Zemei Ge

CovalentDock: Automated covalent docking with parameterized covalent linkage energy estimation and molecular geometry constraints

Covalent linkage formation is a very important mechanism for many covalent drugs to work. However, partly due to the limitations of proper computational tools for covalent docking, most covalent drugs are not discovered systematically. In this article, we present a new covalent docking package, the CovalentDock, built on the top of the source code of Autodock. We developed an empirical model of free energy change estimation for covalent linkage formation, which is compatible with existing scoring functions used in docking, while handling the molecular geometry constrains of the covalent linkage with special atom types and directional grid maps. Integrated preparation scripts are also written for the automation of the whole covalent docking workflow. The result tested on existing crystal structures with covalent linkage shows that CovalentDock can reproduce the native covalent complexes with significant improved accuracy when compared with the default covalent docking method in Autodock. Experiments also suggest that CovalentDock is capable of covalent virtual screening with satisfactory enrichment performance. In addition, the investigation on the results also shows that the chirality and target selectivity along with the molecular geometry constrains are well preserved by CovalentDock, showing great capability of this method in the application for covalent drug discovery.

Iodine–triphenylphosphine mediated sulfenylation of imidazoheterocycles with sodium sulfinates

An efficient approach to sulfenyl imidazoheterocycles has been developed via iodine–triphenylphosphine mediated direct sulfenylation of imidazoheterocycles with sodium sulfinates. The reactions proceed smoothly under transition-metal-free conditions with a broad range of substrate scope, giving the desired products in moderate to excellent yields.

Novel EGFR inhibitors prepared by combination of dithiocarbamic acid esters and 4-anilinoquinazolines.

On the basis of combination strategy, a novel series of EGFR inhibitors were designed and synthesized by combination of dithiocarbamic acid esters and 4-anilinoquinazolines. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay in three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Two compounds (11d and 11f) were found more potent against all three cell lines and five compounds (11a, 11d-11g) were found more potent against both MDA-MB-468 and SK-BR-3 than Lapatinib. SAR studies revealed that the substituents on C6 and C7 positions of quinazoline, the amine component of dithiocarbamate moiety and the linker greatly affected the activity. This work provides a promising new strategy for the preparation of potent tyrosine kinase inhibitors.

Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors

A series of tripeptide boronate proteasome inhibitors were designed and synthesized on the basis of our previously built tripeptide aldehyde 3D-QSAR models. All the synthesized compounds were evaluated for their proteasome-inhibitory activities in an isolated 20S rabbit proteasome, and selected compounds were evaluated for their antitumor activities in vitro against four human cancer cell lines. Biological results showed bulky and negative substituents at P(2) position improved the proteasome-inhibitory potency obviously, which completely conformed to the theoretical models, while those at P(3) position thoroughly deviated from the 3D-QSAR model. Most of the screened compounds showed less than 1 nM inhibitory potency and high selectivity against 20S proteasome, of which 7f is the most potent (IC(50)=0.079 nM) and twofold more active than bortezomib (IC(50)=0.161 nM). Cell viability indicated hydrophilic 4-hydroxyphenyl substituent at P(2) or P(3) position was not favorable to the cellular activities. Especially for the two hematologic cancer cell lines, HL-60 and U266, 7f inhibited them at the level of less than 10 nM and was more potent than the control bortezomib. It is being considered a promising new lead to be developed for the treatment of various cancers.

Primary 1,2-diamine catalysis III: an unexpected domino reaction for the synthesis of multisubstituted cyclohexa-1,3-dienamines

The first organocatalyzed multicomponent domino reactions of aryl ketones, aldehydes and malononitrile were carried out successfully to afford multisubstituted cyclohexa-1,3-dienamines in satisfactory yields.

Discovery and optimization of novel dual dithiocarbamates as potent anticancer agents.

A series of dual dithiocarbamates were synthesized and evaluated for their in-vitro anticancer activities on human non-small cell lung cancer cell line H460. Nine compounds exhibited significant antiproliferative activities with IC50 less than 1 μM. Among them, compound 14m showed the highest inhibitory activity against H460 cell and inhibited the growth of nine types of tumor cells with IC50 values less than 1 μM. It also achieved IC50 of 54 nM and 23 nM against HepG2 and MCF-7 cell lines, respectively. Preliminary structure-activity relationship study indicated that: a) when the methyl group (region A) is substituted with benzene rings, ortho substitution on the benzene ring is favored for activity; b) substitution with heterocyclic structures at region A exhibited greater impact on the anti-tumor activity of compounds, in which pyridine ring, thiazole ring, coumarin and benzo[b]thiophene are favored and quinoline ring is the most favored; c) substitution with different amines (region B) also showed marked effect on the activity of compounds and dimethylamine and morpholine are preferred to other tested amines.

An Efficient One-Pot Synthesis of 2-Hydroxyalkyl Dithiocarbamates

Abstract In the presence of anhydrous potassium phosphate, epoxides reacted with carbon disulfide and primary or secondary amines in acetone to give the corresponding 2-hydroxyalkyl dithiocarbamates regioselectively in moderate to good yield.

New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Pyruvate kinase M2 (PKM2) is a key protein responsible for cancers Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogs were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analog 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line.

IC-4, a new irreversible EGFR inhibitor, exhibits prominent anti-tumor and anti-angiogenesis activities

Accumulating evidence suggested that the irreversible tyrosine kinase inhibitors (TKIs) have potential to override the acquired resistance to target-based therapies. Herein, we reported IC-4 as a novel irreversible TKI for epidermal growth factor receptor (EGFR). IC-4 potentially suppressed proliferation, induced apoptosis and a G2/M cell cycle arrest in breast cancer cells, correlating with inhibition of EGF-induced EGFR activation, but independent of DNA damage. In addition, IC-4 exhibited anti-angiogenetic activities both in vitro and in vivo. It suppressed cell viability and proliferation induced by various growth factors in human umbilical vein endothelial cells (HUVECs). IC-4 also inhibited HUVECs migration and tube formation. In transgenic zebrafish embryo model, IC-4 was shown to suppress formation of intersegmental vessel and development of subintestinal vessels. Taken together, these results demonstrated that IC-4 is a new irreversible EGFR-TKI, exhibiting potent anti-breast cancer and anti-angiogenetic effects.

An efficient dipeptide-catalyzed direct asymmetric aldol reaction of equimolar reactants in solid media

The direct asymmetric aldol reactions of equivalent molar amounts of aldehydes and ketones were carried out at -20 degrees C over alkaline Al(2)O(3) with 20 mol % of Pro-Trp as catalyst and 20 mol % of N-methylmorpholine or 1,4-diazabicyclo[2.2.2]octane as additive. After simple and environmentally friendly work-up, moderate to high isolated yields (up to 95%), good diastereoselectivities (>99:1), and enantioselectivities (up to 98% ee) have been achieved for the reactions of different kinds of ketones with various aldehydes. The catalytic system could be reused without decrease of activity by addition of 10 mol % catalyst and base in the catalytic system.