Aurora kinase A inhibitors: identification, SAR exploration and molecular modeling of 6,7-dihydro-4H-pyrazolo-[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione scaffold.

Tricyclic 6,7-dihydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione was identified as a novel scaffold for Aurora kinase A inhibition through virtual screening. SAR exploration coupled with molecular modeling of 8a reveals the minimum pharmacophore requirements for Aurora kinase A inhibition.

Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor agonists.

Type 2 diabetes has rapidly reached an epidemic proportion becoming a major threat to global public health. PPAR agonists have emerged as a leading class of oral antidiabetic drugs. We report a structure biology analysis of novel indole-based PPAR agonists to explain the structure-activity relationships and present a critical analysis of reasons for change in selectivity with change in the orientation of the same scaffolds. The results would be helpful in designing novel PPAR agonists.

Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity.

Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure-based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC(50) = 15.1 microM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetamidophenyl ring led to the identification of 12w with a approximately 450-fold improved Aurora kinase A inhibition potency (IC(50) = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.

Synthesis and evaluation of 3-aroylindoles as anticancer agents: metabolite approach.

BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterism principle. Metabolites of 2, proposed from in vitro human microsome studies, were synthesized, leading to the identification of metabolite-derived analogue 10 with 40-350 pM potency against various cancer cell lines. Insights gained from the major inactive metabolite of 2 led to the development of 29, with better pharmacokinetics and improved potency in the tumor xenograft model than 2.

Synthesis and structure-activity relationships of 2-amino-1-aroylnaphthalene and 2-hydroxy-1-aroylnaphthalenes as potent antitubulin agents.

A series of aroylnaphthalene derivatives were prepared as bioisosteres of combrestatin A-4 and evaluated for anticancer activity. 2-Amino-1-aroylnaphthalene and 2-hydroxy-1-aroylnaphthalene, 9 and 8, respectively, showed strong antiproliferative activity with IC(50) values of 2.1-26.3 nM against a panel of human cancer cell lines including multiple-drug resistant cell line. Compound 9 demonstrated better antiproliferative activity and has a comparable tubulin binding efficacy as that of colchicine.

Synthesis and anti-viral activity of a series of sesquiterpene lactones and analogues in the subgenomic HCV replicon system.

Hepatitis C virus (HCV) infection is a severe liver disease that often leads to liver cirrhosis and hepatocellular carcinoma (HCC). Current therapy is inadequate to conquer this viral disease. In this study, we identified parthenolide (1), an active component in feverfew, a popular remedy for fever and migraine, as a lead compound with an EC50 value of 2.21 microM against HCV replication in a subgenomic RNA replicon assay system. Parthenolide is able to potentiate the interferon alpha-exerted anti-HCV effect. Several commercially available sesquiterpene lactones (2-5) structurally analogous to parthenolide and a series of synthesized Michael-type adducts of parthenolide (12-18) also exhibit micromolar concentrations for anti-HCV activities. Structure-activity relationship was elucidated to reveal that the spatial arrangement of the terpenoid skeleton fused with an alpha-methylene-gamma-lactone moiety produces maximal anti-HCV activity. In addition, a strong anti-HCV potency indicates a possibility of secondary amino adducts (12-18) converting back to parthenolide or being replaced by the nucleophilic residues of proteins inside cells. This work shows that screening of natural products is a viable and fast way for identifying novel molecular diversity as potential drug leads.

Structure-activity relationship studies of 3-aroylindoles as potent antimitotic agents.

The concise synthesis and structure-activity relationship (SAR) studies of 3-aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the 3-carbonyl linker. The SAR information revealed that the methoxy group of the B ring could be replaced with an electron-donating group such as methyl (in compound 9) or N,N-dimethylamino (in compound 13) while retaining both strong cytotoxic and antitubulin activities. The introduction of amide (compounds 30-33) and carbamate (compounds 34-37) functionalities at the N1 position of 8 gave analogues with potent antiproliferative activities. The cytotoxic potency of 8 was improved by replacing the carbonyl group with sulfide (compound 41) or oxygen (compound 43), indicating that the carbonyl moiety is important but not essential. The N,N-dimethylamino derivative 13 not only displayed potent cytotoxicity and antitubulin activity, but also showed a markedly improved physicochemical profile relative to the parent compound.

Structure-activity and crystallographic analysis of benzophenone derivatives-the potential anticancer agents.

Compounds 1-5, structurally related to combretastatin A-4 showed excellent cytotoxic activities against a panel of human cancer cell lines including multi-drug resistant cell lines. The X-ray three-dimensional structural analysis shows that proton donor in B ring may be required for cytotoxic activity, with intermolecular hydrogen bonding playing an important role.