A Photohormone for Light-Dependent Control of PPARα in Live Cells.

Photopharmacology enables the optical control of several biochemical processes using small-molecule photoswitches that exhibit different bioactivities in their cis- and trans-conformations. Such tool compounds allow for high spatiotemporal control of biological signaling, and the approach also holds promise for the development of drug molecules that can be locally activated to reduce target-mediated adverse effects. Herein, we present the expansion of the photopharmacological arsenal to two new members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα and PPARδ. We have developed a set of highly potent PPARα and PPARδ targeting photohormones derived from the weak pan-PPAR agonist GL479 that can be deactivated by light. The photohormone 6 selectively activated PPARα in its trans-conformation with high selectivity over the related PPAR subtypes and was used in live cells to switch PPARα activity on and off in a light- and time-dependent fashion.

A Scalable and Versatile Synthesis of Oxime-Based Hormone Dimers and Gels for Sustained Release.

Well-defined steroid hormone dimers and organogels were produced via a facile and scalable synthesis using oxime click chemistry. The versatile synthetic procedure extends to a wide range of hormones and linker groups exemplified here through the synthesis of cortisol- and progesterone-dimers linked via hydrophobic, hydrophilic or functional groups. This method was also extended to the synthesis of cortisone-based organogels. Owing to the dynamic nature of the oxime bond, the hormone-based materials are degradable via acidic hydrolysis and transoximination representing new materials for the controlled release of steroid hormones.

Synthesis and chemical reactions of the steroidal hormone 17α-methyltestosterone.

Structural modifications of natural products with complex structures like steroids require great synthetic effort. A review of literature is presented on the chemistry of the steroidal hormone 17α-methyltestosterone that is approved by Food and Drug Administration (FDA) in the United States as an androgen for estrogen-androgen hormone replacement therapy treatment. The analog also offers special possibilities for the prevention/treatment of hormone-sensitive cancers. The testosterone skeleton has important functionalities in the molecule that can act as a carbonyl component, an active methylene compound, α,ß-unsaturated enone and tertiary hydroxyl group in various chemical reactions to access stereoisomeric steroidal compounds with potent activity. In addition, microbiological methods of synthesis and transformation of this hormone are presented.

Synthesis and spectroscopic analysis of a stereoisomer library of the phytophthora mating hormone α1 and derived bis-Mosher esters.

Fluorous mixture synthesis provided all eight diastereomers of the phytophthora hormone α1 with the R configuration at C11 as individual samples after demixing and detagging. The library of all possible bis-Mosher esters (16) was then made by esterification. Complete sets of (1)H, (13)C, and (for the Mosher esters) (19)F NMR spectra were recorded, assigned, and compared with each other and with published spectra. Not all of the spectra are unique, and the (1)H NMR spectra of the Mosher esters provided the most information. The previous assignment of the natural sample as an "all-R" stereoisomer mixed with its 3S-epimer was confirmed.

Total synthesis of Phytophthora mating hormone α1.

Total synthesis of Phytophthora mating hormone α1 (1) has been demonstrated. The required stereochemistries (methyl) are achieved by applying CuI-(S)-Tol-BINAP-catalyzed conjugate addition of Grignard reagents to α,ß-unsaturated esters.

Stereoselective synthesis of some methyl-substituted steroid hormones and their in vitro cytotoxic activity against human gastric cancer cell line MGC-803.

A series of 3-, 7-, 15-, and 16-methyl-substituted steroid analogs were synthesized via a highly stereoselective 1,6-conjugate addition. Under the catalysis of CuBr, AlMe(3) reacted with four steroid dienone precursors to afford either the corresponding alpha-epimer of C-3 and C-7 methyl-substituted steroids as the major products, and the ratio of alpha/beta was up to 10/1. No beta-epimer has been detected for methyl addition at C-16. However, under the same reaction conditions, enantioselective methyl addition at C-15 afforded the 15beta-epimer as the major product. The preliminary SAR analysis showed that the methyl substituents at C-7alpha and C-15beta positions lead to a dramatical increase in potency against human gastric cancer cell line MGC-803.

Allosteric modulators of glycoprotein hormone receptors: discovery and therapeutic potential.

The glycoprotein hormones, luteinizing hormone, follicle-stimulating hormone and thyroid stimulating hormone, are important regulators of reproductive and metabolic processes. However, because of the nature of their ligand-receptor interactions that contain multiple contact sites, classical small molecule drug discovery strategies have not been successful. However, recent advances in screening and combinatorial chemistry strategies have identified chemical series that act allosterically as positive, negative or mixed modulators of the glycoprotein hormone receptors. This review will discuss the discovery and highlight the currently known series of allosteric modulators to this therapeutically important family of G-protein coupled receptors. Lastly, we will present potential mechanisms whereby the different series could modulate receptor function in the context of currently held theory and known structure of G protein-coupled receptors.

Synthesis of somatostatin mimetics based on 1-deoxynojirimycin.

The synthesis of novel somatostatin mimetics from 1-deoxynojirimycin (DNJ) is described. The dipeptide mimetic, which respectively displayed the side chains of tryptophan and lysine at the nitrogen and O6 atoms of the iminosugar scaffold is a ligand (K(i)=3.2 microM) for the human somatostatin receptor subtype 4 (hSSTR4) but has lower affinity (K(i)>100 microM) for hSSTR5. A benzylated analogue of the Trp-Lys mimetic displays higher affinity for hSSTR5 (K(i)=5 microM).

Synthesis of 6,19-cyclopregnanes. Constrained analogues of steroid hormones.

A procedure for the synthesis of 6,19-cyclopregnanes is described involving an intramolecular alkylation reaction of Delta(4)-3-keto steroids with a 19-mesylate in the presence of KOH in isopropanol. Three 6,19-cyclopregnanes were prepared (4, 5 ,9); in the rat, 6,19-cycloprogesterone (4) and its 21-hydroxy derivative 5 displaced [3H]-dexamethasone from glucocorticoid receptors, the former compound being more active. Both compounds did not compete with [3H]-aldosterone for kidney mineralocorticoid receptors nor with [3H]-R5020 for uterus progesterone receptors.

Difluoromethyl analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation.

Three new Vitamin D analogs 3-5 incorporating a -CHF(2) group as an -OH surrogate have been prepared. Two of these new analogs (3 and 5) are strongly antiproliferative toward murine keratinocytes and are approximately 50 times less calciuric in vivo than the natural hormone calcitriol. The transcriptional activity of the 25-CHF(2) analog 3 is higher than that of the 1-CHF(2) analog 4.

Old hormones of the insulin family as new developmental signals

La insulina fue identificada como una hormona anabólica pancreática,responsable de la homeostasis de la glucosa, y el Factor de Crecimiento similar ala Insulina tipo I (IGF-I) como el mediador de la acción de la Hormona deCrecimiento postnatalmente. Nuevas informaciones moleculares, farmacológicas yembriológicas han ampliado el concepto del papel fisiológico de estas hormonasy sus moléculas relacionadas, particularmente del precursor de la insulina, laproinsulina, en el desarrollo de vertebrados. Los estudios de nuestro laboratoriohan demostrado que la proinsulina está expresada y es funcional antes deque aparezca el páncreas. La expresión de proinsulina en los embriones de polloy ratón muestra regulación transcripcional y post-transcripcional muy fina, conla generación de transcritos específicos embrionarios que se traducen de formasdistintas. El producto de estos mRNAs se mantiene como proinsulina sinprocesar, que protege a las células de la apoptosis excesiva durante la neurulación.En contraste, el IGF-I está expresado más tarde que la proinsulina en el embriónde pollo y comienza en el sistema nervioso. En el embrión de ratón, la generaciónde células madre neurales en cultivo ha permitido estudiar el papel de estasmoléculas en la proliferación y diferenciación de precursores neurales. Laproinsulina y el IGF-I pueden cooperar con los mitógenos (EGF y FGF2) en elcontrol de la proliferación de células madre/precursores mientras que el IGF-I esun factor esencial para la diferenciación neural. Los ratones deficientes en IGF-Ipresentan alteración de la citoarquitectura del bulbo olfatorio con disminución delnúmero de neuronas mitrales y glía radial anormal. Este artículo da una visiónglobal del importante papel de las proteínas de la familia de la insulina en eldesarrollo

Insulin was first identified as an anabolic pancreatic hormone responsible forglucose homeostasis, and Insulin-like Growth Factor (IGF-I) as the mediator of theaction of Growth Hormone on postnatal growth. New molecular, pharmacologicaland embryological information has broadened the scope of the physiological rolesof these hormones and their related molecules, particularly the insulin precursorproinsulin, during vertebrate development. Studies in our laboratory havedemonstrated that proinsulin is expressed and functional before emergence of thepancreas. Proinsulin gene expression in the chick and mouse embryo shows finetranscriptional and postrancriptional regulation with generation of specificembryonic transcripts which are differentially translated. The protein productremains as unprocessed proinsulin that protects the cells from excessive apoptosisduring neurulation. In contrast, IGF-I is expressed later than proinsulin in thechick embryo and it starts in the nervous system. In the mouse embryo, generationof olfactory bulb stem cells in culture has allowed the study of these molecules’role in the proliferation and differentiation of neural precursors. Proinsulin andIGF-I can cooperate with mitogens (EGF and FGF2) in the control of stem/precursor cells proliferation and IGF-I is an essential factor for neuraldifferentiation. Mice deficient in IGF-I present a disruption of olfactory bulbcytoarchitecture, with decreased numbers of mitral cells and abnormal radial glia.This article gives thus an overview of the important role of insulin family proteinsin development

Gender differences in corneal thickness values

The aim was to study gender differences in corneal thickness. We analysed the corneal thickness of 100 corneas of 100 healthy subjects (mean age 30.87±7.76 years; range, 19 to 54 years old) with the Orbscan Topography System II (Orbscan, Inc., Salt Lake City, UT. USA). The means of five consecutive measurements of the central and paracentral corneal thickness were obtained. No significant differences in mean corneal thickness between women and men at central (p=0.477), nasal (p=0.247), superonasal (p=0.242), inferonasal (p=0.554), temporal (p=0.538), superotemporal (p=0.524) and inferotemporal (p=0.860) corneal locations were found. In sum, there are no differences in mean central and paracentral corneal thickness values between women and men (AU)

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Studies on the synthesis and anti-Osteoporosis of estrogen-GHRPs linkers.

The linkers of estrogen-GHRPs were prepared by the combination of estradiol, estrone, TyrGlyGlyPheLeuOH, and TyrGlyGlyPheLeuOH. Their anti-osteoporosis effect was evaluated by analyzing the data, for instance the weight of the body, femur, femur ash, the content of calcium and phosphor in the femur, the content of calcium and ALP activity in the serum, obtained from the corresponding bioassay in vivo. The results indicated that the anti-osteoporosis potency for estradiol, estrone, TyrGlyGlyPheLeuOH and TyrGlyGlyPheLeuNH(2) may be totally enhanced each other via the corresponding linkers.

Research on synthetic peptides of pharmaceutical interest at IDR.

Research on synthetic peptides at the Institute for Drug Research (IDR) is exemplified by an overview of the projects that resulted in significant results.

Highly potent growth hormone secretagogues: hybrids of NN703 and ipamorelin.

A series of NN703 analogues with lysine mimetics combined with naphthyl- or biphenylalanine in the core has been prepared and tested in vitro in a rat pituitary cell based assay and subsequently in vivo in pigs in a single dose at 50 nmol/kg. Re-introduction of certain pharmacophores in the C-terminal of NN703, which were originally removed during optimisation for oral bioavailability, led to unexpectedly potent compounds in vitro as well as in vivo.

Growth hormone-releasing hormone and growth hormone secretagogue-receptor ligands: focus on reproductive system.

Growth hormone-releasing hormone (GHRH) and somatostatin are the most important hypothalamic neurohormones controlling growth hormone (GH) secretion. Several neurotransmitters and neuropeptides also play an important role in the control of GH secretion, mainly acting via modulation of GHRH and somatostatin. In the past two decades, particular attention has been given to a new family of substances showing a strong GH-releasing effect: GH secretagogues (GHSs). GHSs increase GH secretion in a dose- and age-related manner after iv and even oral administration. The endocrine effects of GHSs, are not fully specific for GH; they show, in fact, prolactin- (PRL), adenocorticotropic hormone- and cortisol-releasing effects. Specific GHS receptors are present in both the central nervous system and peripheral tissues, where they mediate several extraendocrine effects of GHSs. The isolation of these "orphan" receptors suggested the existence of an endogenous GHS-like ligand that could be represented by a recently discovered gastric peptide, named ghrelin. The interaction between GHSs and GHRH at the central level and in the pituitary gland, but not at peripheral level, has clearly been shown. Because GHRH and GHS receptors share the same localization in some peripheral tissues, they may have some interactions even at this level.

Selective thyromimetics: tissue-selective thyroid hormone analogs.

Thyroid hormone coordinates a diverse array of physiological events in development and homeostasis. Many of the actions of thyroid hormone are tissue-specific and are primarily mediated by a panel of thyroid hormone receptor isoforms that are expressed in different ratios in different tissues. Because these tissue-specific hormone signaling pathways are linked to a number of metabolic diseases, the development of synthetic thyroid hormone analogs that have tissue-selective hormone actions (i.e., selective thyromimetics) is highly desirable. There is a powerful collection of tools available today for this pursuit including efficient receptor binding and activation assays, receptor structures and a variety of thyroid hormone receptor knockout mice. The medicinal chemistry efforts in this area demonstrate that selective thyromimetics can be produced from a variety of approaches. These compounds are proving useful as probes to better define thyroid hormone actions and may one day find use in the clinic for the treatment of metabolic disorders.

Growth hormone secretagogues derived from NN703 with hydrazidesas c-terminal.

A series of GH secretagogues based on modifications in the C-terminal of NN703 is reported. The C-terminal N-methyl amide of NN703 has been replaced with alkylated hydrazides in order to decrease the volume of distribution and identify GH secretagogues with shorter duration of action. Most of the prepared compounds show high potency in a rat pituitary assay. Subsequent to an initial in vivo screening in dogs, four compounds were selected for further pharmacological and pharmacokinetic evaluation. The four compounds showed oral bioavailability around 35% and equipotency in vitro compared to NN703. The relationship between lipophilicity and volume of distribution is discussed and it is speculated whether the lower volume of distribution is attributed to the observed higher in vivo potency and shorter plasma elimination half-life.