Physiological and Pharmacological overview of the Gonadotropin Releasing Hormone

Gonadotropin-releasing Hormone (GnRH) is a decapeptide responsible for the control of the reproductive functions. It shows C- and N-terminal aminoacid modifications and two other distinct isoforms have been so far identified. The biological effects of GnRH are mediated by binding to highaffinity G-protein couple receptors (GnRHR), showing characteristic very short C tail. In mammals, including humans, GnRH-producing neurons originate in the embryonic nasal compartment and during early embryogenesis they undergo rapid migration towards the hypothalamus; the increasing knowledge of such mechanisms improved diagnostic and therapeutic approaches to infertility. The pharmacological use of GnRH, or its synthetic peptide and non-peptide agonists or antagonists, provides a valid tool for reproductive disorders and assisted reproduction technology (ART). The presence of GnRHR in several organs and tissues indicates additional functions of the peptide. The identification of a GnRH/GnRHR system in the human endometrium, ovary, and prostate has extended the functions of the peptide to the physiology and tumor transformation of such tissues. Likely, the activity of a GnRH/GnRHR system at the level of the hippocampus, as well as its decreased expression in mice brain aging, raised interest in its possible involvement in neurogenesis and neuronal functions. In conclusion, GnRH/GnRHR appears to be a fascinating biological system that exerts several possibly integrated pleiotropic actions in the complex control of reproductive functions, tumor growth, neurogenesis, and neuroprotection. This review aims to provide an overview of the physiology of GnRH and the pharmacological applications of its synthetic analogs in the management of reproductive and non-reproductive diseases

Impiego di biocatalizzatori per trasformazioni selettive nella sintesi di molecole farmacologicamente attive

Nel corso della sintesi di composti farmacologicamente attivi che presentano strutture polifunzionali e contengono uno o più centri stereogenici sono richieste trasformazioni chemoselettive, regioselettive, stereoselettive realizzabili attraverso l’impiego di biocatalizzatori (enzimi purificati o microrganismi). Scopo del nostro lavoro è stato l’ottenimento di alcuni principi farmacologicamente attivi con metodi biocatalitici che avrebbero potuto apportare miglioramenti, rispetto alle preparazioni già note, in termini di rese e di semplificazione della via di sintesi. Con l’utilizzo della lipasi da Pseudomonas fluorescens sono stati ottenuti i sintoni enantiomericamente puri per l’ottenimento dell’(R) e (S)-argatroban, un antitrombotico sintetico. L’utilizzo del microorganismo Saccharomyces cerevisiae ha consentito la preparazione del sintone otticamente puro per ottenere sia l’(S)-pramipexolo (Mirapex), un ammino tetraidrobenzotiazolo di origine sintetica utilizzato nel trattamento del morbo di Parkinson, sia l’(R)-pramipexolo (Dexpramipexolo), attualmente in fase di studio per il trattamento della SLA (Sclerosi Laterale Amiotrofica). Attraverso una trasformazione regioselettiva, catalizzata dalla proteasi Alcalase CLEA, è stato possibile preparare la capecitabina (Xeloda), un antitumorale a struttura nucleosidica

Vecuronium bromide and its advanced intermediates : a crystallographic and spectroscopic study

Vecuronium bromide (Piperidinium, 1-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(1-piperidinyl)androstan-16-yl]-1-methyl-, bromide; Norcuron®) has been extensively used in anesthesiology practice as neuromuscular blocking agent since its launch on the market in 1982. However, a detailed crystallographic and NMR analysis of its advanced synthetic intermediates is still lacking. Hence, with the aim of filling this literature gap, vecuronium bromide was prepared starting from the commercially available 3β-hydroxy-5α-androstan-17-one (epiandrosterone), implementing some modifications to a traditional synthetic procedure. A careful NMR study allowed the complete assignment of the 1H, 13C, and 15N NMR signals of vecuronium bromide and its synthetic intermediates. The structural and stereochemical characterization of 2β,16β-bispiperidino-5α-androstane-3α,17β-diol, the first advanced synthetic intermediate carrying all the stereocenters in the final configuration, was described by means of single-crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation

Elagolix analogues as potential new GnRH antagonists: design, synthesis and characterization

Elagolix is the first non-peptide orally active gonadotropin-releasing hormone (GnRH) antagonist approved for the treatment of sex-hormone dependent diseases such as endometriosis and uterine fibroids. Chemically it is an uracil-based derivative having a stereocenter with (R)-configuration and a second source of chirality, called atropisomerism, that arise from the interaction of the o-fluorine of the 5-aryl group with the methyl group at the 6-position of the uracil moiety and the electronegative oxygen atom of the carbonyl functionality, which causes a slow rotation about the C-C bond. Previous studies on two analogues of elagolix evidenced the importance of atropisomerism for this class of compounds showing a remarkable difference on the activity of the two isolated atropisomers. Since the increase in the steric hindrance or the modulation of electronic factors, which can affect the atropisomeric propensity of elagolix, have not been deeply evaluated yet, the aim of this research is the design, synthesis, characterization, and biological evaluation of new potential uracil-based GnRH antagonists to gain a deeper knowledge of the role of atropisomerism and to disclose new potential orally available GnRH antagonists. To reach this aim, the synthesis of elagolix was accomplished improving some steps of a literature procedure. Moreover, some elagolix analogues differently substituted at the 6- and/or 4-position of the uracil moiety were designed and synthetised with the support of molecular modelling techniques. Two of them present an interconversion time between the atropisomers higher than elagolix. The research work will proceed with the separation and analysis of the single atropisomers in order to understand if they are endowed with different chemical and biological properties

Insights on the atropisomeric properties of elagolix and its derivatives

Elagolix is the first non-peptide orally active gonadotropin-releasing hormone (GnRH) antagonist, approved for the treatment of sex-hormone dependent diseases such as endometriosis and uterine fibroids. Chemically it is an uracil-based derivative having a stereocenter with (R)-configuration and an additional source of chirality, called atropisomerism, arising from a restricted rotation around a C-C bond due to steric hindrance involving the o-fluorine of the 5-aryl group with the methyl and the carbonyl oxygen at 6- and 4-position of the uracil moiety, respectively (see figure below). After the recognition and characterization of the atropisomers of elagolix through spectroscopic, analytical, and theoretical techniques, the design and synthesis of some analogues differently substituted at the 6- or 4-position of the uracil moiety were carried out. The increase of the steric hindrance and/or the modulation of the electronic factors at these positions were able to affect the atropisomeric properties of this class of derivatives. Few new congeners showed atropisomeric interconversion rates higher than elagolix, which allowed their separation and analyses as single atropisomers. These outcomes contributed to shed light on the structural determinants involved in the control of the spatial arrangement of the substituents within this molecular framework, useful for future development of derivatives with higher activity

A new class of GnRH receptor modulators endowed with atropisomerism

Elagolix is the first non-peptide orally active gonadotropin-releasing hormone (GnRH) antagonist, approved for the treatment of sex-hormone dependent diseases such as endometriosis and uterine fibroids. Chemically it is an uracil-based derivative having a stereocenter with (R)-configuration and an additional source of chirality, called atropisomerism, arising from the slow rotation about the C-C bond due to the interaction of the of the o-fluorine of the 5-aryl group with the methyl at the 6-position of the uracil moiety and the electronegative oxygen atom of the carbonyl at the 4-position. After the recognition and characterization of the atropisomers of elagolix through spectroscopic, analytical and theoretical techniques, the design and synthesis of some analogues differently substituted at the 6- or 4-position of the uracil moiety were carried out. The increase of the steric hindrance and/or the modulation of the electronic factors at these positions were able to affect the atropisomeric properties of the molecule. Indeed, some of the obtained compounds show an interconversion time between the atropisomers higher than elagolix, allowing their separation and analyses as single atropisomers. The planned biological tests will provide further insight into the role of atropisomerism in this class of compounds and unveil new potential orally available GnRH antagonists

A New Chemoenzymatic Synthesis of the Chiral Key Intermediate of the Antiepileptic Brivaracetam

Brivaracetam is a new anticonvulsant compound, recently approved as an antiepileptic drug. This drug substance presents a 4-substituted pyrrolidone structure: the (4R)-configuration of the stereocenter present on the heterocyclic ring is the main target of the synthesis. The described method allows to prepare the suitable optically pure 2-substituted primary alcohol by means of a Pseudomonas fluorescens lipase-catalyzed transesterification. The obtained (2R)-alcohol was easily transformed into the (3R)-3-propylbutyrolactone, an advanced intermediate of brivaracetam. The described synthetic pathway is completed with the chromatographic methods and the NMR analyses necessary to establish the chemical and the optical purity of the intermediates and of the final lactone

Applications of Lysozyme, an Innate Immune Defense Factor, as an Alternative Antibiotic

Lysozyme is a ~14 kDa protein present in many mucosal secretions (tears, saliva, and mucus) and tissues of animals and plants, and plays an important role in the innate immunity, providing protection against bacteria, viruses, and fungi. Three main different types of lysozymes are known: the c-type (chicken or conventional type), the g-type (goose type), and the i-type (invertebrate type). It has long been the subject of several applications due to its antimicrobial properties. The problem of antibiotic resistance has stimulated the search for new molecules or new applications of known compounds. The use of lysozyme as an alternative antibiotic is the subject of this review, which covers the results published over the past two decades. This review is focused on the applications of lysozyme in medicine, (the treatment of infectious diseases, wound healing, and anti-biofilm), veterinary, feed, food preservation, and crop protection. It is available from a wide range of sources, in addition to the well-known chicken egg white, and its synergism with other compounds, endowed with antimicrobial activity, are also summarized. An overview of the modified lysozyme applications is provided in the form of tables.</jats:p

Applications of Lysozyme, an Innate Immune Defense Factor, as an Alternative Antibiotic

Lysozyme is a ~14 kDa protein present in many mucosal secretions (tears, saliva, and mucus) and tissues of animals and plants, and plays an important role in the innate immunity, providing protection against bacteria, viruses, and fungi. Three main different types of lysozymes are known: the c-type (chicken or conventional type), the g-type (goose type), and the i-type (invertebrate type). It has long been the subject of several applications due to its antimicrobial properties. The problem of antibiotic resistance has stimulated the search for new molecules or new applications of known compounds. The use of lysozyme as an alternative antibiotic is the subject of this review, which covers the results published over the past two decades. This review is focused on the applications of lysozyme in medicine, (the treatment of infectious diseases, wound healing, and anti-biofilm), veterinary, feed, food preservation, and crop protection. It is available from a wide range of sources, in addition to the well-known chicken egg white, and its synergism with other compounds, endowed with antimicrobial activity, are also summarized. An overview of the modified lysozyme applications is provided in the form of tables