Discovery of novel hybrids of mTOR inhibitor and NO donor as potential anti-tumor therapeutics.

Nitric oxide (NO) may be beneficial to overcoming drug resistance resulting from mutation of mTOR kinases and bypass mechanisms. In this study, a novel structural series of hybrids of mTOR inhibitor and NO donor were designed and synthesized via structure-based drug design (SBDD). Throughout the 20 target compounds, half of the compounds (13a, 13b, 19a-19d, 19f-19j) demonstrated attractive mTOR inhibitory activity with IC50 at single-digit nanomolar level. In particular, 19f exerted superior anti-proliferative activity against HepG2, MCF-7, HL-60 cells (HepG2, IC50 = 0.24 µM; MCF-7, IC50 = 0.88 µM; HL-60, IC50 = 0.02 µM) to that of the clinical investigated mTOR inhibitor MLN0128, and show mild cytotoxicity against normal cells with IC50 over 10 µM. 19a, with the most potent mTOR inhibitory activity in this series (IC50 = 3.31 nM), also displayed attractive cellular potency. In addition, 19f treatment in HL-60 reduces the levels of Phos-Akt and Phos-S6 in a dose-dependent manner, and releases NO in cells. In summary, 19f deserves further development as a novel mTOR-based multi-target anti-cancer agent.

Study on contaminant distribution in a mobile BSL-4 laboratory based on multi-region directional airflow.

The outbreak of COVID-19 has caused increasing public attention to laboratory-acquired infections (LAIs), especially for a mobile Bio-Safety Level 4 Lab (BSL-4) with high potential of exposure. In this paper, the distribution and removal mechanism of bioaerosols in the biosafety laboratory were studied. A simulation model of airflow distribution in the opening and closing state of air-tight door was established and verified. The results showed that the airflow entrainment velocity during the opening of the door was approximately 0.12 m/s. It increased the probability of vortex generation in the laboratory. The deposition rate of particles was doubled when the air-tight door opening is compared with air-tight door closing. Besides, nearly 80% of the particles deposited on the surface of the wall and ceiling, increasing the possibility of LAIs. The findings of this paper could provide new scientific methods for high-level biosafety laboratories to avoid cross-infection. Moreover, future work regarding air-tight door rotation speed regulation and control should be emphasized.