Synthesis and Structure-Activity Analysis of Icaritin Derivatives as Potential Tumor Growth Inhibitors of Hepatocellular Carcinoma Cells.

The prenylated flavonoid icaritin (ICT, 1), a new drug for treating advanced hepatocellular carcinoma (HCC), was selected as a template to develop more potent inhibitors. An initial semisynthetic modification of ICT was performed to obtain a structure-activity relationship (SAR), which indicated that the cytotoxicity is enhanced by OH-3 rhamnosylation and that OH-7 is an important modification site. Based on the results of the SAR study, 46 N-containing ICT derivatives were synthesized and evaluated as the anti-HCC inhibitors. The results showed that most of the derivatives produced inhibited three HCC cell lines used (Hep3B, HepG2 and SMMC-7721). The modification strategy was validated by 3D-QSAR, which provided information for the further design and optimization of ICT. The most potent compound, 11c, exhibited IC50 values of 7.6 and 3.1 µM against HepG2 and SMMC-7721 cells, respectively, which were more potent than those of ICT and sorafenib, respectively. Further mechanistic studies indicated that 11c caused arrest at the G0/G1 phase in the cell cycle and induced cell apoptosis in HepG2 and SMMC-7721 cells.

An Authentication and Secure Communication Scheme for In-Vehicle Networks Based on SOME/IP.

The rapid development of intelligent networked vehicles (ICVs) has brought many positive effects. Unfortunately, connecting to the outside exposes ICVs to security threats. Using secure protocols is an important approach to protect ICVs from hacker attacks and has become a hot research area for vehicle security. However, most of the previous studies were carried out on V2X networks, while those on in-vehicle networks (IVNs) did not involve Ethernet. To this end, oriented to the new IVNs based on Ethernet, we designed an efficient secure scheme, including an authentication scheme using the Scalable Service-Oriented Middleware over IP (SOME/IP) protocol and a secure communication scheme modifying the payload field of the original SOME/IP data frame. The security analysis shows that the designed authentication scheme can provide mutual identity authentication for communicating parties and ensure the confidentiality of the issued temporary session key; the designed authentication and secure communication scheme can resist the common malicious attacks conjointly. The performance experiments based on embedded devices show that the additional overhead introduced by the secure scheme is very limited. The secure scheme proposed in this article can promote the popularization of the SOME/IP protocol in IVNs and contribute to the secure communication of IVNs.

Design of a CANFD to SOME/IP Gateway Considering Security for In-Vehicle Networks.

In recent years, Ethernet has been introduced into vehicular networks to cope with the increasing demand for bandwidth and complexity in communication networks. To exchange data between controller area network (CAN) and Ethernet, a gateway system is required to provide a communication interface. Additionally, the existence of networked devices exposes automobiles to cyber security threats. Against this background, a gateway for CAN/CAN with flexible data-rate (CANFD) to scalable service-oriented middleware over IP (SOME/IP) protocol conversion is designed, and security schemes are implemented in the routing process to provide integrity and confidentiality protections. Based on NXP-S32G, the designed gateway is implemented and evaluated. Under most operating conditions, the CPU and the RAM usage are less than 5% and 20 MB, respectively. Devices running a Linux operating system can easily bear such a system resource overhead. The latency caused by the security scheme accounts for about 25% of the entire protocol conversion latency. Considering the security protection provided by the security scheme, this overhead is worthwhile. The results show that the designed gateway can ensure a CAN/CANFD to SOME/IP protocol conversion with a low system resource overhead and a low latency while effectively resisting hacker attacks such as frame forgery, tampering, and sniffing.

13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents.

Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.

A comprehensive review: Biological activity, modification and synthetic methodologies of prenylated flavonoids.

Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities including cytotoxicity, anti-inflammation, anti-Alzheimer, anti-microbial, anti-oxidant, anti-diabetes, estrogenic, vasorelaxant and enzyme inhibition. Recently, prenylated flavonoids have become an indispensable anchor for the development of new therapeutic agents, and have received increasing from medicinal chemists. The prenylated flavonoids have been outstanding developed through isolation, semi or fully synthesis in a very short period of time, which proves the great value in medicinal chemistry researches. In this review, research progress of prenylated flavonoids including natural prenylated flavonoids, structural modification, synthetic methodologies and pharmacological activities was summarized comprehensively. Furthermore, the structure-activity relationships (SARs) of prenylated flavonoids were summarized which provided a basis for the selective design and optimization of multifunctional prenylated flavonoid derivatives for the treatment of multi-factorial diseases in clinic.

Flavonoid-triazolyl hybrids as potential anti-hepatitis C virus agents: Synthesis and biological evaluation.

A series of flavonoid-triazolyl hybrids were synthesized and evaluated as novel inhibitors of hepatitis C virus (HCV). The results of anti-HCV activity assays showed that most of the synthesized derivatives at a concentration of 100 µg/mL inhibited the generation of progeny virus. Among these derivatives, 10m and 10r exhibited the most potent anti-HCV activity and inhibited the production of HCV in a dose-dependent manner. Interestingly, 10m and 10r had no significant inhibitory effect on viral translation or replication. Additional action mechanism studies revealed that the most potent compounds, 10m and 10r, significantly inhibited viral entry to 34.0% and 52.0%, respectively, at 10 µM. These results suggest further effective application of 10m and 10r as potential HCV preventive agents.