Muscone derivative ZM-32 inhibits breast tumor angiogenesis by suppressing HuR-mediated VEGF and MMP9 expression.

Inhibition of tumor angiogenesis is a highly effective strategy for cancer treatment. Human antigen R (HuR), an RNA-binding protein, is overexpressed in many cancers and regulates the mRNAs of multiple angiogenic factors by binding to the adenylate-uridylate-rich element in their 3' untranslated region. HuR protein has been demonstrated to be an important regulatory factor in macrophage-mediated angiogenesis, a process in which macrophages are critical for tumor progression. Muscone is a synthetic equivalent of musk, and recent studies have shown that it has a regulatory effect on angiogenesis. In this study, we synthesized five series of muscone derivatives and discovered that compound ZM-32 was effective in preventing HuR RRM1/2-Vegf-a mRNA complex formation. ZM-32 bound to HuR RRM1/2 protein with a KD value of 521.7 nmol/L. Furthermore, ZM-32 inhibited endothelial cell proliferation, migration, and tubule formation, and suppressed the VEGF/VEGFR2/ERK1/2 signaling axis mediated by macrophages in vitro. We also demonstrated that ZM-32 effectively prevented the proliferation and migration of breast cancer cells and inhibited the growth and angiogenesis of MDA-MB-231 xenograft tumors without any obvious toxicity in vivo. Mechanistically, exposure to ZM-32 influenced the mRNA stability of Vegf-a and Mmp9 in a HuR-dependent manner in both macrophages and MDA-MB-231 cells. Thus, in this study we identified a new muscone derivative, ZM-32, with anti-angiogenesis effects mediated via targeting HuR in breast cancer, that may become a potentially valuable lead compound for anti-cancer angiogenesis.

Arylation/Intramolecular Conjugate Addition of 1,6-Enynes Enabled by Manganese(I)-Catalyzed C-H Bond Activation.

An arylation/intramolecular conjugate addition of cyclohexadienone-containing 1,6-enynes has been established through initiation by manganese(I)-catalyzed C-H bond activation. This tandem reaction involved unusual E/ Z-isomerized alkenyl-Mn intermediates and proceeded smoothly with high chemoselectivities and perfect atom economy. The cyclization products could be further transformed to various structures. Mechanistic studies suggested that cleavage of the C-H bond was involved in the turnover-limiting step, and a manganese carbene anion intermediate was proposed to explain such an E/ Z isomerization process.

Bisannulation of Benzamides and Cyclohexadienone-Tethered Allenes Triggered by Cp*Rh(III)-Catalyzed C-H Activation and Relay Ene Reaction.

The diastereoselective bisannulation of N-(pivaloyloxy)benzamides and cyclohexadienone-tethered allenes was accomplished through Cp*Rh(III)-catalyzed C-H activation and relay ene reaction, providing a 3-isoquinolonyl cis-hydrobenzofuran framework with high yields and diastereoselectivities. This reaction tolerates a wide range of functional groups, enabling further conversions to tricyclic and bridged-ring structures. Moreover, the dearomatization modification of phenol-contained bioactive molecule is also elaborated.

Efficient access to cis-decalinol frameworks: copper(i)-catalyzed borylative cyclization of allene cyclohexanediones.

Cu-catalyzed borylative cyclization of allene cyclohexanediones has been described through a tandem ß-borylation and intramolecular allylic addition process, affording borylated cis-decalinols with excellent yields and diastereoselectivities. A good enantioselectivity is also achieved in the asymmetric version. The hemiboronate group in the cyclization products could be subjected to several useful transformations.

Two phenyls are better than one or three: synthesis and application of terminal olefin-oxazoline (TOlefOx) ligands.

A novel terminal olefin-oxazoline ligand was introduced into rhodium-catalyzed asymmetric conjugate addition of arylboronic acids to enones and gave excellent enantioselectivities. The two phenyls proved better than one or three in ligand evaluations.

Copper-catalyzed asymmetric allylation of chiral N-tert-butanesulfinyl imines: dual stereocontrol with nearly perfect diastereoselectivity.

Copper-catalyzed asymmetric allylation of chiral N-tert-butanesulfinyl imines has been described. Dual stereocontrol, through the combination of a chiral auxiliary and a chiral copper complex, has played an important role in achieving the nearly perfect diastereoselectivities (all dr > 99 : 1), especially for ketimine substrates.

Copper-catalyzed asymmetric hydroboration of α-dehydroamino acid derivatives: facile synthesis of chiral ß-hydroxy-α-amino acids.

The Cu-catalyzed asymmetric conjugate hydroboration reaction of ß-substituted α-dehydroamino acid derivatives has been established, affording enantioenriched syn- and anti-ß-boronate-α-amino acid derivatives with excellent combined yields (83-99%, dr ≈ 1:1) and excellent enantioselectivities (92-98% ee). The hydroboration products were expediently converted into valuable ß-hydroxy-α-amino acid derivatives, which were widely used in the preparation of chiral drugs and bioactive molecules.