Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury. The cardioprotective effects of IMD-0354 include not only reduction of harmful neutrophil accumulation in myocardium but also inhibition of harmful cytokine and chemokine production by cardiomyocytes.

In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.

Further development of the potent carborane-containing estrogenic agonists described here, having a new skeletal structure and unique characteristics, should yield novel therapeutic agents, especially selective estrogen receptor modulators. Furthermore, the suitability of the spherical carborane cage for binding to the cavity of the estrogen receptor-alpha ligand-binding domain should provide a basis for a similar approach to developing novel ligands for other steroid receptors.

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Synthetic urea derivatives such as N-phenyl-N′-(4-pyridyl)urea (4PU) and N-(2-chloro-4-pyridyl)-N′-phenylurea (4PU30) have strong cytokinin activities. Using tritiated 4PU30 as a probe, we previously established the presence of a cytokinin-specific binding protein (CSBP) of high affinity (K a for 4PU30 ϭ 4ϫ10 10 M Ϫ1 ) in the soluble fraction of etiolated mung bean seedlings [Nagata, R., Kawachi, E., Hashimoto, Y. & Shudo, K. (1993) Biochem. Biophys. Res. Commun. 191, 543Ϫ549]. In this report, we purified CSBP by the use of 4PU-Sepharose 4B, an affinity gel liganded with 4PU. We determined partial amino acid sequences of CSBP and isolated its cDNA by reverse-transcription (RT) PCR. The cDNA encoded a protein with a calculated molecular mass of 17 kDa. A data base homology search revealed that CSBP is a novel member of a major pollen allergen/pathogenesis-related protein family. Recombinant CSBP was expressed in Escherichia coli and was confirmed to bind specifically to cytokinins.Keywords : cytokinin; binding protein; purification; cDNA cloning ; recombinant protein.Cytokinins are plant growth hormones that control the proliferation and differentiation of plants [1,2]. Natural cytokinins include purine analogues such as zeatin and N 6 -(∆ 2 -isopentenyl)-adenine, which exert potent and specific biological activities at nanomolar concentrations. We have found a series of synthetic urea derivatives with very potent cytokinin activity, such as N-. 4PU30 possesses activity almost equivalent to that of natural purine-type cytokinins, while 4PU1080 possesses much stronger activity. In the tobacco callus growth test, the optimum concentrations of 4PU, 4PU30 and 4PU1080 were 0.5 µM, 4 nM and Ͻ 1 nM, respectively [4]. At first glance, the chemical structures of urea-type and purine-type cytokinins are different. However, both urea-type and purinetype cytokinin antagonists inhibited the biological responses of both types of cytokinins [5], suggesting that both structural types of cytokinins share a common molecular mechanism of action. Lineweaver-Burk analysis of the inhibitory effects of these antagonists and the quantitative structure/activity relationships Note. The novel nucleotide sequence data reported in this paper have been submitted to the DDBJ/EMBL/GenBank nucleotide sequence databases and are available under accession numbers AB012218, AB012219 and AB012220. Y. Fujimoto and R. Nagata contributed equally to this publication.[6] also suggested that urea-type and purine-type cytokinins have a common site of action. However, despite the potent and specific biological activities of these cytokinins, and the accumulated data on the structure/activity relationships of a variety of cytokinin structures, the molecular mechanisms of their biological actions have not been fully elucidated.Various kinds of soluble cytokinin-binding proteins have been found in various plant species using purine-type cytokinins as probes [7Ϫ14]. However, most of these proteins binds potent cytokinins with association constants (K a's) of les...

Introduction.The carboranes (dicarba-closo-dodecaboranes) 1 exhibit remarkable thermal stability, are resistant to attack by most types of reagents, and are generally biologically inactive. Their icosahedral geometry, in which the carbon and boron atoms are hexacoordinated, accounts for these unusual properties, which make such molecules and their carbon and boron derivatives uniquely suitable for several specialized applications, including synthesis of polymers for hightemperature use and neutron-shielding purposes. 2 In the field of medical and pharmaceutical sciences, incorporation of large numbers of boron atoms into tumor cells for boron neutron capture therapy (BNCT) 3 has attracted much interest in recent years. For this purpose, various compounds have been synthesized by adding carborane units to nucleic acids, 4 amino acids, 5 etc. In contrast, little attention has been paid to the possible use of carboranes as components of biologically active molecules. The exceptionally hydrophobic character and spherical geometry of carboranes may allow their use as a hydrophobic pharmacophore in biologically active molecules which interact hydrophobically with receptors. Recently, we have reported the first example of design, synthesis, and biological evaluation of retinoids containing a carborane cage as a hydrophobic pharmacophore. 6 In this article, we describe the synthesis and biological evaluation of novel carboranecontaining estrogenic agonists which are more potent than 17β-estradiol.Estrogen (17β-estradiol, 1) is an important hormone that mediates a wide variety of cellular responses through its binding to a specific nuclear estrogen receptor (ER). The hormone-bound ER forms an active dimer, which functions as a transcription factor that mediates biological response by binding to specific promoter elements of DNA to initiate gene transcription. Compounds that either induce or inhibit cellular estrogen responses have potential value as biochemical tools and candidates for drug development.

Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.

Alzheimer’s disease(AD) is associated with a variety of pathophysiological features, including amyloid plaques, inflammation, immunological changes, cell death and regeneration processes, altered neurotransmission, and age-related changes. Retinoic acid receptors (RARs) and retinoids are relevant to all of these. Here we review the pathology, pharmacology, and biochemistry of AD in relation to RARs and retinoids, and we suggest that retinoids are candidate drugs for treatment of AD.