S670, an amide derivative of 3-O-acetyl-11-keto-ß-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome.

Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 µM. Furthermore, we found that S670 (6 µM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg-1·d-1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.

Angiogenic effect of motherwort (Leonurus japonicus) alkaloids and toxicity of motherwort essential oil on zebrafish embryos.

There is growing evidence that motherwort (Leonurus japonicus Houtt.), and Chinese patent medicines derived from motherwort, alleviate postpartum uterine subinvolution, as well as the effects on myocardial and cerebral ischemic injuries. We hypothesized that these beneficial effects of motherwort may be related to angiogenesis. To test this hypothesis, we investigated the angiogenic effects of motherwort total alkaloids and essential oil, as well as their respective primary components, on zebrafish embryos. Motherwort total alkaloids significantly increased angiogenesis in transgenic Tg (flk1: EGFP) zebrafish embryos treated with sunitinib, as did stachydrine, the most abundant alkaloid produced by motherwort. Unexpectedly, motherwort essential oil was toxic to zebrafish embryos. Our results indicated, for the first time, that motherwort alkaloids were potent angiogenic agents, while even low concentrations of motherwort essential oil were toxic. As angiogenesis is a critical aspect of postpartum recovery, our results provide evidence for traditional application of motherwort water decoction and its Chinese patent medicines (e.g. motherwort injection) to promote postpartum recovery.

Synthesis, biological evaluation and molecular docking study of N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif antagonists.

Viral infectivity factor (Vif) is protective against APOBEC3G (A3G)-mediated viral cDNA hypermutations, and development of molecules that inhibit Vif mediated A3G degradation is a novel strategy for blocking HIV-1 replication. Through optimizations of the central ring of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), we found a potent compound 12c with EC50 value of 1.54 µM, enhancing the antiviral activity more than 150-fold compared with RN-18 in nonpermissive H9 cells. 12c protected A3G from degradation by inhibiting Vif function. Besides, 12c suppressed different HIV-1 clinical strains (HIV-1KM018, HIV-1TC-1 and HIV-1WAN) and drug-resistant strains (NRTI, NNRTI, PI, and FI) with relatively high activities. Amidation of 12c with glycine gave a prodrug 13a, improving the water solubility about 2600-fold compared with 12c. Moreover, 13a inhibited the virus replication efficiently with an EC50 value of 0.228 µM. These results suggested that the prodrug 13a is a promising candidate agent for the treatment of AIDS.

3-(5-Oxo-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzonitrile.

In the title compound, C(16)H(11)N(3)O, the dihedral angles between the 3-cyano-benzene and benzene planes and the 1H-pyrazol-5(4H)-one plane are 4.97 (9) and 9.91 (9)°, respectively.

5-Bromo-N-(3,4-dimeth-oxy-benz-yl)pyridin-2-amine.

The title compound, C(14)H(15)BrN(2)O(2), an inter-mediate in drug discovery, was synthesized by the reaction of 5-bromo-pyridin-2-amine and 3,4-dimeth-oxy-benzaldehyde. In the crystal, molecules are linked via pairs ofN-H⋯N hydrogen bonds, leading to the formation of inversion dimers. A short contact occurs between the aryl H atom (ortho position from N) and the centroid of the benzene ring.

N-Cyclo-hexyl-4-[(2-nitro-anilino)-meth-yl]thio-phene-2-sulfonamide.

In the title compound, C(17)H(21)N(3)O(4)S(2), an intra-molecular N-H⋯O hydrogen bond involving the proximate amine and nitro groups is observed. In the crystal, inter-molecular N-H⋯O hydrogen bonds involving the amine and SO(2) groups occur. One of the notro O atoms is disordered over two conformations with occupancies of 0.578 (12) and 0.422 (12).

5-(1H-Indol-3-yl-methyl-idene)-2,2-di-methyl-1,3-dioxane-4,6-dione.

In the title compound, C(15)H(13)NO(4), the conjugated double-bond system between the two rings adopts a cis configuration and there is an intra-molecular indole-ketone C-H⋯O inter-action. The indole N-H group forms an inter-molecular hydrogen bond with a ketone O-atom acceptor, giving a chain structure along the ab direction. The O-heterocyclic ring adopts a boat conformation and makes a dihedral angle of 16.72 (6)° with the indole ring system.

2,2-Dimethyl-5-[(2-nitro-anilino)methyl-idene]-1,3-dioxane-4,6-dione.

The crystal of the title compound, C(13)H(12)N(2)O(6), contains a bifurcated intra-molecular hydrogen bond between the N-H group and one of the O atoms from both the nitro group and the dioxane-4,6-dione moiety. In addition, mol-ecules are linked by a series of inter-molecular C-H⋯O secondary inter-actions. The dihedral angles between the benzene ring and the nitro group and the conjugated part of the dioxane-4,6-dione moiety are 19.1 (2) and 17.89 (7)°, respectively.

2,2-Dimethyl-5-[(pyridin-2-yl-amino)-methyl-idene]-1,3-dioxane-4,6-dione.

In the title compound, C(12)H(12)N(2)O(4), the dihedral angle between the pyridine and enamine planes is 3.5 (3)°, while the angle between the dioxanedione (seven atoms) and enamine planes is 4.6 (3)°. The dioxane ring approximates an envelope conformation.

4-[4-(Piperidin-1-yl)piperidin-1-yl]benzonitrile.

In the title compound, C(17)H(23)N(3), both piperidine rings adopt chair conformations. In the crystal packing, intermolecular C-H⋯N hydrogen bonds and C-H⋯π interactions are present.

5-(4-Bromo-anilinomethyl-ene)-2,2-dimethyl-1,3-dioxane-4,6-dione.

In the title compound, C(13)H(12)BrNO(4), the dihedral angles between the amino-methyl-ene group and the dioxane ring and between the benzyl ring and the amino-methyl-ene unit are 7.96 (4) and 12.15 (4)°, respectively. The dioxane ring shows a half-boat conformation, in which the C atom between the dioxane ring O atoms is 0.460 (8) Šout of the plane through the remaining ring atoms. An intra-molecular N-H⋯O hydrogen bond may stabilize the planar conformation of the mol-ecule. An inter-molecular C-H⋯O inter-action is also present.

5-(4-Chloro-anilinomethyl-ene)-2,2-dimethyl-1,3-dioxane-4,6-dione.

The title compound, C(13)H(12)ClNO(4), is approximately planar, with a dihedral angle of 8.23 (4)° between the mean plane of the amino-methyl-ene unit and the planar part of the dioxane ring. The dioxane ring has a half-boat conformation, in which the C atom between the dioxane O atoms is -0.464 (8) Šout of the plane of the other five atoms. In the mol-ecule there is an intra-molecular N-H⋯O hydrogen bond, involving the NH H atom and the adjacent dioxane carbonyl O atom. In the crystal, weak intermolecular C-H⋯O hydrogen-bonding contacts, result in the formation of sheets parallel to the ab plane.

5-[(3,4-Dimethoxy-benzyl)-aminomethyl-ene]-2,2-dimethyl-1,3-dioxane-4,6-dione.

The title compound, C(15)H(17)NO(6), is approximately planar, with dihedral angles of 3.11 (4) and 2.12 (4)° between the connecting amino-methyl-ene unit and the planar part of the dioxane ring, and between the dimethoxy-benzyl ring and the amino-methyl-ene group, respectively. The dioxane ring exhibits a half-boat conformation, in which the C atom between the dioxane O atoms is 0.5471 (8) Šout of the plane. The mol-ecule has an intra-molecular N-H⋯O hydrogen bond which may stabilize the planar conformation. In the crystal, weak inter-molecular C-H⋯O hydrogen-bonding contacts, result in the formation of sheets parallel to the ab plane.