An efficient construction of highly functionalized polycyclic spiro-fused carbocyclicoxindoles has been developed via an asymmetric organocatalytic quadruple domino reaction of (E)-3-(2-hydroxybenzylidene)oxindole derivatives and two molecules of α,β-unsaturated aldehyde under quadruple iminium–enamine–iminium–enamine catalysis. The complex cascade products bearing a spiro quaternary center and five contiguous stereocenters were obtained in moderate to high yields (up to 90%) with good diastereoselectivities (up to 8 : 1) and excellent ee values (up to 99% ee). The structure and absolute configuration of the products were confirmed by NMR spectroscopy and single crystal X-ray analysis. In addition, the biological study showed that these compounds had moderate antitumor activities in the micromolar range.

•Nineteen novel polycyclic spiro-fused carbocyclicoxindoles were investigated.•Compound 10i displayed inhibitory activities against seven cancer cell lines.•10i arrested cell cycle in G1 phase and induced apoptosis.•10i enhanced the protein levels of cleaved caspase-3, p53, and MDM2.•Docking studies showed 10i might block the MDM2-p53 interactions.A series of novel polycyclic spiro-fused carbocyclicoxindoles were synthesized and investigated for their in vitro antiproliferative activities against nine human cancer cell lines. Five compounds (10i, 10l, 10n, 10p, and 10r) demonstrated anticancer activities against A2780s cells with IC50 values of less than 30 μM. In particular, compound 10i showed anticancer activities against seven cancer cell lines and stronger activities than cisplatin in A2780s, A2780T, CT26, and HCT116 cells. Further studies illustrated that compound 10i arrested cell cycle in G1 phase and induced apoptosis of HCT116 cells. This compound also effectively increased the protein levels of cleaved caspase-3, p53, and MDM2. Molecular docking results revealed that compound 10i could bind well to the p53-binding site on MDM2, indicating that it might work by blocking the MDM2-p53 interactions.Download high-res image (256KB)Download full-size image

Described here is an enantioselective approach of making chiral, β-substituted homoallylic organoboronic esters. In the presence of LiOtBu and a catalytic amount of silver salt, commercial bis[(pinacolato)boryl]methane participated in the iridium-catalyzed asymmetric allylation reactions, delivered a “CH2B(pin)” group, and yielded the title compounds from allylic carbonates. The synthetic utility of the prepared chiral organoboronates was demonstrated by their conversion to other important classes of compounds.Keywords: bis[(pinacolato)boryl]methane; boronic esters; catalysis; enantioselective allylation; iridium; silver

A series of novel pyrrolo[1,2-c]imidazol-1-ones were efficiently synthesized via a three-component, regioselective 1,3-dipolar cycloaddition reaction. The azomethine ylides generated in situ from imidazolidin-4-ones and aldehydes reacted with the nitroalkenes to yield the novel pyrrolo[1,2-c]imidazol-1-one derivatives with multiple stereogenic centers in moderate to high yields (up to 99%) and in high diastereoselectivities (up to 98:2). The structure and relative stereochemistry of cycloadducts were confirmed by 1H NMR spectroscopy and X-ray crystallography.

A novel series of C3-functionalized oxindoles, 3-(2-oxo-4-phenylbut-3-en-1-ylidene)indolin-2-ones, were designed, synthesized and investigated for inhibition of cell proliferation against different types of human cancer cell lines, including SW620, HeLa and A549. This biological study showed that these compounds containing the scaffolds of indole and aromatic α,β-unsaturated ketone had moderate to significant antitumor activities. Further study suggested that compound 4b, as one of this kind of structure derivative, showed broad-spectrum antitumor activities against MCF-7, PC-3, SKOV-3, U87, SMMC-7721, SY5Y and A875 cancer cell lines. Besides, the results of the inhibition of Pim kinases indicated that compound 4b showed selective and efficient anti-Pim-1 kinase activity (IC50 = 5 μM). Docking simulation, flow cytometry (FCM), and Hoechst 33342 staining assay suggested that the most active compound 4b induced cell death through apoptosis via binding to the active ATP pocket of Pim-1. Moreover, it showed that compound 4b had strong inhibition of tubulin polymerization which may be caused by inhibiting Pim-1.

The asymmetric synthesis of 3-alkyl-3-hydroxyindolin-2-ones via direct aldol reaction of isatin with ketones catalyzed by natural amino acid salts is described, in which the phenylalanine lithium salt was found to be the best catalyst. This strategy was then applied to a variety of isatin and ketone substrates and the corresponding aldol products were obtained in excellent yields (up to 97%) with good to excellent enantioselectivities (up to 90%).(S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-oneC11H13NO370% ee[α]D25 = −11.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-3-Hydroxy-1-methyl-3-(2-oxopropyl)indolin-2-oneC12H13NO381% ee[α]D25 = −15.2 (c 2.4, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-1-Benzyl-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC18H17NO387% ee[α]D25 = −16.4 (c 2.8, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-3-Hydroxy-1-(4-methoxybenzyl)-3-(2-oxopropyl)indolin-2-oneC19H19NO487% ee[α]D25 = −16.3 (c 3.7, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-3-Hydroxy-5-methyl-3-(2-oxopropyl)indolin-2-oneC12H13NO366% ee[α]D25 = −13.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-5-Fluoro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10FNO377% ee[α]D25 = −17.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-5-Chloro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10ClNO378% ee[α]D25 = −22.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, may target mitochondrial proteins for lysine deacetylation and also regulate cellular functions. And, SIRT3 is an emerging instrumental regulator of the mitochondrial adaptive response to stress, such as metabolic reprogramming and antioxidant defense mechanisms. Accumulating evidence has recently demonstrated that SIRT3 may function as either oncogene or tumor suppressor on influencing cell death by targeting a series of key modulators and their relevant pathways in cancer. Thus, in this review, we present the structure, transcriptional regulation, and posttranslational modifications of SIRT3. Subsequently, we focus on highlighting the Janus role of SIRT3 with oncogenic or tumor-suppressive function in cancer, which may provide more new clues for exploring SIRT3 as a therapeutic target for drug discovery.

An efficient synthesis of novel endo′-selective spiro[pyrrolidin-2,3′-oxindoles] has been achieved via a three component regioselective 1,3-dipolar cycloaddition reaction. The azomethine ylides generated in situ from 3-amino oxindoles and aldehydes reacted with the nitroalkenes to furnish novel pyrrolidine–spirooxindole derivatives bearing one spiro quaternary center and multiple chiral centers in moderate to high yields (up to 99%) with high diastereoselectivities (up to 99:1). The structure and relative stereochemistry of cycloadducts were confirmed by NMR spectra and single crystal X-ray diffraction. The possible mechanism was proposed and the cycloaddition proceeded via endo′-transition state.

An efficient method for the regioselective synthesis of potentially biologically active tetrasubstituted 1-pyrazolines has been achieved via a 1,3-dipolar cycloaddition reaction. A range of tetrasubstituted 1-pyrazolines bearing one Boc group and two ester groups were obtained in high yields (up to 99%). The structure and relative stereochemistry of cycloadducts were confirmed by NMR spectra and single crystal X-ray diffraction. The possible mechanism was proposed and the major Z-cycloadducts as a single diastereomer could be separated from each other by chromatography.Figure optionsDownload full-size imageDownload as PowerPoint slide