Nuclear receptors (NR) comprise a family of transcription factors that regulate gene expression in a liganddependent manner. Members of the NR superfamily include receptors for steroid hormones, such as estrogens (ER) and glucocorticoids (GR), receptors for nonsteroidal ligands, such as thyroid hormones (TR) and retinoic acid (RAR), as well as receptors that bind diverse products of lipid metabolism, such as fatty acids and prostaglandins (for review, see Beato et al. 1995; Chambon 1995; Mangelsdorf and Evans 1995). The NR superfamily also includes a large number of so-called orphan receptors for which regulatory ligands have not been identified (Mangelsdorf and Evans 1995). Although many orphan receptors are likely to be regulated by small-molecular-weight ligands, other mechanisms of regulation, such as phosphorylation (Hammer et al. 1999; Tremblay et al. 1999) have also proven to be of importance. Remarkably, the sequence of the Caenorhabditis elegans genome has revealed the presence of >200 members of the NR family, suggesting a critical role of these proteins in environmental adaptation (Sluder et al. 1999). Although mammalian genomes are unlikely to contain such a large complement of these factors, >24 distinct classes of NR have been identified in humans, and these factors exert diverse roles in the regulation of growth, development, and homeostasis. Based on their importance in biology and medicine, as well as the relatively simple mechanism of regulation, NR represent one of the most intensively studied and best-understood classes of transcription factors at the molecular level. Members of the NR family regulate transcription by several mechanisms (Fig. 1). Nuclear receptors can activate or repress target genes by binding directly to DNA response elements as homoor heterodimers or by binding to other classes of DNA-bound transcription factors. A subset of NRs, including TR and RAR, can actively repress target genes in the presence or absence of ligand binding, and many NR have been demonstrated to inhibit transcription in a ligand-dependent manner by antagonizing the transcriptional activities of other classes of transcription factors. These activities have been linked to interactions with general classes of molecules that appear to serve coactivator or corepressor function. In this review, we will discuss recent progress concerning the molecular mechanisms by which NR cofactor interactions serve to activate or repress transcription.

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The coregulator exchange in transcriptional functions of nuclear receptors

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

https://www.cell.com/cell/pdf/S0092-8674(00)81575-5.pdf

PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL

The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different “orphan” receptors of unknown ligand. Ligands for some of...

https://www.physiology.org/doi/pdf/10.1152/physrev.2001.81.3.1269

Nuclear Hormone Receptors and Gene Expression

Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

Prodrugs: design and clinical applications

Signalling by all-trans retinoic acid is mediated through RXR-RAR retinoid receptor heterodimers, in which RXR has been considered to act as a transcriptionally silent partner However, we show here that in cultured NB4 (ref 6) human acute promyelocytic leukaemia cells treated with either an RAR-alpha-selective agonist alone, or certain RAR-alpha antagonists in combination with an RXR agonist, receptor-DNA binding is induced in vivo, resulting in expression of the target genes of retinoic acid as well as acute promyelocytic leukaemia protein (PML) relocation to nuclear bodies and differentiation before apoptosis These results indicate that RAR-alpha ligands can induce two separate events: one enables RXR-RAR-alpha heterodimers to bind to DNA in vivo and allows RXR agonists to act; the other induces transcriptional activity of RAR-alpha The availability of receptor-specific synthetic retinoids that can induce distinct receptor functions has potential in extending the therapeutic repertoire of retinoids

Two distinct actions of retinoid-receptor ligands

A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; 1). The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosphonate 2. Basic hydrolysis of the bis(esters) or bis(amides) provided the corresponding monoesters or monoamides. Synthesis of bis[(acyloxy)alkyl] phosphonates 10a-c was accomplished by alkylation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine. The systemic levels of PMEA following oral administration of a PMEA prodrug to rats were determined by measuring the concentration of PMEA in the urine for 48 h after administration of the prodrug. The oral bioavailability of PMEA employing this method was determined to be 7.8%. Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (> or = 40%), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA. The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (< or = 5%). Phosphonamides 5, 6, and 9 were unstable under acidic conditions and provided levels of PMEA comparable to the parent compound after oral administration. Bis[(acyloxy)alkyl] phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6%, 14.6%, and 15.4%, respectively. When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active than PMEA.

Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

There are disclosed novel oral prodrugs of phosphonate nucleotide analogs which are hydrolyzable under physiological conditions to yield compounds which are useful as antiviral agents, especially as agents effective against RNA and DNA viruses. They may also find use as antitumor agents.

Prodrugs of phosphonates

Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.

Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, and hydrates, thereof, (I) are useful as kinase modulators, including MK2 modulation, wherein one of E and F is a nitrogen atom and the other of E and F is a carbon atom, and Z is N or CR3, and R1, R2, R3, X and Y are as defined herein.

David R. Tortolani

Papers

Two distinct actions of retinoid-receptor ligands

Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

Prodrugs of phosphonates

Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.

Fused heterocyclic compounds useful as kinase modulators