Letters in Drug Design & Discovery - Volume 5, Issue 7, 2008

Some pyrrolo[2,1-c][1,4]benzodiazepine-G1 poly (aryl ether) dendrimer hybrids have been synthesized and evaluated for their DNA binding ability as well as anticancer activity. The linkage of dendrimer component significantly increased DNA binding ability and anticancer activity apart from the enhancement of their solubility, and taking part as a drug carrier.

A new sesquiterpene lactone, 6β-O-isobutyrylbritannilactone (5) and five known sesquiterpene lactones; britannilactone (1), 1-O-acetylbritannilactone (2), Hydroxy alantolactone (3), 8-epi-ivangustin (4) and 1,6-O,Odiacetylbritannilactone (6), were isolated from the flowers of Inula britannica. In the known sesquiterpene lactones, (3) and (4) were isolated for the first time from Inula britannica. The structures of these compounds were established unambiguously by UV, MS and a series of 1D and 2D NMR analyses. Compounds 3, 4, 5 and 6 exhibited significant cytotoxicity for tumor cells in vitro in bioassay.

3D-QSAR analysis has been performed on a series of diaryl urea derivatives of multi-targeted receptor tyrosine kinase inhibitors. Models were developed using the most widely used computational approach molecular field analysis (MFA) from our dataset for the KDR, cKit and FLT3 inhibitors using genetic partial least square (G/PLS) method. These models showed excellent internal predictability and consistency and validation using test set compounds yielded a good predictive power for the activity values of three set of inhibitors. These models would offer utility in guiding the rational design of multi-targeted KDR, cKit and FLT3 receptor tyrosine kinase inhibitors for therapeutic applications.

The chemical signaling like N-acylhomoserine lactones (AHLs) controlling quorum sensing (QS) processes has been emerged as a possible target for the design of a novel antimicrobial compounds. Twenty-four new N-phenylacetanoyl- L-homoserine lactones (PHLs) relative to AHLs with variable inhibition of QS were selected to develop models to establish the three-dimensional quantitative structure-activity relationships (3D-QSAR) by using the comparative molecular field analysis (CoMFA). The statistical results showed that the CoMFA model exhibited a good cross-validated q2 and conventional r2 values up to 0.528 and 0.914. The resulting CoMFA contour map provides information on the steric and electrostatic fields whose contributions were 0.457 and 0.543, respectively. The CoMFA model can interpret the structure activities of the inhibitors of QS well and afford us important information for structure-based drug design.

A series of novel diphenyl(piperidin-4-yl)methanol derivatives 10(a-j) were synthesized and characterized by 1H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evaluated for their cell antiproliferation activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The antiproliferative effects of the synthesised compounds were tested against viable human skin fibroblast cell line and carcinoma cell lines namely HeLa, HT-29, MCF-7, HepG-2 by adopting positive and negative control. The importance of the methoxy and fluorine group on diphenyl(piperidin-4-yl)methanol moiety was confirmed and it was noted that, the substitution at 4th position of the aryl ring plays a dominant role and was responsible for the antiproliferative activity. Among the synthesized compounds, only (10a) and (10b) have potent antiproliferative activity on all the carcinoma cell lines tested.

The aim of this study was to evaluate the use of a β-cyclodextrin-based polymer, and more exactly a highly crosslinked cyclodextrin-based polyester, as an excipient to accelerate the release of poorly soluble drugs from pellets obtained by extrusion-spheronisation. The cross-linked β-cyclodextrin based polymer was associated to microcrystalline cellulose to facilitate the process of extrusion/spheronisation, and nimesulide was chosen as a poorly soluble model drug. Different formulations with natural α and β-cyclodextrins, or a β-cyclodextrin-based polymer associated to microcrystalline cellulose and 10 % (w/w) of nimesulide were compared. Yield between 800 and 1000 μm, pellets dimensions and surface morphology by scanning electron microscopy (SEM), Fourier Transform - Infrared Spectroscopy (FT-IR) spectra, disintegration and in-vitro drug release were evaluated. Due to pellet disintegration, accelerated dissolution of nimesulide was achieved with β-cyclodextrin-based polymer, i.e. 75±2% in 120 min vs. 12±1% for pellets with only microcrystalline cellulose (p<0.05). On the other hand, pellets with the same percentage of cyclodextrins as cyclodextrinbased polymer, were not disintegrated, and the dissolution was limited around 35±1% after 120 min, with a release linked to the porosity enhancement by leaching of water soluble excipients. In conclusion, the formulations of nimesulide with cross-linked β-cyclodextrin-based polymer appears the most promising for testing in vivo bioavailability studies.

Surface tension based microtensiometric method for HTS (high throughput screening) of drug solubility properties is presented. Method was tested by determining physiologically relevant parameters on the solubility of ibuprofen and indomethacin. Linear correlation was found with equilibrium solubility. According to this study, microtensiometry is a promising technique for HTS solubility testing.