Medicinal Chemistry - Volume 1, Issue 4, 2005

The inhibition of the aldose reductase enzyme (AR) is considered to be a promising approach to control chronic diabetes complications as well as a number of other pathological conditions. Thus considerable efforts are devoted to the development of aldose reductase inhibitors (ARIs) as possible pharmacotherapeutic agents. The establishment of adequate QSAR models would serve to this purpose. In the present study multivariate statistics was applied in order to analyse the AR inhibitory activity data of twenty three pyrrol-1-yl-acetic acid derivatives on the basis of essential molecular descriptors. The compounds contain one or two carbonyl keto groups, which serve as a bridge to link the pyrrole moiety to aromatic nuclei with or without further substitution. An adequate one component model with satisfactory statistics was obtained and validated for its robustness and predictive ability. The influence of the different descriptors in ARI activity is discussed. The derived model was further used to predict the activity of four independent compounds and the contribution of their specific structural characteristics in ARI activity was evaluated.

Several medicinal plants can be employed to produce extracts exhibiting biological effects. The aim of this work was to verify the ability of extracts derived from different medicinal plants of Bangladesh in interfering with specific DNA-protein interactions. The rationale for this study is based on the observation that alteration of gene transcription represents a very promising approach to control the expression of selected genes and could be obtained using different molecules acting on the interactions between DNA and transcription factors (TFs). We have analysed the antiproliferative activity of extracts from the medicinal plants Hemidesmus indicus, Polyalthia longifolia, Aphanamixis polystachya, Moringa oleifera, Lagerstroemia speciosa, Paederia foetida, Cassia sophera, Hygrophila auriculata and Ocimum sanctum. Antiproliferative activity was assayed on different human cell lines, including erythroleukemia K562, Blymphoid Raji, T-lymphoid Jurkat and erythroleukemia HEL cell lines. We employed the electrophoretic mobility shift assay (EMSA) as a suitable technique for the identification of plant extracts altering the binding between transcription factors and the specific DNA elements. We found that low concentrations of Hemidesmus indicus, Polyalthia longifolia, Moringa oleifera and Lagerstroemia speciosa, and very low concentrations of Aphanamixis polystachya extracts inhibit the interactions between nuclear factors and target DNA elements mimicking sequences recognized by the nuclear factor kappaB (NF-kB). On the contrary, high amount of extracts from Paederia foetida, Cassia sophera, Hygrophila auriculata or Ocimum sanctum were unable to inhibit NF-kB/DNA interactions. Extracts inhibiting both NF-kB binding activity and tumor cell growth might be a source for anti-tumor compounds, while extracts inhibiting NF-kB/DNA interactions with lower effects on cell growth, could be of interest in the search of compounds active in inflammatory diseases, for which inhibition of NF-kB binding activity without toxic effects should be obtained.

Estrogen receptors are therapeutic intervention targets for diseases such as osteoporosis and breast cancer with both tamoxifen and raloxifene established as clinical estrogen receptor antagonists. We report a series of novel selective estrogen receptor modulators (SERMs) whose structures are based on a flexible core scaffold differing from the triphenylethylene of tamoxifen analogues through the insertion of a benzylic methylene group as a flexible spacer between the aryl ring C and the ethylene group. A facile synthesis of the target compounds utilises the titanium tetrachloride/zinc mediated McMurry coupling reaction. Successive introduction onto the parent scaffold of hydroxyl functional groups afforded a series of increased potency ligands for the ER - essentially exploring the predicted in vivo metabolic activiation of such aromatic SERM ligands. This second generation compound series demonstrated high antiproliferative potency against the MCF-7 human breast cancer cell line, with low cytotoxicity. High ER binding affinity (IC50 20nM) together with up to 12 fold ERα/β selectivity was also observed. In addition, the compounds displayed antiestrogenic effects at 40nM when evaluated in the Ishikawa cell line with little estrogenic stimulation. Representative ligands were shown to be pro-apoptotic in human MCF-7 cells in a FACS based assay. Comparison of the docked structure obtained for the most active compound with the X-ray crystal structure reported for the complex of ERα and 4-hydroxytamoxifen, predict that these ligands bind in an antiestrogenic manner with some differences being observed in the benzylic Ring C orientation, as expected. This work further demonstrates the tolerance of the estrogen receptor towards flexible modulators.

Cytochrome P450 1A (CYP1A) is a subclass of enzymes involved in the biotransformation of heterocyclic amines present in cooked red meat to carcinogenic compounds. Anti-cancer properties have long been associated with flavonoids, and some compounds of this class have been shown to interact directly with CYP1A2. The understanding of this interaction is the purpose of this work. As the number of experimentally tested molecules is limited, two complementary methods in terms of information provided, are proposed for the study of protein-inhibitor interaction as alternatives to a QSAR analysis, using quantum mechanics as well as molecular mechanics.

Cysteine proteases are connected to various viral and parasitic infections, as well as to other severe diseases like arthritis, stroke and cancer. Due to its α,β-unsaturated carbonyl moiety etacrynic acid, a well known diuretic, can inhibit cysteine proteases in a Michael-type reaction by reaction with the nucleophilic cysteine residue of the active site. For first structure-activity-relationship studies modifications at various positions of the etacrynic acid structure have been investigated concerning inhibition potency against the CAC1 protease papain: length of the side chain, substitution pattern of the aromatic ring as well as influence and necessity of acidic groups, esters or amides. Additionally, the effect of the aromatic ring was evaluated by replacement with a cyclohexyl moiety.

The enaminones represent potentially useful agents for the clinical treatment in generalized tonic-clonic seizures (Epilepsia, 1993, 34(6), 1141-1145, Biopharm. Drug Disp. 2003, 397-407). A regression analysis was performed to provide a quantitative structure-activity relationship (QSAR) correlation model for prediction of activity for the anticonvulsant enaminones. Molecular modeling was performed to determine the molecular confluence of the Unverferth model (J. Med. Chem. 1998, 41, 63-73) to the enaminones. Conclusions related to the sodium channel model were assessed.

The topoisomerase enzymes are essential for DNA metabolism, where they act to adjust the number of supercoils in DNA, a key requirement in the cellular processes of transcription and replication. Their enzymatic mechanism creates transient nicks (type I) or breaks (type II) in the double stranded DNA polymer, allowing DNA to be converted between topological isomers. Humans possess both types of topoisomerase enzymes, however the two types utilize very different enzymatic mechanisms. Both type I and type II topoisomerases have been identified as clinically important targets for cancer chemotherapy and their inhibitors are central components in many therapeutic regimes. Over the course of the last 30 years inhibitors with extensive structural diversity have been developed through a combination of drug screening and rational design programs. Simultaneously much emphasis has been placed upon establishing the mechanisms of action of both classes of topoisomerase enzyme. Crucial structural insights have come from the crystal structure of topoisomerase I, while modelling comparisons are beginning to map out a possible framework for topoisomerase II action. This review discusses these recent advances in the fields of enzyme mechanism and inhibitor design. We also address the development of drug resistance and dose-limiting side effects as well as cover alternative methods in drug delivery.

Gastroduodenal HCO3 - secretion is a key process that aids in preventing acid-peptic injury. Endogenous prostaglandins (PGs) play a particularly important role in the local control of this secretion. The secretion of HCO3 - in both the stomach and duodenum was increased in response to PGE2 as well as mucosal acidification, the latter occurring with concomitant enhancement of mucosal PG generation. These HCO3 - responses in the duodenum were markedly reduced by prior administration of the EP4 antagonist in rats, and profoundly decreased in the animals lacking EP3 receptors but not EP1 receptors. In contrast, gastric HCO3 - responses induced by PGE2 and mucosal acidification were prevented by the EP1 antagonist and disappeared in EP1, but not EP3-knockout mice. Consistent with these findings, duodenal HCO3 - secretion was stimulated by both EP3 and EP4 agonists but not EP1 or EP2 agonists, while gastric HCO3 - secretion was increased by the EP1 agonist but not EP2, EP3 or EP4 agonists. In addition, the HCO3 - stimulatory action of sulprostone (EP1/EP3 agonist) in the stomach was inhibited by the Ca2+ antagonist verapamil but not affected by IBMX, the inhibitor of phosphodiesterase, while that in the duodenum was inhibited by verapamil and enhanced by IBMX. Forskolin, the stimulator of adenlate cyclase, increased HCO3 - secretion in the duodenum but not the stomach. Thus, the HCO3 - stimulatory action of PGE2 in the duodenum is mediated by both EP3 and EP4 receptors being coupled intracellularly with both Ca2+ and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca2+.

This review describes current and new therapeutic agonists and antagonists of G-protein-coupled receptors (GPCRs) currently used in the clinic. GPCRs are classified under the GRAFS system (Glutamate, Rhodopsin, Adhesion, Frizzled/taste2 and Secretin), with therapies having been developed for about 30 GPCRs from the glutamate, rhodopsin and secretin families. Most of these therapies target the biogenic amine receptors of the rhodopsin family. Advancing technology has assisted in the identification of an increasing number of GPCRs, as well as contributing to the understanding of function and potential as pharmaceutical targets. With this has come the development of new therapies that target specific GPCRs, including peptide activated GPCRs. Where possible, agonists and antagonists are described individually, focusing on new therapies and their corresponding target receptors. However, the large number of reported biogenic amine therapies precludes, discussion of individual compounds and instead, they are discussed in relation to the receptor pharmacophore. Despite the large number of significant physiological responses known to be mediated by GPCRs, only about 4% of known GPCRs are currently targeted by therapeutics. This provides a great number of promising new targets for pharmaceutical development.