Iodine-Promoted Reductive Sulfenylation Using Ketones as Hydride Donors.

Herein, an iodine-promoted reductive sulfenylation reaction of ketones with disulfides has been developed. This method provides an approach for synthesizing unsymmetrical alkyl-alkyl and alkyl-aryl sulfides in a single step. Investigation of the reaction mechanism revealed that ketones play a dual role in this process. They react with disulfides to produce vinyl thioethers and act as effective organic hydride donors, reducing the number of vinyl thioethers that are formed in situ. This study expands the range of applications of ketones in chemical synthesis.

Advances in SHP2 tunnel allosteric inhibitors and bifunctional molecules.

SHP2 is a non-receptor tyrosine phosphatase encoded by PTPN11, which performs the functions of regulating cell proliferation, differentiation, apoptosis, and survival through removing tyrosine phosphorylation and modulating various signaling pathways. The overexpression of SHP2 or its mutations is related to developmental diseases and several cancers. Numerous allosteric inhibitors with striking inhibitory potency against SHP2 allosteric pockets have recently been identified, and several SHP2 tunnel allosteric inhibitors have been applied in clinical trials to treat cancers. However, based on clinical results, the efficacy of single-agent treatments has been proven to be suboptimal. Most clinical trials involving SHP2 inhibitors have adopted drug combination strategies. This review briefly discusses the research progress on SHP2 allosteric inhibitors and pathway-dependent drug combination strategies for SHP2 in cancer therapy. In addition, we summarize the current bifunctional molecules of SHP2 and elaborate on the design and structural optimization strategies of these bifunctional molecules in detail, offering further direction for the research on novel SHP2 inhibitors.

A novel solid phase extraction sample preparation method for sensitively determining doxepin and N-nordoxepin in human plasma and its application in a bioequivalence study in healthy Chinese volunteers.

Doxepin, a tricyclic antidepressant (TCA), is widely used in the treatment of depressive disorder and anxiety. There are some liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods that have been reported for detecting doxepin, but inadequacies in recovery and cumbersome sample preparation obstruct the pharmacokinetics study. Therefore, we aimed to develop and validate a rapid sample preparation method based on solid-phase extraction (SPE) for the precise quantification of doxepin and its metabolites. Chromatography separation was performed on a Waters ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm) and a mobile phase consisting of 70% of mobile phase A (0.1% formic acid and 10 mM ammonium formate) and 30% mobile phase B (0.1% formic acid in acetonitrile) at a flow rate of 0.4 mL min-1 in the step gradient elution conditions. The lower limits of quantification for doxepin and N-nordoxepin were 4 pg mL-1 and 2 pg mL-1, respectively. This method was validated with satisfactory results including good precision and accuracy. A rapid, sensitive, and specific LC-MS/MS method was developed and validated for the determination of doxepin in human plasma. This method could be applied for determining doxepin and N-nordoxepin concentrations in plasma that could be useful for bioequivalence study of 3 mg doxepin.

Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects.

Most vascular disrupting agents (VDAs) fail to prevent the regrowth of blood vessels at the edge of tumors, causing tumor rebound and relapse. Herein, a series of novel multifunctional vascular disrupting agents (VDAs) capable of inhibiting microtubule polymerization and histone deacetylases (HDACs) were designed and synthesized using the tubulin polymerization inhibitor TH-0 as the lead compound. Among them, compound TH-6 exhibited the most potent antiproliferative activity (IC50 = 18-30 nM) against a panel of cancer cell lines. As expected, TH-6 inhibited tubulin assembly and increased the acetylation level of HDAC substrate proteins in HepG2 cells. Further in vivo antitumor assay displayed that TH-6 effectively inhibited tumor growth with no apparent toxicity. More importantly, TH-6 disrupted both the internal and peripheral tumor vasculatures, which contributed to the persistent tumor inhibitory effects after drug withdrawal. Altogether, TH-6 deserves to be further investigated for the new approach to clinical cancer therapy.

Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities.

A series of novel N-benzylbenzamide derivatives were designed and synthesized as tubulin polymerization inhibitors. Among fifty-one target compounds, compound 20b exhibited significant antiproliferative activities with IC50 values ranging from 12 to 27 nM against several cancer cell lines, and possessed good plasma stability and satisfactory physicochemical properties. Mechanism studies demonstrated that 20b bound to the colchicine binding site and displayed potent anti-vascular activity. Notably, the corresponding disodium phosphate 20b-P exhibited an excellent safety profile with the LD50 value of 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth and decreased microvessel density in liver cancer cell H22 allograft mouse model without obvious toxicity. Collectively, 20b and 20b-P are novel promising anti-tubulin agents with more druggable properties and deserve to be further investigated for cancer therapy.