM. Further studies showed that Cel-N effectively suppressed the colony formation and sphere formation ability, decreased the percentage of CD44+CD24- and ALDH+ cells, and induced ROS production. Furthermore, western blot analysis indicated that Cel-N significantly inhibited both Tyr705 and Ser727 phosphorylation and reduced the protein expression of STAT3. In addition, Cel-N could dramatically induce apoptosis and cell cycle arrest, and inhibit migration and invasion. Importantly, Cel-N showed a potent antitumor efficacy with no or limited systemic toxicity in mice xenograft models. The anticancer effect of Cel-N is stronger than celastrol. Cel-N attenuates cancer cell stemness, inhibits the STAT3 pathway, and exerts anti-ovarian cancer effects in cell and mouse models. Our data support that Cel-N is a potent drug candidate for ovarian cancer.

Photoexcited nitroarenes for alkylation of quinoxalin-2(1H)-ones.

A straightforward method for the dehydrogenative alkylation of quinoxalin-2(1H)-ones with alkylbenzenes has been developed, facilitated by a photoexcited nitroarene. The reaction's success hinges on the dual role of the photoexcited nitroarene molecule, acting as both a hydrogen atom transfer (HAT) reagent and an oxidant. This technique is both atom-economical and cost-effective, due to the readily available nitroarene, which serves as the sole intermediary in the reaction process.

Lewis base-catalyzed cascade [4 + 2]-annulation reaction of N-alkoxy acrylamides and acyl isothiocyanates: facile access to 2-imino-1,3-thiazinone derivatives.

A formal [4 + 2]-cycloaddition reaction of N-alkoxy acrylamides and acyl isothiocyanates was developed via a Lewis base-catalyzed cascade aza-nucleophilic addition/thio-Michael addition process under mild conditions. This study provides a facile approach for preparing 2-imino-1,3-thiazinone derivatives in moderate to excellent yields and enriches the field of heterocyclic acrylamide chemistry. The reported method features metal-free reaction conditions, high atom economy, and easy operation. Moreover, the reaction was successfully scaled up and derivatization reactions were successfully performed.

Synthesis of Polycyclic Imidazolidinones via Cascade [3 + 2]-Annulation of ß-Oxo-acrylamides with Cyclic N-Sulfonyl Imines.

An Et3N-catalyzed cascade [3 + 2]-annulation of ß-oxo-acrylamides with cyclic N-sulfonyl ketimines or sulfamate-derived imines is developed under mild reaction conditions, which provides a concise and efficient route to access valuable sultam- or sulfamidate-fused imidazolidinone derivatives in good to excellent yields (80-95% yields) with excellent diastereoselectivities (>20:1 drs). The current protocol features atom economy, a transition-metal-free process, and broad functional group tolerance. Moreover, the asymmetric variant of the [3 + 2]-cycloaddition reaction was achieved in the presence of diphenylethanediamine or quinine-based bifunctional squaramide organocatalysts C-1 and C-11, giving the corresponding chiral polycyclic imidazolidinones in 68-90% yields with 25-94% ees and >20:1 drs in all cases.

Organocatalytic cascade nucleophilic/aza-Michael addition reactions: metal-free catalytic strategy for the synthesis of hydantoins.

Lewis base-catalyzed cascade nucleophilic/aza-Michael addition reaction of N-alkoxy ß-oxo-acrylamides with isocyanates has been developed to afford various highly functionalized hydantoin derivatives in 80-98% yields under mild reaction conditions. The intriguing features of this method include metal-free reaction conditions, low catalyst loading, broad substrate scope and short reaction time.

Discovery of semisynthetic celastrol derivatives exhibiting potent anti-ovarian cancer stem cell activity and STAT3 inhibition.

The hallmark of ovarian cancer is its high mortality rate attributed to the existence of cancer stem cells (CSCs) subpopulations which result in therapy recurrence and metastasis. A series of C-29-substituted and/or different A/B ring of celastrol derivatives were synthesized and displayed potential inhibition against ovarian cancer cells SKOV3, A2780 and OVCAR3. Among them, compound 6c exhibited the most potent anti-proliferative activity and selectivity, gave superior anti-CSC effects through inhibition of the sphere formation and downregulation of the percentage of CD44+CD24- and ALDH+ cells. Further mechanism research demonstrated that compound 6c could attenuate the expression of STAT3 and p-STAT3. The results suggested that the inhibition of celastrol derivative 6c on ovarian cancer cells may be related to resistance to cancer stem-like characters and regulation of STAT3 pathway.

Linking deep CO2 outgassing to cratonic destruction.

Outgassing of carbon dioxide from the Earth's interior regulates the surface climate through deep time. Here we examine the role of cratonic destruction in mantle CO2 outgassing via collating and presenting new data for Paleozoic kimberlites, Mesozoic basaltic rocks and their mantle xenoliths from the eastern North China Craton (NCC), which underwent extensive destruction in the early Cretaceous. High Ca/Al and low Ti/Eu and δ 26Mg are widely observed in lamprophyres and mantle xenoliths, which demonstrates that the cratonic lithospheric mantle (CLM) was pervasively metasomatized by recycled carbonates. Raman analysis of bubble-bearing melt inclusions shows that redox melting of the C-rich CLM produced carbonated silicate melts with high CO2 content. The enormous quantities of CO2 in these magmas, together with substantial CO2 degassing from the carbonated melt-CLM reaction and crustal heating, indicate that destruction of the eastern NCC resulted in rapid and extensive mantle CO2 emission, which partly contributed to the early Cretaceous greenhouse climate episode.

Quantitative influence and performance analysis of virtual reality laparoscopic surgical training system.

BACKGROUND: Virtual reality (VR) surgery training has become a trend in clinical education. Many research papers validate the effectiveness of VR-based surgical simulators in training medical students. However, most existing articles employ subjective methods to study the residents' surgical skills improvement. Few of them investigate how to improve the surgery skills on specific dimensions substantially. METHODS: Our paper resorts to physiological approaches to objectively study the quantitative influence and performance analysis of VR laparoscopic surgical training system for medical students. Fifty-one participants were recruited from a pool of medical students. They conducted four pre and post experiments in the training box. They were trained on VR-based laparoscopic surgery simulators (VRLS) in the middle of pre and post experiments. Their operation and physiological data (heart rate and electroencephalogram) are recorded during the pre and post experiments. The physiological data is used to compute cognitive load and flow experience quantitatively. Senior surgeons graded their performance using newly designed hybrid standards for fundamental tasks and Global operative assessment of laparoscopic skills (GOALS) standards for colon resection tasks. Finally, the participants were required to fill the questionnaires about their cognitive load and flow experience. RESULTS: After training on VRLS, the time of the experimental group to complete the same task could drop sharply (p < 0.01). The performance scores are enhanced significantly (p < 0.01). The performance and cognitive load computed from EEG are negatively correlated (p < 0.05). CONCLUSION: The results show that the VRLS could highly improve medical students' performance and enable the participants to obtain flow experience with a lower cognitive load. Participants' performance is negatively correlated with cognitive load through quantitative physiological analysis. This might provide a new way of assessing skill acquirement.