Binding mode analysis of topoisomerase inhibitors, 6-arylamino-7-chloro-quinazoline-5,8-diones, within the cleavable complex of human topoisomerase I and DNA.

A series of 6-arylamino-7-chloro-quinazoline-5,8-diones have been evaluated as novel human topoisomerase I (TOP1) inhibitors based on the antitumor activity of 1,4-naphthoquinone. Besides their in vitro cytotoxicity, their ability to inhibit human TOP1-DNA in vitro was tested with human TOP1 and a supercoiled (Form I) plasmid substrate DNA (Park et al., 2004).

Synthesis and cytotoxicity evaluation of substituted pyridazino[4,5-b]phenazine-5,12-diones and tri/tetra-azabenzofluorene-5,6-diones.

The substituted pyridazino[4,5-b]phenazine-5,12-diones and tri/tetra-azabenzo[a]fluorene-5,6-diones were synthesized from 6,7-dichlorophthalazine-5,8-dione and 6,7-dichloroquinoline-5,8-dione, respectively. The cytotoxic activities of the prepared compounds were evaluated by an SRB (Sulforhodamine B) assay against the following human cancer cell lines: A549 (lung), SK-OV-3 (ovarian), SK-MEL-2 (melanoma), XF 498 (CNS), and HCT 15 (colon). Almost all synthesized pyridazino[4,5-b]phenazine-5,12-diones (7a-j) presented higher cytotoxicity than that of doxorubicin (IC(50)=0.

Homology modeling and molecular docking study of translationally controlled tumor protein and artemisinin.

Translationally controlled tumor protein (TCTP), also known as histamine releasing factor (HRF), is found abundantly in different eukaryotic cell types. The sequence homology of TCTP between different species is very high, belonging to the MSS4/DSS4 superfamily of proteins. TCTP is involved in both cell growth and human late allergy reaction, as well as having a calcium binding property; however, its primary biological functions remain to be clearly elucidated.

Inhibitory effects of a benz[f]indole-4,9-dione analog on cancer cell metastasis mediated by the down-regulation of matrix metalloproteinase expression in human HT1080 fibrosarcoma cells.

In our previous study, a synthetic benz[f]indole-4,9-dione analog, 2-amino-3-ethoxycarbonyl-N-methylbenz[f]indole-4,9-dione (SME-6), exhibited a potential anti-tumor activity. We, in this study, further explored the anti-metastatic and anti-invasive effect of SME-6 by determining the regulation of matrix metalloproteinases (MMPs). MMPs, zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates.

Synthesis and cytotoxicity of 1-substituted 2-methyl-1H-imidazo[4,5-g]phthalazine-4,9-dione derivatives.

A series of 1-substituted 2-methyl-1H-imidazo[4,5-g]phthalazine-4,9-dione derivatives 8 was synthesized from 6,7-dichlorophthalazine-5,8-dione 5 and evaluated for in vitro cytotoxicity against several human tumor cell lines. Most of the tested compounds showed potential cytotoxic activity considerably higher than that of the reference compounds, ellipticine and doxorubicin.

Cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs.

A series of benz[f]indole-4,9-diones, based on the antitumor activity of 1,4-naphthoquinone, were synthesized and evaluated for their cytotoxic activity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer), and also for the inhibition of human DNA topoisomerases I and II activity in vitro. Several compounds including 2-amino-3-ethoxycarbonyl-N-methyl-benz[f]indole-4,9-dione showed a potential cytotoxic activity judged by IC50<20.0 microg/ml in the panel of cancer cell lines.

Preferred conformations of cyclic Ac-Cys-Pro-Xaa-Cys-NHMe peptides: a model for chain reversal and active site of disulfide oxidoreductase.

The conformational study on cyclic Ac-Cys-Pro-Xaa-Cys-NHMe (Ac-CPXC-NHMe; X=Ala, Val, Leu, Aib, Gly, His, Phe, Tyr, Asn and Ser) peptides has been carried out using the Empirical Conformational Energy Program for Peptides, version 3 (ECEPP/3) force field and the hydration shell model in the unhydrated and hydrated states. This work has been undertaken to investigate structural implications of the CPXC sequence as the chain reversal for the initiation of protein folding and as the motif for active site of disulfide oxidoreductases. The backbone conformation DAAA is commonly the most feasible for cyclic CPXC peptides in the hydrated state, which has a type I beta-turn at the Pro-Xaa sequence.

Flexible docking of an acetoxyethoxymethyl derivative of thiosemicarbazone into three different species of dihydrofolate reductase.

Dihydrofolate reductases (DHFR) of human, Candida albicans and E coli were docked with their original ligands of X-ray crystal complex using QXP (Quick eXPlore), a docking program. Conditions to reproduce the crystal structures within the root mean square deviation (rmsd) of 2.00 A were established.

Preferred conformations of RGDX tetrapeptides to inhibit the binding of fibrinogen to platelets.

The conformational study on Arg-Gly-Asp (RGD)-containing tetrapeptides in the unhydrated and hydrated states has been carried out using the force field ECEPP/3 and the hydration shell model. The tetrapeptides studied here are H-RGDX-OH (X = Trp, Tyr, Phe, Leu, Val, Cys, Gln, and Ser), which show the inhibitory activity for binding of fibrinogen to platelets in the order of RGDW approximately equal to RGDY approximately equal to RGDF approximately equal to RGDL > RGDV > or = RGDC > or = RGDQ > or = RGDS. The backbone conformations with two C(7) backbone-to-backbone hydrogen bonds between Asp and Arg residues and between Xaa and Gly residues are in common most probable for the RGD sequence of RGDX tetrapeptides in the hydrated state.

Effects of the competitor on antibody-hapten binding in immunoassays.

The effects of competitors on antibody (Ab)-hapten binding in an immunoassay were investigated using a goat antimethamphetamine (MA) antibody (Ab). An N-4-aminobutyl derivative of methamphetamine (4-ABMA) was conjugated with keyhole limpet hemocyanine (KLH) and used as an immunogen. The antiserum was purified by affinity chromatography with various ligands, including 4-ABMA-protein conjugates, free haptens, and protein G.