I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Introduction 1. Woman's Place in Man's Life Cycle 2. Images of Relationship 3. Concepts of Self and Morality 4. Crisis and Transition 5. Women's Rights and Women's Judgment 6. Visions of Maturity References Index of Study Participants General Index

In a Different Voice. Psychological Theory and Women’s Development. Cambridge, MA (Harvard University Press) 1982.

Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.

Fluorine in Pharmaceuticals: Looking Beyond Intuition.

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

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Fluorine in medicinal chemistry.

Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available1, rapidly killing all asexual stages of Plasmodium falciparum2. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria1, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience3, 4, 5 their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins6. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.

Artemisinins target the SERCA of Plasmodium falciparum

This article reviews current knowledge of the metabolism of drugs that contain fluorine. The strategic value of fluorine substitution in drug design is discussed in terms of chemical structure and basic concepts in drug metabolism and drug toxicity.

Metabolism of fluorine-containing drugs.

Despite international efforts to ‘roll back malaria’ the 2008 World Malaria Report revealed the disease still affects approximately 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some ‘cautious optimism’; more than one third of malarious countries have documented greater than 50% reductions in malaria cases in 2008 compared to 2000. The goal of the Member States at the World Health Assembly and ‘Roll Back Malaria’ (RBM) partnership is to reduce the numbers of malaria cases and deaths recorded in 2000 by 50% or more by the end of 2010. Although malaria is preventable it is most prevalent in poorer countries where prevention is difficult and prophylaxis is generally not an option. The burden of disease has increased by the emergence of multi drug resistant (MDR) parasites which threatens the use of established and cost effective antimalarial agents. After a major change in treatment policies, artemisinins are now the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of symptoms. Since artemisinin and its derivatives are eliminated rapidly, artemisinin combination therapies (ACT’s) are now recommended to delay resistance mechanisms. In spite of these precautionary measures reduced susceptibility of parasites to the artemisinin-based component of ACT’s has developed at the Thai-Cambodian border, a historical ‘hot spot’ for MDR parasite evolution and emergence. This development raises serious concerns for the future of the artemsinins and this is not helped by controversy related to the mode of action. Although a number of potential targets have been proposed the actual mechanism of action remains ambiguous. Interestingly, artemisinins have also shown potent and broad anticancer properties in cell lines and animal models and are becoming established as anti-schistosomal agents. In this review we will discuss the recent evidence explaining bioactivation and potential molecular targets in the chemotherapy of malaria and cancer.

/pdf/the-molecular-mechanism-of-action-of-artemisinin-the-debate-43n2mkccpp.pdf

The molecular mechanism of action of artemisinin - the debate continues.

ion and allylic carbon radical formation with subsequent triplet ground-state oxygen capture result ultimately in the formation of lipid hydroperoxides. The explicit mechanism depicted in Scheme 1 is supported by the work of Berman and Adams and others, and it was proposed that the damage caused to the parasite’s FV membrane leads to vacuolar rupture and parasite autodigestion.41 This mechanism is consistent with the observed oxygen dependence of antimalarial action of artemisinin and the morphological changes seen following artemisinin administration to parasites in vitro.44 The biological significance of hydroperoxides in relation to biological hydroxylation and autoxidation of, for example, lipids and membrane bilayers is well established. The generation of unsaturated lipid hydroperoxides provides a means of initiation of such processes. In contrast to these proposals, other workers in the field have suggested that membrane-bound heme may have a role to play in reducing the effectiveness of endoperoxides such as dihydroartemisinin. Further work is required to clarify the role of vacuolar membrane bound heme in the mechanism of action of endoperoxide antimalarials.45 An alternative nonlipid “artemisinin derived source of hydroperoxide” is discussed below. Although Scheme 1 would appear chemically plausible, several workers have proposed that the parasite death in the presence of artemisinin is probably not due to nonspecific or random cell damage caused by freely diffusing oxygen radical species but might involve specific radicals and targets, some of which are described later in this review. The following section details the specific “transitory” species that may be responsible for the antimalarial mechanism of action of artemisinin. Targets of these species are discussed and will conclude with the most recent studies by Eckstein-Ludwig who suggest that artemisinin derivatives target the PfATP6, the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) of the parasite.46 Transitory Species Mediating the Antimalarial Activity of Artemisinin: Carbon Radicals, Carbocations, Hydroperoxides, and High-Valent IronOxo Species. On the basis of the seminal work of Posner and co-workers in the early 1990s, the free radical chemistry of artemisinin is now very welldefined and has been shown to involve an initial chemical decomposition induced by heme Fe(II) (reduced hemin) or other sources of ferrous iron within the malaria parasite to produce initially an oxy radical that subsequently rearranges into one or both of two distinctive carbon-centered radical species.47 Scheme 2a summarizes the main radical pathways available for artemisinin following endoperoxide-mediated bioactivation. Since artemisinin is an unsymmetrical endoperoxide, the oxygen atoms of the peroxide linkage can associate with reducing ferrous ions in two ways. Association of Fe(II) with oxygen 1 provides an oxy radical that goes on to produce a primary carbon-centered radical (5a). A surrogate marker for the intermediacy of this radical species is the ring-contracted tetrahydrofuran (RCT) product 5b. Alternatively, association with oxygen 2 provides an oxy radical species that, via a 1,5-H shift, can produce a secondary carbon-centered radical (5c). Again, like the previous route, a stable end-product, hydroxydeoxoartemisinin (HDA) (5d), functions as a surrogate marker for this secondary carbon-centered radical species. It has been proposed that final alkylation by these reactive intermediates of biomacromolecules such as Scheme 1. Proposed Chemical Mechanism for the Observed Artemisinin Mediated Lipid Peroxidation of Cell Membranesa a Carbon radicals, generated from artemisinin, abstract allylic hydrogen atoms from unsaturated lipid bilayers to set in motion the downstream generation of a variety of reactive oxygen species by a classic lipid peroxidation mechanism. Heme or hematin/thiols associated with the lipid bilayer may be the catalysts responsible for initiation of these processes. Perspective Journal of Medicinal Chemistry, 2004, Vol. 47, No. 12 2947

Paul M. O'Neill

Papers

Artemisinins target the SERCA of Plasmodium falciparum

Metabolism of fluorine-containing drugs.

The molecular mechanism of action of artemisinin - the debate continues.

A medicinal chemistry perspective on artemisinin and related endoperoxides.

4-Aminoquinolines—Past, present, and future; A chemical perspective