The Fight Against AIDS

New Avenues for Inhibiting Reverse Transcriptase (RT), an Old Target The acquired immunodeficiency syndrome (AIDS) related to HIV-1 infection is one of the most serious threats to human health, and it has been estimated that more than 25 million people have died since it was first recognized. In the fight against AIDS, first- and second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) are now established as part of highly active antiretroviral therapy (HAART) for treating HIV...

Peptide and gene therapy related to bfGf and pdgf IN IBD

Recent clinical and animal studies suggest alteration and dysfunction of the intestinal microvasculature in IBD pathogenesis .99 101-105 One of these studies showed increased microvascular density in IBD mucosa, upregulation of VEGF, bFGF, TGFp, TNFa, and ET-1 . We also detected differential changes in the serum and tissue levels of bFGF and PDGF in patients with Crohn's disease and ulcerative colitis 106 More recently, we found a time-dependent increased expression of hypoxia-inducible...

Stress Activates Corticotropin Releasing Factor Signaling Pathways

Implication in Functional Bowel Disorders From Hans Selye to Biochemical Coding of Stress CRF Signaling Pathways Ligands and CRF CRF Receptors Cloning and Pharmacological CRF Receptor Brain CRFj Receptors and Stress-Induced Stimulation of Colonic Motor Brain CRFj Receptors and Stress-Related Hypersensitivity CRFj Receptors and Pathophysiology of IBS FROM HANS SELYE TO BIOCHEMICAL CODING OF STRESS RESPONSE Hans Selye pioneered the concept of biological stress, borrowing the word stress from the...

Regioselectivity in the metabolism of chemical carcinogens by cytochrome P450

Although a number of cytochrome P450 proteins can metabolize the same compound, they may display regioselectivity in that they metabolize it at different sites, so that some may direct its metabolism toward the formation of reactive intermediates and thus facilitate its bioactivation, whereas others produce inactive, readily excretable metabolites and promote its deactivation and elimination. For example, the human bladder carcinogen -naphthylamine is metabolized selectively by CYP1A2 through...

References

Ames, B.N. and Gold, L.S., The prevention of cancer, Drug Metab. Rev., 30, 201, 1998. 2. Moyers, S.B. and Kumar, N.B., Green tea polyphenols and cancer chemoprevention multiple mechanisms and endpoints for phase III trials, Nutr. Rev., 62, 204, 2004. 3. Hecht, S.S., Inhibition of carcinogenesis by isothiocyanates, Drug Met. Rev., 32, 395, 2000. 4. Mori, H. and Nishikawa, A., Naturally occurring organosulphur compounds as potential anticarcinogens, in Nutrition and Chemical Toxicity, Ioannides,...

Recombinatorial chemistry

Drug discovery remains a challenging effort. In this regard, we report on a random strategy for generation of small compound libraries.3940 The idea is based on the use of y irradiation as an initiator of random free radical recombinations in aqueous or alcohol solutions of educts. By exposure of a sample to y irradiation, primary and secondary products of solvent radiolysis are generated and they can react with the dissolved compound and built products.4142 The starting compound should be a...

Syntheses of FomocAine Inn

The first technical synthesis of fomocaine (Figure 9.5) entails a Blanc chloromethyl-ation as the key reaction. This was optimized very carefully to keep the percentage of the ortho isomer low.2 The second technique (Figure 9.6) also works without regioisomers. Essentially, it entails a Willgerodt-Kindler reaction in which the thioamide is reductively desul-furated with Raney nickel.3 Ortho-fomocaine FIGURE 9.5 First technical synthesis of fomocaine. FIGURE 9.6 Second technical synthesis of...

Design of structures against neurodegeneration of Alzheimers type

Neurodegenerative diseases like senile dementia of Alzheimer's type (SDAT) are among the greatest challenges in pharmacochemistry It is estimated that there will be about 4 x 107 sufferers from this disorder by 2020.18 SDAT, cardiovascular disorders, and cancer are the first three causes of morbidity worldwide At present, there is no effective treatment for SDAT. The applied pharmacotherapy is based on the cholinergic hypothesis . 19 These drugs are of limited benefit, quite toxic, and fail to...

Alkyl55diphenylimidazolidinediones as new cannabinoid receptor antagonists

Huffman et al.1617 at Clemson University found that simplified derivatives of amino-alkylindoles such as l-alkyl-3-(l-naphthoyl)pyrroles also exhibit a significant affinity for cannabinoid receptors.17,18 The more potent ligand was the n-pentyl derivative (JWH-030, Scheme 8.1) with a Ki of 87 nM on brain cannabinoid receptors. On analyzing the structures of 1-alkyl-3-(1-naphthoyl)pyrroles and of diarylpyrazoles antagonists, and considering that in the past our laboratory was involved in...

Switching from one compound to another

If resistance would develop to oxathiin carboxanilide UC84, therapy could be readily switched to one of the thiocarboxanilide derivatives, which retained sensitivity to the resistant (i . e . , 100 Leu - Ile, 103 Lys - Asn, 106 Val - Ala, 138 Glu - Lys, or 181 Tyr- Cys) mutant strains . 28 There are plenty of other examples where switching from one compound to another restores sensitivity. For example, retains activity against those HIV-1 strains that, because of the 103 Lys- Asn or 181 Tyr -...

Biochemical characteristics of LpPLA2

The presence of an enzyme in human plasma that catalyzes the hydrolysis of the sn-2 ester bond of the potent proinflammatory phospholipid, platelet-activating factor (PAF) (and which thus attenuates its bioactivity) was first demonstrated by Farr et al. in 1980.2 This enzyme was named PAF-acetylhydrolase (PAF-AH) (EC 3.1.1.47). Plasma PAF-acetylhydrolase is categorized in the subfamily VIIA of phospholipases A2, and its activity does not require calcium. Unlike other PLA2, PAF-acetylhydrolase...

Crf receptor antagonists

Key to the assessment of the role of endogenous CRF ligands and CRF receptors in the stress response was the development of specific CRF antagonists. Earlier studies relied on the use of specific peptide CRF antagonists subtypes such as a-helical CRF9-41, D-Phe12CRF12_41, and the longer acting more potent, astressin and astressin-B.63-65 These peptides are competitive antagonists that bind to both CRFj and CRF2 receptors and equally to the a, p, and y variants of CRF2 receptors and...

The Cholinergic Treatment Hypothesis

Loss of basal forebrain cholinergic neurons is a significant feature of the disease and appears to be correlated with the memory deficits. Experimental lesions of cholinergic systems also produce memory deficits in animals. Treatments for the memory loss in AD have therefore focused on cholinergic replacement approaches (the cholinergic hypothesis). Much research has been devoted to the design and testing of acetylcholinesterase inhibitors (AChE-I) as a means of preserving acetylcholine (ACh)...

Petra Kapkova Vildan Alptuzun Eberhard Heller Eva Kugelmann Gerd Folkers and Ulrike Holzgrabe

DUO Compounds as Ditopic Optimized Ditopic Compounds of Smaller Tertiary Compounds of Recombinatorial One of the most prominent features of Alzheimer's disease (AD) is a significant deficit in cholinergic transmission in certain brain areas.1,2 The concentrations of acetylcholine (ACh) decrease by nearly 90 in patients with AD. Therefore, one main focus of AD treatment is the use of agents that increase the availability of intrinsic ACh by inhibiting the acetylcholinesterase (AChE) enzyme. This...

Role of lppla2 in atherosclerosis

Lp-PLA2 may play a significant role in atherogenesis and cardiovascular disease due to its role in the metabolism of bioactive lipids such as PAF and oxidized phospholipids. PAF activates leukocytes and platelets and enhances leukocyte adhesion to the vessel wall. Furthermore, PAF is a vasoactive mediator that may be synthesized locally at the site of endothelial injury during thrombosis. Equally, PAF accumulates in the atherosclerotic plaques of subjects with advanced CAD, suggesting that this...

Synthesis of Biologically Active Taxoids

C2-Ester Derivatives of Taxol Prodrugs for Taxol Taxol Figure 7.1 1 , a diterpene originally isolated from the American Pacific yew Taxus brevifolia,1 has emerged as one of the most effective chemotherapeutic agents for the treatment of breast and ovarian cancers.2 The compound is also in development for non-small-cell lung cancers,3 and head and neck cancers.4 Taxol's development has included periods of both unusual languor and speed.5 It acts by blocking the normal depolymerization of...

Design Of Novel Antidyslipidemic Agents

Atheromatosis is the main contributor to cardiovascular problems, which are the most common cause of death in Western societies . Dyslipidemias are the prime cause of atheromatosis .2 As low-density lipoprotein cholesterol LDL constitutes the main cholesterol carrier in the plasma, it influences cholesterol plasma levels and is closely related to the etiology of atheromatosis . 3 In atheromatosis the following pathologic events take place hypercholesterol-emia, hypertriglyceridemia, oxidation...

Cellular Sources Of Human Plasma LpPLA2

Early studies demonstrated that peripheral blood-monocyte-derived macrophages11 and the human hepatocarcinoma cell line HepG212 secrete the plasma form of Lp-PLA2. Other cell types that secrete this enzyme are neutrophils, differentiated HL-60 cells, activated bone-marrow-derived mast cells, and activated platelets.13-15 The Lp-PLA2 mRNA has been detected in differentiated macrophages, as well as in thymus, tonsils, and human placenta, but not in liver cells and monocytes. Such a cellular...

Contributors

Faculty of Pharmacy Ege-University Bornova-Izmir, Turkey Universit degli Studi di Siena Siena, Italy Katholieke Universiteit Leuven Brussels, Belgium Sun Health Research Institute Sun City, Arizona National Magnet Laboratory Massachusetts Institute of Technology Cambridge, Massachusetts Universit degli Studi di Siena Siena, Italy VA Medical Center Long Beach, California and University of California, Irvine Irvine, California Research Center Borstel Leibniz Center for Medicine and Katholieke...