Showing papers by "Kaixian Chen published in 2010"

A Series of α-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase IIα Catalytic Activity

Abstract: A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.

Design, synthesis, and interaction study of quinazoline-2(1H)-thione derivatives as novel potential Bcl-xL inhibitors.

Abstract: Development of inhibitors to antagonize the activities of antiapoptotic Bcl-2 family proteins is of particular interest in cancer chemotherapy. We discovered a quinazoline-2(1H)-thione derivative (DCBL55) as a new Bcl-xL, Bcl-2, and Mcl-1 inhibitor by virtual database screening. We systematically modified the structure of compound 1 by chemical synthesis. The interactions of the compounds with Bcl-xL were predicted by molecular modeling simulations, which were confirmed by structure−activity relationship analysis and protein mutation studies. Three locations at the hydrophobic groove of Bcl-xL, referred to as P2, P4, and P5, were found to contribute to the ligand interactions. Although the compounds induced mitochondrial potential reduction, caspase activation, and ROS generation, the cytotoxicities and the ultrastructural changes of outer mitochondrial membrane suggested that the compounds may target additional proteins outside the Bcl-2 family. Altogether, the present study provides new lead compounds a...

Quantum chemical studies on antimalarial of artemisinin (qinghaosu) derivatives

Abstract: In this paper theoretical studies were performed on artemisinin (qinghaosu) derivatives with semiempirical quantum chemical methods AMI and PM3. The antimalarial activity -logC has an obvious correlation with the net charge of C(16) and bond orders of bonds O(1)-C(10), O(2)-C(6), O(1)-O(2) and O(5)-C(16). According to the calculation results, we derived structure-activity relationship, presented the probable pharmacophore of qinghaosu derivatives and the interaction fashion between the drugs and the plasmodium receptor.

An enzyme-linked immunosorbent assay to compare the affinity of chemical compounds for β-amyloid peptide as a monomer.

Abstract: Aβ1–42 is the proteolytic cleavage product of cleavage of the amyloid precursor protein by β- and γ-secretases. The aggregation of Aβ1–42 plays a causative role in the development of Alzheimer’s disease. To lock Aβ1–42 in a homogenous state, we embedded the Aβ1–42 sequence in an unstructured region of Bcl-xL. Both the N-terminus and the C-terminus of Aβ1–42 were constrained in the disordered region, whereas the conjunction did not introduce any folding to Aβ1–42 but maintained the sequence as a monomer in solution. With Bcl-xL-Aβ42, we developed an enzyme-linked immunosorbent assay to compare the affinity of compounds for monomeric Aβ1–42. Bcl-xL-Aβ42 was coated on a microplate and this was followed by incubation with different concentrations of compounds. Compounds binding to Leu17-Val24 of Aβ1–42 inhibited the interaction between Bcl-xL-Aβ42 and antibody 4G8. The method can not only reproduce the activities of the reported Aβ1–42 inhibitors such as dopamine, tannin, and morin but can also differentiate decoy compounds that do not bind to Aβ1–42. Remarkably, using this method, we discovered a new inhibitor that binds to monomeric Aβ1–42 and inhibits Aβ1–42 fibril formation. As the structure of Bcl-xL-Aβ42 monomer is stable in solution, the assay could be adapted for high-throughput screening with a series of antibodies that bind the different epitopes of Aβ1–42. In addition, the monomeric form of the Aβ1–42 sequence in Bcl-xL-Aβ42 would also facilitate the identification of Aβ1–42 binding partners by coimmunoprecipitation, cocrystallization, surface plasmon resonance technology, or the assay as described here.

One-Pot Approach for C-CBond Formation through Ruthenium-Amido Complex Catalyzed TandemAldol Reaction/Hydrogenation

Abstract: A one-pot novel and efficient approach was developed for the α-alkylation of various nitriles with carbonyl compounds using ruthenium-amido complex catalyst 1. The C―C bond was formed through aldol reaction followed by hydrogenation with triethylamine―formic acid (TEAF) and 1. Moderate to high yields were obtained, and a variety of functional groups were tolerated, including nitro and chloro groups, and a furan ring.

Ligand‐Free Iron/Copper Cocatalyzed N‐Arylations of Aryl Halides with Amines under Microwave Irradiation.

Abstract: Ligand-free iron/copper cocatalyzed cross-coupling reactions of aryl halides with amines were carried out to provide the corresponding coupling products in good yields. It is worth noting that the method displays a broad substrate scope, and is convenient, rapid, low-cost and environmentally friendly.

A Simple and Convenient Copper-Catalyzed Tandem Synthesis of Quinoline-2-carboxylates at Room Temperature.

Abstract: We developed a simple and convenient copper-catalyzed method for the synthesis of quinoline-2-carboxylate derivatives through sequential intermolecular addition of alkynes onto imines and subsequent intramolecular ring closure by arylation. The efficiency of this system allowed the reactions to be carried out at room temperature.

One-Pot Approach for C—C Bond Formation Through Ruthenium-Amido Complex Catalyzed Tandem Aldol Reaction/Hydrogenation.

Abstract: The procedure is highly suitable for the transformation of aromatic aldehydes and tolerates a broad spectrum of functionalities.

Comparative studies on the mechanism of uridine phosphorolysis

Abstract: We have used quantum mechanical method to study the transition states(TSs) of uridine phosphorolysis reaction. Comparing the four different reaction pathways and the five transition states obtained, we conclude that enzymatic uridine phosphorolysis takes place mainly according to acid-catalyzed Sn2 mechanism. The proposed reaction pathway is consistent with many experimental results.