Novel fluorescent probes of 10-hydroxyevodiamine:autophagy and apoptosis-inducing anticancer mechanisms

Natural product evodiamine and its derivatives represent a promising class of multi-target antitumor agents. However, the clinical development of these compounds has been hampered by a poor understanding of their antitumor mechanisms. To tackle this obstacle, herein, novel fluorescent probes were designed to elucidate the antitumor mode of action of 10-hydroxyevodiamine. This compound was proven to be distributed in the mitochondria and lysosomes and to act by autophagy and apoptosis mechanisms.

Radiosensitization of human pancreatic cancer by piperlongumine analogues

Radiotherapy is commonly used to treat advanced pancreatic cancers and can improve survival by2 months in combination with gemcitabine.However,prognosis and survival improvement remain unsatisfactory,and effective therapies are urgently needed.Piperlongumine has been demonstrated to have therapeutic potentials against various cancers.In this study,we synthesized a series of piperlongumine derivatives and provided evidence that piperlongumine derivatives could be used as effective radiosensitizers in pancreatic cancer.Two compounds enhanced the radiosensitivity of Panc-1 and SW1990 cells.In a pancreatic bi-flank xenograft tumor model,they significantly inhibited tumor growth.Piperlongumine derivatives could induce reactive oxygen species(ROS)expression and regulate the Keapl-Nrf2 protective pathway with enhancement of radiation-induced DNA damage,G2/M-phase cell cycle arrest,and apoptosis.Collectively,our data offer a proof of concept for the use of piperlongumine derivatives as a novel class of radiosensitizers for the treatment of pancreatic cancer.

Design and synthesis of novel water-soluble amino acid derivatives of chlorin p6 ethers as photosensitizer

Eight new water-soluble amino acid conjugates 6 a-h of chlorin p6 ethers(5 a-d) were synthesized and preliminarily investigated for their in vitro PDT antitumor activity and structure-activity relationship(SAR). The results showed that all compounds exhibited much higher phototoxicity against tumor cells than talaporfin. SAR analysis indicated that PDT antitumor effect enhanced with the increase of carbon chain length of alkoxyl ether bonds at 3~1-position, and L-aspartic acid was superior to L-glutamic acid. In particular, the IC_50 values of most phototoxic compound 6 d were 0.20 mmol/L against A549 cell and0.41υmmol/L against B16-F10 cell, which individually represented 31-and 24-fold increase of antitumor potency compared to talaporfin, suggesting that it was a promising candidate photosensitizer(PS) for PDT applications due to its strong absorption at long wavelength, high phototoxicity, low dark cytotoxicity and good water-solubility.

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Receptor-interacting protein(RIP)kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis(UC)by regulating necroptosis and inflammation.Our group previously identified TAK-632(5)as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3.In this study,using ligand-based substituent-anchoring design strategy,we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3.Among them,a conformational constrained fluorine-substituted derivative(25)exhibited 333-fold selectivity for RIP1(K_(d)= 15 nmol/L)than RIP3(K_(d)>5000 nmol/L).This compound showed highly potent activity against cell necroptosis(EC_(50)=8 nmol/L)and systemic inflammatory response syndrome(SIRS)induced by TNF-α in vivo.Especially,it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC.Taken together,the highly potent,selective,orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.

Asymmetric Synthesis, Antifungal Activity and Molecular Modeling of Iodiconazole Isomers

Iodiconazole is a novel antifungal agent that was developed in its racemic form. In order to investigate the ef- fects of the chiral center on the antifungal activity, R- and S-isomers of iodiconazole were prepared on the basis of the asymmetric Sharpless epoxidation. （S）-Iodiconazole was proved to have better antifungal activity than the （R）- isomer. The binding modes of the two isomers with lanosterol 14~z-demethylase were clarified by molecular dock- ing.

Discovery of a Potent Botulinum Neurotoxin A Inhibitor ZM299 with Effective Protections in Botulism Mice

Botulinum neurotoxins serotype A(BoNT/A)is the deadliest toxins known to humans and the"Category A"agent for bioterrorism.Over the past 20 years,significant efforts have been put forth to develop effective inhibitors of BoNT/A.Unfortunately,few identified inhibitors possess noteworthy efficacy against BoNT/A in vivo.Here,we performed a high-throughput virtual screening based on the structure-based docking simulations and found a novel potent scaffold 2-thionicotinate that inhibits the BoNT/A light chain(LC).We then synthesized and optimized a novel series of 2-thionicotinate derivatives and comprehensively evaluated their activity against BoNT/A in vitro and in vivo.An optimized compound ZM299 effectively exhibits anti-BoNT/A activity in primary neurons and displayed remarkably therapeutic efficacy against BoNT/A in vivo,which could raise the survival rate of intoxicated mice to 100%(12/12)after lethal doses of BoNT/A exposures.These findings demonstrate that 2-thionicotinates is a promising scaffold for producing more effective anti-BoNT/A analogs,and compound ZM299 is worthy of further preclinical evaluation as a drug candidate for the treatment of botulism.

Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury

Targeting RIPK1 is a promising strategy for the treatment or alleviation of acute lung injury(ALI).SZM594,a benzothiazole compound previously developed by our research group,possessed good dual-targeting receptor-interacting protein kinase 1(RIPK1)and RIPK3 activity and anti-necroptosis activity as well as acceptable in vivo efficacy.In this study,the cyclopropyl moiety of SZM594 was modified based on a structure-based design strategy.The resulting cyclohexanone-containing analogue 41 improved the selectivity toward RIPK1 over RIPK3 and the anti-necroptosis activity was also increased compared with those of SZM594.More importantly,compound 41 could inhibit the tumor necrosis factor-α(TNF-α)ex-pression in lipopolysaccharide(LPS)-induced peritoneal macrophage cell model,and significantly allevi-ate LPS-induced ALI in a mouse model.This compound could significantly inhibit the expressions of the phosphorylation of RIPK1 and down-stream RIPK3 and mixed lineage kinase domain-like protein(MLKL).Thus,these cyclohexanone-containing benzothiazole analogues represent promising lead structures for the discovery of novel protective agents of ALI.