Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 12, Number 21, 2005

Contents


Xanthone (Dibenzo-γ-Pyrone): An Interesting Framework In Medicinal Chemistry
Guest Editor: Madalena M.M. Pinto


Editorial Pp. 2411


Naturally-Occurring Xanthones: Recent Developments Pp. 2413
L.M.M. Vieira and A. Kijjoa
[Abstract]


Synthesis of Xanthones: An Overview Pp. 2447
M.E. Sousa and M.M.M. Pinto
[Abstract]


Structure Elucidation of Xanthone Derivatives: Studies of Nuclear Magnetic Resonance Spectroscopy Pp. 2481
A.M.S. Silva and D.C.G.A. Pinto
[Abstract]


Xanthones–A Structural Perspective Pp.2499
L. Gales and A.M. Damas
[Abstract]


Xanthone Derivatives: New Insights in Biological Activities Pp. 2517
M.M.M. Pinto, M.E. Sousa and M.S.J. Nascimento
[Abstract]


Xanthones as Antimalarial Agents: Discovery, Mode of Action, and Optimization Pp. 2539
M. Riscoe, J.X. Kelly and R. Winter
[Abstract]




Abstracts

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Editorial

The xanthone structure is one of the most interesting frameworks since a large number of the substituents, depending on their chemical nature and position on the aromatic rings, can lead to a myriad of biological activities of its derivatives.

As a large number of naturally-occurring and synthetic xanthones with interesting biological and pharmacological activities have been reported in the past years, this group of compounds should deserve special attention. Consequently, this special issue will start with the xanthone derivatives isolated from various sources in the past five years with emphasis on the new structures and some relevant biological activities.

Besides natural xanthones with substitution patterns controlled by the biosynthetic pathways, a number of xanthone derivatives, even with more complex structures, have been obtained by classic and biomimetic synthesis. As the synthetic methods for xanthones and related derivatives have been evolved constantly, it is pertinent to examine thoroughly the methodology for the synthesis of these compounds.

Equally important are the techniques for structure elucidation of xanthones, especially for the more complex structures. Thus, a variety of modern NMR techniques currently used for structure elucidation of xanthones and their derivatives are also discussed. X-ray crystallography has also found its place in structure elucidation of xanthones; consequently we have included this chapter.

Since the ultimate goal of this issue is the potential application of this group of compounds in Medicinal Chemistry, the final chapters are dedicated to the new insights of their biological activities. Finally, it could not be more appropriate to choose a topic emphasizing the recognition of xanthones as potential new antimalarial agents as the closing chapter.

I am very optimistic that all the topics in this special issue will arouse the interest of all the readers and that xanthones will find their outstanding place in Medicinal Chemistry in the near future.

As a guest editor, I would like to deeply thank all the contributing authors of this issue for their valuable time and effort. My special thanks also go to all the experts who have accepted to act as referees of the articles. Their thorough work and criticism have contributed to a success of this issue.

Madalena M. M. Pinto
Faculty of Pharmacy, University of Porto
Rua Aníbal Cunha, 164
4050-047 Porto
Portugal
E-mail: madalena@ff.up.pt


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Naturally-Occurring Xanthones: Recent Developments
L.M.M. Vieira and A. Kijjoa

A literature survey covering the report of naturally occurring xanthones from January 2000 to December 2004, with 219 references, is presented in this review. Among 515 xanthones reported in this period, 278 were new natural xanthones. These xanthones have been identified from 20 families of higher plants (122 species in 44 genera), fungi (19 species) and lichens (3 species). The structural formulas of 368 identified xanthones, their distribution and a brief mention of their biological properties are also included.


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Synthesis of Xanthones: An Overview
M.E. Sousa and M.M.M. Pinto

Among the known synthetic routes to obtain xanthones, the Grover, Shah, and Shah reaction, the cyclodehydration of 2, 2’-dihydroxybenzophenones and electrophilic cycloacylation of 2-aryloxybenzoic acids are the most popular methods. Due to important biological applications of xanthones, some synthetic strategies leading to more complex derivatives have been widely explored in the past years. Thus, the purpose of this review is to report some recent improvements of the classical synthetic methods as well as of some non-classical methods to obtain simple oxygenated xanthones. The strategies for introduction of substituents into the xanthonic nucleus are also summarized. Furthermore, different approaches used to synthesize complex structures, with an emphasis on the total synthesis of bioactive natural products, accomplished in the last twenty years, are also discussed. Besides the synthesis of xanthones, the reactivity of the xanthonic nucleus and its role as a key intermediate for the synthesis of other important classes of compounds are also highlighted.


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Structure Elucidation of Xanthone Derivatives: Studies of Nuclear Magnetic Resonance Spectroscopy
A.M.S. Silva and D.C.G.A. Pinto

¹H and ¹³C NMR spectra remain the first tool used by chemists to perform the structure elucidation of their products on a routine basis. It is common to provide NMR data on both proton and carbon spectra based on one-dimensional experiments, but often only proton resonances are assigned. The increasing complexity of natural compounds and their synthetic related derivatives imply the use of some more recent 1D and 2D NMR techniques.

The purpose of this review is to describe the main NMR features of the most common and important classes of xanthones and also to discuss the application of several 1D and 2D NMR techniques in the structure elucidation of these compounds. A brief discussion of these NMR techniques from the point of view of structure elucidation of organic compounds will also be considered. The calculated NMR chemical shifts in the structure elucidation of xanthones and the use of NMR to study their mode of action in biological activities will be also described.


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Xanthones–A Structural Perspective
L. Gales and A.M. Damas

Xanthones, synthesized or isolated from a natural source, display a wide range of biological and pharmacological activities. In a few cases, their chemical characterization has involved the structure elucidation by single crystal X-ray diffraction. The purpose of this review is to assess in detail this three-dimensional structural data, and thus contribute to a better understanding of the molecular mechanisms involved in the different biological activities presented by xanthones.


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Xanthone Derivatives: New Insights in Biological Activities
M.M.M. Pinto, M.E. Sousa and M.S.J. Nascimento

Xanthones or 9H-xanthen-9-ones (dibenzo-γ-pirone) comprise an important class of oxygenated heterocycles whose role is well-known in Medicinal Chemistry. The biological activities of this class of compounds are associated with their tricyclic scaffold but vary depending on the nature and/or position of the different substituents. In this review, an array of biological/pharmacological effects is presented for both natural and synthetic xanthone derivatives, with an emphasis on some significant studies on structure-activity relationships. The antitumor activity of some xanthones as well as the related targets, particularly PKC modulation studies, is also discussed in detail. Examples of the "hit" compounds involved in cancer therapy, namely DMXAA, psorospermin, mangiferin, norathyriol, mangostins, and AH6809, a prostanoid receptor antagonist, are also mentioned. Finally, a historical perspective of these xanthonic derivatives, their relevance as therapeutic agents and/or their uses as pharmacological tools and as extract components in folk medicine are also highlighted.


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Xanthones as Antimalarial Agents: Discovery, Mode of Action, and Optimization
M. Riscoe, J. X. Kelly and R. Winter

It is believed that at no time in the history of the human race malaria has been absent. This disease, which is caused by protozoa of the genus Plasmodium, in all likelihood has been responsible for the death of about half of all people who ever lived. Even today, after attempts at intervention on a worldwide scale, malaria remains the most significant parasitic disease in the tropics and sub-tropics, where it causes at least 500 million clinical episodes and claims 1.5 million lives each year, mostly young children and pregnant women. Widespread resistance to the best and least expensive antimalarials, chloroquine and S/P (i.e., a combination of sulfadoxine and pyrimethamine), combined with an increasing tolerance to insecticides in the mosquito vector, threaten a global malaria tragedy unless new countermeasures are developed. For malaria therapy, the great panacea would be the development of a long-lasting vaccine, but until this becomes a reality, people living in and traveling to endemic regions must rely on a dwindling cache of more expensive drugs; many beyond the economic reach of impoverished people living in malarious regions of the world.

Our course to recognition of xanthones as potential antimalarial agents took a rather circuitous route, involving both serendipity and empiricism, and is described together with mechanistic details of drug action. From a chance encounter with a sea urchin collected near the city of Cannon Beach on the Oregon coast to naturally occurring and functionalized xanthones, it is revealed how these compounds target the Plasmodium parasite’s most vulnerable feature - the digestive vacuole.