Letters in Drug Design & Discovery - Volume 2, Issue 3, 2005

Inhibition of the blood fibrinolytic system (plasminogen/plasmin) occurs either at the level of plasminogen activators, regulated by specific plasminogen activator inhibitors (PAIs) or at the level of plasmin, mainly regulated by α2-antiplasmin (α2-AP). In this contribution, we focused on the roles of α2-AP in acute myocardial infarction and vascular remodeling associated with cardiovascular diseases. Our findings have identified a new target for the development of new therapeutics for the clinical therapy of cardiovascular diseases.

X-ray structure analysis of human factor VIIa/soluble tissue factor in complex with a peptide mimetic inhibitor reveals that Asp60, Tyr94, and Thr98 in the S2 site play an important role for the improvement of selectivity against thrombin.

Lectins are carbohydrate-binding proteins that can modulate cellular activity through cell membrane glycoproteins. A cell-based binding was set up to screen the lectin-like substances in natural products. Lectins, after binding to tumor cells, are detected with a biotinylated carbohydrate-polyacrylamide complex by ELISA. Sugar specificity can also be determined within the assay.

An expeditious four-step synthesis of the 1H-pyrrolo[2,3-f]quinoline-2-carboxamides (5a-h) is described. Readily available 6-quinolinecarboxaldehyde is converted to the parent acid (6) by nucleophilic attack of the azido-ester (9) and intramolecular cyclization of (10) followed by hydrolysis of the methyl ester (11). The cytotoxicity of the target molecules (5a-h) was evaluated in four tumour cell lines in vitro. One compound (5d) showed sufficient activity (IC50 = 10.2 μM) in the human non-small cell lung cell line NSCLCN16- L16 to be worthy of further study.

Formulation ingredients may influence the pharmacokinetics of co-administered drugs. We investigated whether oral pre-dosing with the 'inactive' formulation ingredient Solutol affects the pharmacokinetic profile of intravenously administered colchicine in rats. Colchicine was administered intravenously to male Wistar rats as solution in isotonic sodium chloride (NaCl 0.9%, control group) at 1.5 mg/kg. A second group of rats received the intravenous dose of colchicine 20 minutes after oral pre-dosage with 4 mg/kg of a 90:10 (v/v) mixture of NaCl 0.9% and Solutol HS 15 (Solutol). At predetermined time points, plasma and urine were collected from the animals and analyzed for colchicine and its demethylated metabolites by LC/MS-MS. After oral pre-treatment with Solutol, colchicine plasma clearance (Cl) was decreased by a factor of two and its maximum plasma concentration (cmax) was almost twofold increased as compared to the control group. Moreover, the amount of parent colchicine excreted into urine within 24 hours after administration did increase twentyfold in the Solutol treated group. Renal excretion of colchicine metabolites was slightly increased. We conclude that absorption of Solutol and/or its degradation products into the systemic circulation seems to be a major contributor to the observed effects. Our results suggest that oral administration of formulation ingredients may alter the distribution kinetics of drugs, which are co-administered orally as well as intravenously.

Hyperthermia has been shown in many studies to be a strong sensitizer for cisplatin treatment and this sensitization may be in part due to the inhibition of DNA repair processes. We have set out to test this in cells with specific gene knockouts for known repair processes. The chicken DT40 cell system was used with a parental line (DT40) and knockouts of homologous recombination (HR) repair DT40Rad54, nonhomologous recombination endjoining (NHEJ) repair (DT40Ku70) and a double knockout mutant DT40Ku70Rad54. The results show that thermal cisplatin sensitization was achieved in all cell lines when hyperthermia at 45°C for 1.5h was given before cisplatin treatment and 42°C hyperthermia was given concurrently with cisplatin treatment. The data show that inhibition of the HR repair system did not significantly affect sensitization, while inhibition of NHEJ reduced thermal sensitization at low cisplatin doses and short treatments and for concurrent treatments. These data indicate that there may be a partial involvement of NHEJ in thermal cisplatin sensitization under specific treatment conditions.

A series of tartronic acid analogs of a non-peptide RGD mimetic were prepared and evaluated both for antagonism of the vitronectin receptor and for affinity to hydroxyapatite, the main inorganic component of bone matrix. The hydroxy bis acid unit was found to be optimal for both receptor binding and hydroxyapatite affinity, while the N-terminus affected only receptor binding affinity.

Estrone sulfatase (ES) is a membrane-bound enzyme that is responsible for maintaining high levels of estrogens in breast cancer cells. This may be due to the conversion of estrone-sulfate into estrone by estronesulfatase, which acts as a pool of potentially available estrogens. There is now abundant evidence that estrogens have a pivotal role in the growth and development of hormone-dependent breast cancer. Thus, inhibitors of ES should have considerable therapeutic potential for the treatment of hormone-dependent breast cancer. Recently, a large number of sulfamate-based steroidal and non-steroidal ES inhibitors have been developed. The sulfamate moiety is believed to be involved in the irreversible inhibition of ES. In the present paper, we have undertaken quantitative structure-activity relationships for different series of non-steroidal sulfamate-based compounds in order to understand the chemical-biological interactions governing their inhibitory potency against ES. QSAR results have shown that the inhibitory potency against ES for these nonsteroidal sulfamate-based compounds is largely dependent on their hydrophobicity and molar refractivity.

We have identified a novel series of tricyclic pyrazinobenzodiazepines, represented by general structure 2, as potent vasopressin receptor antagonists. For example, 3 binds with high affinity to human V2 receptors and is very selective relative to V1a receptors. Compound (R)-(+)-3 exhibited pronounced aquaretic activity in rats and dogs on oral administration.

The synthesis and biological activities of a series of 2-amino-2-thioxoacetamide derivatives are described. These compounds have inhibitory effects against the protein tyrosine phosphatase activity of CD45. Compound 4i inhibited the PCA reaction in vivo.

Bullous pemphigoid and pemphigus vulgaris are blistering diseases. Our results show that expression of the integrins α6β4 α3β1is altered in both diseases: α6β4 to a greater extent in the former and α3β1 in the latter disease, respectively. Instead, the extracellular matrix examined resulted normally expressed.

The binding affinity (log nK) between human serum albumin and acidic drugs was quantitatively analyzed using a computational chemical method with several model phases. A flat guanidino-phase was the most efficient for calculating log nK values, and docking was easily performed. A flowerpot type model phase bonded a guanidino group at the center bottom demonstrating that ion-ion interaction was the main driving force. A large molecule pushed aside the hydrophobic wall of log P = 5, and reached the guanidino group. Ionized acidic compounds may reach the guanidino group inside a protein by ion-ion interaction through a narrow channel of length 10Å.

Oxidative stress is a major contributing factor to high mortality rates associated with several diseases such as sepsis. This condition can be controlled to a certain degree by antioxidants for instance ascorbic acid (vitamin C). This review focuses on the potential treatment of sepsis by ascorbic acid and its effects on the immune cell function.

Frontal dementia gives rise to characteristic behavioral changes, which include altered emotions, profound alterations in personality and social conduct, and behavioral alterations constitute core and supportive symptoms laid out in the diagnostic criteria. There are some behavioral symptoms which are considered specific for frontal dementia, being present in at least 50% of cases. These includes loss of basic emotions and social embarrassment, selfishness, disinhibition, irritability, neglect, apathy, altered preference for sweet foods, with a tendency to continue eating for as long as food is present, or to steal food from other's plates, motor and verbal stereotypies, wandering, and an absence of insightfulness. Albeit anatomical pathways are well known, there is no known therapy to prevent the advance of frontal dementia. The circuits involve a number of transmitters, receptor subtypes, and second messengers that can be potentially mediated pharmacologically. Though, rational treatments are currently limited . We present the possible actual and future therapeutic choices on the basis of anatomical and biochemical substrates.

It has been suggested that resin wettability is advantageous for dietary phosphate binding in the gastrointestinal tract. To evaluate the effect of anion exchange resin wetting properties on in vivo phosphate binding ability, four types of ethylene glycol dimethacrylate cross-linking 4-vinylpyridinium anion exchange resins (EGDMA-4VP) were synthesized.