Publications by authors named "Joseph Gal"

Background: The stereochemical aspects of drugs are generally recognized as fundamentally important influencers of drug action and disposition. Nevertheless, the nonproprietary names of the vast majority of stereochemically relevant therapeutic agents in the USP Dictionary of United States Adopted Names (USAN) and International Drug Names and in the WHO Drug Information listings provide no information on the stereochemical aspects.

Objective: In view of the importance of stereochemistry in drug action and disposition, it is desirable to have a nonproprietary drug nomenclature system that provides basic information on the stereochemical identity and composition of drugs.

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Louis Pasteur discovered the phenomenon of molecular chirality, based on his studies of tartrate crystals. His finding remains one of the most important discoveries in the history of chemistry and a fundamentally important chemical phenomenon, with essential implications in biology. In his 1995 book The Private Science of Louis Pasteur, the eminent historian of science Gerald L.

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In this chapter some background material concerning molecular chirality and enantiomerism is presented. First some basic chemical-molecular aspects of chirality are reviewed, after which certain relevant terminology whose use in the literature has been problematic is discussed. Then an overview is provided of some of the early discoveries that laid the foundations of the science of molecular chirality in chemistry and biology, including the discovery of the phenomenon of molecular chirality by L.

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This opening chapter recalls the history of the discoveries that led to the appreciation of the nature and importance of molecular chirality in biology, as well as the development of stereochemistry as an interdisciplinary field connecting chemistry and biology. The discoveries described cover roughly the period of ca. 1840-1940, although certain relevant events of earlier or later times are also addressed.

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In 1886, Italian chemist Arnaldo Piutti isolated, for the first time, d-asparagine, the enantiomer of the known l-asparagine. He obtained 100 g of D-asparagine from 6500 kg of vetches. Using an ingenious synthetic scheme, Piutti established the chemical structure of asparagine and demonstrated that his isolation of D-asparagine from plants was not the result of the racemization of L-asparagine during the extraction procedure.

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Asymmetric objects are necessarily chiral, but a structure may be chiral and not asymmetric if it possesses one or more proper rotation axes. Chiral but not asymmetric molecules are important in chemistry and its applications, but no suitable term exists for the designation of such structures, and their terminology in the literature is confused and chaotic. Dissymmetric has been redefined by some authors as "chiral but not asymmetric," in conflict both with Pasteur's definition of the term as "not superposable on its mirror image" (without other restrictions, i.

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Itraconazole is an antifungal drug widely used in a variety of fungal infections, which have become a significant public-health problem in recent decades. Itraconazole is a chiral drug consisting of two diastereoisomeric racemates, i.e.

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Louis Pasteur resolved sodium ammonium (±)-tartrate in 1848, thereby discovering molecular chirality. Although hindered by the primitive state of organic chemistry, he introduced new terminology and nomenclature for his new science of molecular and crystal chirality. He was well prepared for this task by his rigorous education and innate abilities, and his linguistic achievements eventually earned him membership in the supreme institution for the French language, the Académie française.

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Very few antagonists have been identified for the human pregnane X receptor (PXR). These molecules may be of use for modulating the effects of therapeutic drugs, which are potent agonists for this receptor (e.g.

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Louis Pasteur presented his historic memoir on the discovery of molecular chirality to the Académie des sciences in Paris on May 22nd, 1848. The literature, however, nearly completely ignores this date, widely claiming instead May 15th, 1848, which first surfaced in 1922 in Pasteur's collected works edited by his grandson Louis Pasteur Vallery-Radot. On May 21st, 1848, i.

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Nearly a decade after discovering molecular chirality in 1848, Louis Pasteur changed research direction and began investigating fermentations. Conflicting explanations have been given for this switch to microbiology, but the evidence strongly suggests that Pasteur's appointment in 1854 to the University of Lille--an agricultural-industrial region where fermentation-based manufacturing was of great importance--and an appeal for help in 1856 by a local manufacturer experiencing problems in his beetroot-fermentation-based alcohol production played a significant role. Thus began, in late 1856, Pasteur's pioneering studies of lactic and alcoholic fermentations.

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Enantiomorphism and enantiomorphous were the first enantio-based terms, introduced 150 years ago, by Carl Friedrich Naumann, a German crystallographer, to refer to non-superposable mirror-image crystals. The terminology was not adopted by Pasteur, the discoverer of molecular chirality, and was not embraced at first in the stereochemical context, until it was accepted in 1877 by Van't Hoff in the German edition of his proposal for the tetrahedral asymmetric carbon atom. In the 1890s the use of enantio terms began to spread in the research literature, and many new derivatives of Naumann's original two terms were subsequently introduced.

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The absolute configuration assignments of three antifungal agents, (+)-(2R,4S)-ketoconazole, (+)-(2R,4S)-itraconazole (with (S)-configuration at the sec-butyl group) and (+)-(S)-miconazole nitrate have been confirmed by using vibrational circular dichroism (VCD). For these three antifungal drugs, this study also provides evidence for the most abundant conformations of miconazole and for the relative conformations of the azole, dichlorophenyl, and methoxyphenyl groups in ketoconazole and itraconazole, in chloroform solution.

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In 1992, the Food and Drug Administration (FDA) issued new guidelines governing stereoisomerism in new-drug development. The guidelines strongly encourage the development of single isomers and discourage stereoisomeric (eg, racemic) mixtures. As a result, most new chiral drugs are being developed as single enantiomers (ie, single isomers).

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Single-isomer drugs are of great importance in modern therapeutics. In this article, the basics of the underlying phenomenon are explained. Some molecules are chiral, ie, their mirror image is not superposable on the original.

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Racemic ketoconazole (KTZ) was the first orally active azole antifungal agent used in clinical practice and has become widely used in the treatment of mucosal fungal infections associated with AIDS immunosuppression and cancer chemotherapy. However, the use of KTZ has been limited because of adverse drug-drug interactions. KTZ blocks ergosterol biosynthesis by inhibiting the fungal cytochrome P450 (CYP51).

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Methadone is a clinically used opioid agonist that is oxidatively metabolized by cytochrome P450 (CYP) isoforms to a stable metabolite, EDDP. Methadone is a chiral drug administered as the racemic mixture of (R)-(-)- and (S)-(+)-methadone, but (R)-methadone is the active isomer. The cytochrome P450 (CYP) isoform involved in methadone's metabolism is thought to be CYP3A4, but human drug-drug interaction studies are not consistent with this.

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