Author
Arnaud Parenty
Other affiliations: Centre national de la recherche scientifique
Bio: Arnaud Parenty is an academic researcher from Institut de Chimie des Substances Naturelles. The author has contributed to research in topics: Total synthesis & Diglyme. The author has an hindex of 7, co-authored 9 publications receiving 630 citations. Previous affiliations of Arnaud Parenty include Centre national de la recherche scientifique.
Papers
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398 citations
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TL;DR: Products A. Parenty,† X. Moreau,†,§ Gilles Niel,‡ and J.-M.
Abstract: Products A. Parenty,† X. Moreau,†,§ Gilles Niel,‡ and J.-M. Campagne*,†,‡ †Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, F-91198 Gif sur Yvette, France Institut Lavoisier de Versailles, UMR CNRS 8180, Universite ́ de Versailles-Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France ‡Institut Charles Gerhardt, UMR5253, Ecole Nationale Supeŕieure de Chimie, 8 rue de l’Ecole Normale, F-34296 Montpellier, France
146 citations
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TL;DR: Xestoquinone exhibited a weak in vivo activity in Plasmodium berghei NK65 infected mice and was toxic at higher doses, and in vitro antiplasmodial activity against a FCB1 P. falciparum strain with an IC(50) of 3 microM and a weak selectivity index (SI 7).
74 citations
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TL;DR: A bioassay-guided fractionation led to the isolation of a derivative of homogentisic acid [methyl (2,4-dibromo-3,6-dihydroxyphenyl)acetate, 4a] which inhibited Pfnek-1 with an IC50 around 1.8 μM.
Abstract: As part of our search for new antimalarial drugs in South Pacific marine sponges, we have looked for inhibitors of Pfnek-1, a specific protein kinase of Plasmodium falciparum. On the basis of promising activity in a preliminary screening, the ethanolic crude extract of a new species of Pseudoceratina collected in Vanuatu was selected for further investigation. A bioassay-guided fractionation led to the isolation of a derivative of homogentisic acid [methyl (2,4-dibromo-3,6-dihydroxyphenyl)acetate, 4a] which inhibited Pfnek-1 with an IC50 around 1.8 μM. This product was moderately active in vitro against a FcB1 P. falciparum strain (IC50 = 12 μM). From the same sponge, we isolated three known compounds [11,19-dideoxyfistularin-3 (1), 11-deoxyfistularin-3 (2) and dibromo-verongiaquinol (3)] which were inactive against Pfnek-1. Synthesis and biological evaluation of some derivatives of 4a are reported.
32 citations
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TL;DR: Natural abundance deuterium 2D NMR spectroscopy in chiral liquid crystal was successfully used to efficiently analyze the enantiomeric composition of organic chiral building blocks involved in the syntheses of natural and synthetic bioactive products.
23 citations
Cited by
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TL;DR: This review concludes that Etherification without Cyclization and N-Alkylation should be considered as separate science, and the proposed treatment of Etherification with Cyclization as a separate science should be reconsidered.
Abstract: 10. Patented Literature 2616 10.1. Esterification 2616 10.2. Ether Formation 2619 10.2.1. Etherification without Cyclization 2619 10.2.2. Etherification with Cyclization 2624 10.3. N-Alkylation 2625 10.4. Other Reactions 2627 11. Summary and Outlook 2628 12. Note Added in Proof 2628 13. Abbreviations Used in This Review 2629 14. Acknowledgments 2629 15. Supporting Information Available 2630 16. References 2630
909 citations
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TL;DR: Recent solutions to some of the major challenges in this important area of contemporary synthesis of peptide macrocycles are reviewed.
Abstract: Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis.
820 citations
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TL;DR: The goal of this article is to put into perspective the current applications, opportunities, and challenges associated with synthetic macrocycles in drug discovery.
Abstract: Macrocycles occupy a unique segment of chemical space. In the past decade, their chemical diversity expanded significantly, supported by advances in bioinformatics and synthetic methodology. As a consequence, this structural type has now been successfully tested on most biological target classes. The goal of this article is to put into perspective the current applications, opportunities, and challenges associated with synthetic macrocycles in drug discovery. Historically, macrocyclic drug candidates have originated primarily from two sources. The first, natural products, provided unique drugs such as erythromycin, rapamycin, vancomycin, cyclosporin, and epothilone. Excellent reviews are dedicated to this class and how it inspired further synthetic and medicinal chemistry efforts; thus, it will not be covered here. From a molecular evolution standpoint, the medicinal chemistry of macrocyclic natural products usually involved direct use as a therapeutic agent or functionalization of the natural product scaffold by hemisynthesis. It parallels significant advances in the total synthesis of macrocyclic natural products during the past 2 decades. The second traditional source of macrocycles stems from peptides, some of which are natural products and, hence, also belong to the first category. Macrocyclization was recognized early in peptide chemistry as an efficient way to restrict peptide conformation, reduce polarity, increase proteolytic stability, and consequently improve druggability. Chemists accessed macrocyclic peptides with different geometries (head to tail, side chain to side chain, head to side chain), including the incorporation of nonpeptidic groups. Compelling examples of macrocyclic scaffolding of peptides include the works on somatostatins, melanocortins, and integrins, among others. Macrocyclic peptides generated several drugs from synthetic or natural sources, including octreotide, cyclosporine, eptifibatide, and caspofungin. Purely peptidic, depsipeptidic, and peptoid macrocycles will also not be covered in this article; the reader is instead referred to previous reviews. It is well understood that the boundary between synthetic macrocycles and the above categories is not always clear-cut; as a result, examples presented in the following sections could occasionally belong to one of these categories. In these cases, they were selected owing to their relevance to the perspective. Macrocycles are defined herein as molecules containing at least one large ring composed of 12 or more atoms. On the basis of standard molecular descriptors, macrocycles as a class are at the outskirts of the window generally considered optimal for good PK-ADME properties using these criteria. Indeed, their molecular weights tend to be on the higher end (often in the 500-900 g 3mol -1 range), their numbers of H-bond donors and acceptors, as well as their polar surface area (PSA), tend to be on the far side of the accepted druglike spectrum. For an equal number of heavy atoms, macrocycles inherently possess a lower number of rotatable bonds than their acyclic analogues, a beneficial feature for oral bioavailability (in the following, “acyclic” will be used in the sense of “nonmacrocyclic”). As a result, macrocycles are more conformationally restricted than their acyclic analogues, which potentially can impart higher target binding and selectivity and improved oral bioavailability (in this assessment, endocyclic bonds are considered to be nonrotatable, which is only an approximation; see ref 18). For a systematic chemoinformatic analysis of biologically active macrocycles, the reader is referred to the recent review of Brandt et al. Topologically, macrocycles have the unique ability to span large surface areas while remaining conformationally restricted compared to acyclic molecules of equivalent molecular weight. This characteristic makes them especially suited for targets displaying shallow surfaces, which can prove to be quite challenging for acyclic small molecules. Medicinal chemistry relies strategically on robust synthetic methods capable of producing an acceptable chemical diversity to adequately interrogate the chemical space of a biological target. Macrocycles are often (and rightly so) perceived as difficult to synthesize and hence deterred many medicinal chemists because of the lack of versatile synthetic platforms. The macrocyclization step is regularly plagued by low yields and often requires high dilution conditions to counterbalance entropic loss. In other words, the reduction in entropy responsible for beneficial conformational restrictions to the final molecule comes at a price during synthesis: what goes around comes around. Accordingly, the first part of this article is dedicated to the drug discovery aspects ofmacrocycles and highlights salient features of their medicinal chemistry. This section is organized by target class, a choice aimed at providing the reader an appreciation of the structural diversity generated for each class. To give the reader an appreciation of the tools available to construct macrocyclic scaffolds, the site and method of the pivotal macrocyclization step are indicated in the figures. Readers are referred to the source articles for further details. In the second part, the technologies and synthetic approaches that already have demonstrated utility or possess a high potential for macrocycle-based
638 citations
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TL;DR: The current understanding of the biology of asexual blood-stage parasites and gametocytes and the ability to culture them in vitro lends optimism that high-throughput screenings of large chemical libraries will produce a new generation of antimalarial drugs.
Abstract: Plasmodium falciparum malaria, an infectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each year in Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisinin derivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeast Asia. Renewed initiatives to eliminate malaria will benefit from an expanded repertoire of antimalarials, including new drugs that kill circulating P. falciparum gametocytes, thereby preventing transmission. Our current understanding of the biology of asexual blood-stage parasites and gametocytes and the ability to culture them in vitro lends optimism that high-throughput screenings of large chemical libraries will produce a new generation of antimalarial drugs. There is also a need for new therapies to reduce the high mortality of severe malaria. An understanding of the pathophysiology of severe disease may identify rational targets for drugs that improve survival.
510 citations
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TL;DR: Marine pharmacology research during 2005-2006 was truly global in nature, involving investigators from 32 countries, and the United States, and contributed 183 marine chemical leads to the research pipeline aimed at the discovery of novel therapeutic agents.
459 citations