Letters in Drug Design & Discovery - Volume 2, Issue 4, 2005

These diterpenes (1) and (2) were synthesized via epoxidation and rearrangements of (-)-Kaur-9(11), 16-dien-19-oate (7) isolated from Venezuelan species of espeletia (frailejon), and their antimicrobial and antitumoral activity were evaluated. Compound (1) showed GI50 values of 51.6 nM against CNS SF-539, LC50 = 100 μM, log10 GI50 = -7.29; compound (2) showed GI50 at 4.17 μM against breast cancer T47D, LC50 = 39 μM and Log10 GI50 = -5.38. Our results suggest that these compounds are highly cytotoxic and cytostatic against human cancer cell lines.

The synthesis of two antineoplastic compounds is accomplished by placing threemethanesulfonate groups on folic acid (I) and triethanolamine (II). Methane-sulfonate agents (I) and (II), alkylate an aqueous nucleophilic primary amine group at physiological pH 7.4 and 37 °C. Compound (I) utilizes folic acid as a drug carrier for highly specific delivery into tumor cells that have increased folic acid receptors. There are three reactive sites within (I) and (II) for alkylation of nucleophilic targets within tumor cells. Alkylation activity of compounds (I) and (II) showed first-order and second-order reaction kinetics, respectively. Molecular properties such as Log P,molar refractivity, aqueous solubility, polar surface area, halflife of reaction, and Log BB are determined.

Primary or secondary resistance towards conventional chemotherapeutic agents presents the major clinical obstacle in the induction of remission and definite cure of hematological malignancies. Definition of the underlying molecular mechanisms determining response or resistance not only enables the clinician to define prognostic markers, but moreover, facilitates the design of molecularly targeted therapies aiming to reverse the causative lesion and/or the therapeutic resistance. Prostate-apoptosis-response-gene-4 (par-4), which is expressed in a broad spectrum of normal and neoplastic tissues, was originally described in prostate cancer cells forced to undergo apoptosis. In particular, the observation that overexpression of par-4 potentiates apoptosis in malignant cells while sparing normal tissues, renders the assessment of its biological properties and their potential therapeutic exploitation worthwhile. This article focuses on the functional properties of par- 4 in hematopoietic cells, describing their pro-apoptotic and anti-transforming role, and provides an outlook on the potential therapeutical employment of this knowledge.

The deregulated cell cycle is a prominent hallmark of oncogenesis. In addition to the genetic alterations in G1 and S phase, emerging data demonstrate that the loss of checkpoint control at the G2/M transition is also closely involved in neoplastic transformation. Among many modulators of the G2/M transition, the defective regulation of cyclin B1, the regulatory subunit of cyclin dependent kinase 1 (Cdk1), and of Polo-like kinase 1 (Plk1) is attracting increasing attention as both of them are overexpressed in a wide spectrum of human tumors. Cyclin B1 and Plk1 serve as negative prognostic markers for patients with various tumors. In this review, we focus on these two molecules and highlight their roles in normal cell cycle, the involvement in oncogenesis and their potential as intervention targets for antitumor therapy.

Hydralazine is a drug used as anti-hypertensive, and recently reported to be a DNA methylation inhibitor able to demethylate and reactivate the expression of tumor suppressor genes in cancer. The aim of the present study was to explore the potential mechanism by which hydralazine inhibits DNA methylation. For this purpose, we assessed the structural and electronic properties between 1-hydrazinophthalazine (hydralazine) and a putative ligand methyltransferase.

A quantitative structure-activity relationship (QSAR) study is made on a series of Na+ channel blockers (diphenylacetamide derivatives) and on a series of K+ channel blockers (blockers of cardiac delayed rectifier potassium current IKs) (benzodiazepine derivatives). In both the cases, the blocking activity is found to be significantly correlated with Kier's first-order valence molecular connectivity index.

A bicyclic spiro analogue of D-proline was synthesized from perbenzylated methyl D-fructoside. The synthetic steps required first a three carbon chain elongation at the anomeric position by C-glycosylation, secondly the introduction of the amino function at C-1, and finally the cyclization to the pyrrolidine ring and introduction of the carboxylic group.

In order to gain inside the mechanism of action of a series of benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives with in vitro anti-trypanosomal activity, electrochemical and biological studies were performed. Cyclic voltammetry and electron spin resonance spectroscopy were used to predict the bio-reduction processes. Effects on the parasitic respiration were studied.

A novel series of nonradiolabeled, polyfluorinated phenyltropanes were developed containing three or more 19 F atoms/molecule in a magnetic resonance (MR) equivalent chemical environment to increase coherent MR signal characteristics. Competitive radioreceptor affinity assays of such compounds yielded nM affinity at dopamine (DAT) and serotonin (SERT) transporters in rat brain tissue. Compound 3b (MCL-314) at 50 μM gave a clear magnetic resonance spectroscopy signal, and 9 (MCL-319) yielded very high DAT potency and improved selectivity over SERT. Such compounds might potentially serve as MRI- or MRS-detectable index ligands for the dopamine transporter proteins, and preliminary observations call for further study of additional polyfluorinated phenyltropanes.

The title compounds have been synthesized and tested for structure activity relationship for Phospholipase A2 (PLA2) [E.C. 3.1.1.4] enzyme inhibition. The in vitro PLA2 enzyme inhibitory activity of azetidin-2-one derivatives and in vivo anti-inflammatory activity studies using mice are highlighted. The results show that some azetidin-2-one derivatives are very good PLA2 inhibitors and can also be used as antiinflammatory drugs.

The present study summarizes results obtained with PACAP treatment in models of neurodegenerative diseases. The data show that PACAP protected a significant number of neurons in quinolinic acid- and 6-hydoxydopamine-induced lesions, which correlated with the less severe behavioral symptoms. These effects may have clinical implications in Huntington and Parkinson's diseases.

Recently, it has been emphasized that oxidative stress could play a synergistic role with tau phosphorylation, cell shape changes, cytoskeletal disruption and cell death in Alzheimer's disease. Okadaic acid induces oxidative damage, cell shape alterations, tau hyperphosphorylation and cytoskeletal disorganization similar to Alzheimer's disease. In this sense, different evidence suggests that indolamines may be useful for protection against oxidative stress and cellular disorganization. In this study, we looked at the effects of melatonin, 5-hydroxytryptophan (5OHTrp), 5-hydroxytryptamine (5HT), N-acetyl-5- hydroxytryptamine (NA5OHT) or 6-hydroxymelatonin (6OHMEL) (10-5 M) on the oxidative changes and cell shape alterations produced by okadaic acid (50 nM) in N1E-115 neuroblastoma cells. The effects of okadaic acid were evaluated as changes in the quantity of lipid peroxidation products, reduced glutathione (GSH) content, activity of anti-oxidative enzymes and major length axes (as an index of cell shape changes). Okadaic acid gives rise to lipid peroxidation products (P< 0.001), GSH consumption (P< 0.001), major length axis (P< 0.001) and a reduction in the activity of GSH-transferase, GSH-reductase and catalase between 43.33 - 55.17%. These changes were completely prevented by melatonin, whereas 5OHTrp, 5HT, NA5OHT and 6OHMEL partially blocked the alterations induced by okadaic acid. In conclusion, our data indicates: (i) The importance of oxidative stress in both this experimental model and in the development and course of neurodegenerative diseases, especially Alzheimer's. (ii) The protective effects of indolamines (iii) and that melatonin is much more efficient than its precursors and metabolites in reducing the extent of oxidative stress and cell shape changes induced by okadaic acid.

Ab initio molecular orbital calculations are employed to elucidate structural and electronic characteristics of a series of eicosanoids, which have been used to examine the specificity of a 14,15-DHET ELISA. The results of the calculations show that activity is correlated to two combined factors: molecular volume and energy of the HOMO.

A number of novel 1,5-diarylpyrazoles possessing N-substitution on the sulfonamide (-SO2NH2) moiety were synthesized and tested for COX-1/COX-2 inhibition in vitro. Many of these 1,1-dioxo-2,3- dihydrobenzo[d]isothiazolyl substituted 1,5-diarylpyrazoles, where the SO2NH2 group was a part of the fused ring, showed COX inhibitory activity. Few of them were identified as selective COX-2 inhibitors. Structure Activity Relationship study within the series are discussed.