Biomedical subjects

H Kagechika

Publications and source records attributed to H Kagechika.

At least 19 recordsLinked to original sources

PubMed2001

Structure-Activity study of retinoid agonists bearing substituted dicarba-closo-dodecaborane. Relation between retinoidal activity and conformation of two aromatic nuclei.

We have investigated the structure activity relationships of the potent retinoid agonist, 4-[4-(2-propyl-1,2-dicarba-closo-dodecaboran-l-yl)phenylamino]benzoic acid (BR403), which we have previously reported. Substitution of a methyl group on the aromatic nucleus or a methyl group on the nitrogen atom, or replacement of the amino group with ether, methylene, carboxyl or 1,1-ethylene greatly decreased the activity. The relatively planar conformation at the phenyl-N-phenyl moiety seems to play a critical role in the appearance of the biological activity.

Animals↗

PubMed2001

Inhibition by retinoids of antigen-induced IL-4 production in rat mast cell line RBL-2H3.

The retinoic acid receptor (RAR) agonists, Re80 and Am80, partially inhibited the antigen-induced IL-4 production by rat mast cell line RBL-2H3 in a concentration-dependent manner (0.1 to 1000 nM). Both Re80 and Am80 also reduced the antigen-induced increase in IL-4 mRNA levels. The RAR antagonist LE540 at 4 microM reversed Re80 (100 nM)- and Am80 (100 nM)-induced inhibition of IL-4 production. The retinoid X receptor agonist HX600 (1 microM) by itself did not affect IL-4 production, but enhanced the inhibitory effect of Re80 (10 nM) and of Am80 (10 nM). Cyclosporin A suppressed the antigen-induced IL-4 production almost completely at 0.3 microM. These findings indicated that the antigen-induced IL-4 production by RBL-2H3 cells is partially inhibited by retinoids via RAR-dependent mechanisms.

Animals↗

PubMed2001

Synergistic potentiation of thiazolidinedione-induced ST 13 preadipocyte differentiation by RAR synergists.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) belongs to a nuclear receptor super family that functions as a master regulator of adipocyte differentiation. PPAR gamma binds its DNA response element together with a partner, retinoid X receptor (RXR), in fat cells. Five RXR ligands (HX600, HX630, DA022, DA124, LGD1069, referred to as retinoid synergists) by themselves exhibit weak transactivation activity on the PPAR gamma response element. However, addition of PPAR gamma-specific ligand in this assay gave rise to a 5- to 13-fold increase, indicating a strong synergy between these ligands. LGD1069 was the most effective activator of the RXR/PPAR gamma heterodimer on the transactivation of the reporter gene. But, in contrast to the other four RXR ligands, LGD1069 did not show synergistic induction of ST 13 preadipocytes to adipocytes. This apparent contradiction may result from the ligand-binding property of LGD1069. In this article we discuss the fact that retinoid synergists also act as PPAR gamma synergists.

Adipocytes↗

PubMed2001

The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.

Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.

Adiponectin↗

PubMed2001

Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.

PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.

3T3 Cells↗

PubMed2001

Novel retinoidal tropolone derivatives. Bioisosteric relationship of tropolone ring with benzoic acid moiety in retinoid structure.

Several tropolone derivatives (4-7) were designed as novel retinoids on the assumption that the tropolone ring may mimic the benzoic acid moiety in retinoid structures, such as Am80 (2). Among the synthesized compounds, 5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethynyl]tropolone (7a) showed moderate potency as a differentiation-inducer of HL-60 cells. The activities of the tropolones were greatly enhanced in the presence of HX630, an RXR agonist (retinoid synergist).

Benzoates↗

PubMed2001

Alpha-glucosidase inhibitors with a 4,5,6,7-tetrachlorophthalimide skeleton pendanted with a cycloalkyl or dicarba-closo-dodecaborane group.

Previous studies of alpha-glucosidase inhibitors derived from thalidomide revealed that 4,5,6,7-tetrachloro-N-alkylphthalimide derivatives are superior lead compounds. Structure-activity relationship studies indicated that a hydrophobic group at the N(2) position is mandatory for potent activity. Accordingly, we have designed and synthesized some 4,5,6,7-tetrachloro-N-cycloalkylphthalimide and 4,5,6,7-tetrachloro-N-dicarba-closo-dodecaborane derivatives. The prepared compounds exhibited potent alpha-glucosidase-inhibitory activity. Among them, 4,5,6,7-tetrachloro-N-cycloheptylphthalimide (9) showed the most potent activity, being approximately 30 times more active than the classical inhibitor, 1-deoxynojirimycin (1).

Boranes↗

PubMed2000

Polymethylcarborane as a novel bioactive moiety: derivatives with potent retinoid antagonistic activity.

4[(Deca-B-methyl-1,12-dicarba-closo-dodecaboran-1-yl)c arbamoyl]benzoic acid and its congeners showed potent antagonistic activity at concentrations of 10(-7)-10(-8) M on the differentiation-inducing action of retinoids towards human promyelocytic leukemia HL-60 cells. This is the first example of derivatives of polymethylcarborane, which resembles C60 in size, with biological activity.

Benzoates↗

PubMed2000

Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids.

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.

Animals↗

PubMed1999

Identification of a novel class of retinoic acid receptor beta-selective retinoid antagonists and their inhibitory effects on AP-1 activity and retinoic acid-induced apoptosis in human breast cancer cells.

Four candidate retinoid antagonists (LE135, LE511, LE540, and LE550) were designed on the basis of the ligand superfamily concept and synthesized. Analysis of these related retinoids by transient transfection assay demonstrated that LE135, LE540, and LE550 are effective retinoic acid receptor (RAR) antagonists, whereas LE511 selectively induced RARbeta transcriptional activity. Both LE135 and LE540 inhibited retinoic acid (RA)-induced transcriptional activation of RARbeta, but not RARalpha, RARgamma or retinoid X receptor alpha (RXRalpha), on a variety of RA response elements. The retinoid antagonists also inhibited all-trans-RA-induced transcriptional activation of RARbeta/RXRalpha heterodimers, although they did not show any effect on transactivation activity of RXR/RXR homodimers. In ZR-75-1 human breast cancer cells, cotreatment of LE135 and LE540 with all-trans-RA inhibited all-trans-RA-induced apoptosis of the cells, further demonstrating that RARbeta plays a role in RA-induced apoptosis of breast cancer cells. We also evaluated the effect of these retinoids on AP-1 activity. Our data showed that LE135 and LE540 strongly repressed 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 activity in the presence of RARbeta and RXRalpha. Interestingly, LE550 induced AP-1 activity when RARbeta and RXRalpha were expressed in HeLa cells but not in breast cancer cells. These results demonstrate that LE135 and LE540 were a novel class of RARbeta-selective antagonists and anti-AP-1 retinoids and should be useful tools for studying the role of retinoids and their receptors.

Animals↗

PubMed1999

Potent homophthalimide-type inhibitors of B16F10/L5 mouse melanoma cell invasion.

Recently, we developed a series of novel and potent aminopeptidase inhibitors with a homophthalimide skeleton. Among them, N-(2,6-diethylphenyl)homophthalimide (PIQ-22) possesses a specific aminopeptidase-inhibiting activity more potent than that of bestatin or actinonin, as assayed in terms of hydrolysis of L-alanine 4-methylcoumaryl-7-amide (Ala-AMC) by human acute lymphoblastic leukemia MOLT-4 cells. We show here that PIQ-22 and its 2,6-dimethylphenyl derivative (PIQ-11) are more potent inhibitors of tumor cell invasion than bestatin and actinonin in a Matrigel assay using mouse melanoma B16F10/L5 cells.

Aminopeptidases↗

PubMed1999

Thiazolidinediones with thyroid hormone receptor agonistic activity.

Several thiazolidinedione derivatives (3-7) were designed and synthesized as candidate thyromimetic drugs. Among them, the dihydrogenated compounds, such as 5-2-[[4-(3-tert-butyl-4-hydroxyphenyl)oxy-3,5-diiodophenyl] ethyl]-2,4-thiazolidinedione (6b) and its 3-isopropyl analog (7b), exhibited potent thyroid hormone receptor alpha 1 (TR alpha 1) activation activity.

Animals↗

PubMed1999

Retinoid X receptor-antagonistic diazepinylbenzoic acids.

Several dibenzodiazepine derivatives were identified as novel retinoid X receptor (RXR) antagonists on the basis of inhibitory activity on retinoid-induced cell differentiation of human promyelocytic leukemia cells HL-60 and transactivation assay using retinoic acid receptors (RARs) and RXRs in COS-1 cells. 4-(5H-2,3-(2,5-Dimethyl-2,5-hexano)-5-n- propyldibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX603, 6c) is an N-n-propyl derivative of an RXR pan-agonist HX600 (6a), and exhibited RXR-selective antagonistic activity. Similar RXR-antagonistic activities were observed with 4-(5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyl- 8-nitrodibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX531, 7a) and 4-(5H-10,11-dihydro-5,10-dimethyl-2,3-(2,5-dimethyl- 2,5-hexano)-dibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX711, 8b), which also inhibited transactivation of RARs induced by an RAR agonist, Am80. These compounds inhibited HL-60 cell differentiation induced by the combination of a low concentration of the retinoid agonist Am80 with an RXR agonist (a retinoid synergist, HX600). These results indicated that HX603 (6c), and the related RXR antagonists inhibit the activation of RAR-RXR heterodimers as well as RXR homodimers, which is a distinct characteristic different from that of the known RXR antagonist, LG100754 (9).

Animals↗

PubMed1999

Dicarba-closo-dodecaboranes as a pharmacophore. Retinoidal antagonists and potential agonists.

Synthesis and biological evaluation of the first dicarba-closo-dodecaborane (carborane) derivatives of retinoids are described. Their retinoidal activity were examined in terms of the differentiation-inducing ability toward human promyelocytic leukemia HL-60 cells. High retinoidal activity (agonist or antagonist for retinoic acid receptor (RAR) requires a carboxylic acid moiety and an appropriate hydrophobic group located at a suitable position on the molecule. The 4-carboranyl-substituted compounds (7, 11) showed antagonistic activity but no agonistic activity even in the presence of the potent synergist HX630. On the other hand, the 3-carboranyl-substituted compounds (8, 12) showed potential agonistic activity, but no antagonistic activity. The results indicates that carboranes are applicable as the hydrophobic moiety of biologically active molecules.

Boron Compounds↗

PubMed1999

Dicarba-closo-dodecaboranes as a pharmacophore. Novel potent retinoidal agonists.

The synthesis and biological evaluation of the dicarba-closo-dodecaborane (carborane) derivatives of retinoids are described. Retinoidal activity was examined in terms of the differentiation-inducing ability toward human promyelocytic leukemia HL-60 cells. High retinoidal activity (agonist or antagonist for the retinoid receptor RAR) requires a carboxylic acid moiety and an appropriate hydrophobic group located at a suitable position on the molecule. 4-[4-(1,2-Dicarba-closo-dodecaboran-1-yl)phenylamino]b enzoic acids and 4-[3-(1,2-dicarba-closo-dodecaboran-1-yl)phenylamino]b enzoic acids showed potent agonistic activity at concentrations of 10(-8)-10(-9) M. The results indicate that carboranes are applicable as the hydrophobic moiety of biologically active molecules.

Boron Compounds↗

PubMed1998

Potent retinoid synergists with a diphenylamine skeleton.

4-[N-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)amino]benzoic acid (5) exhibited weak retinoidal and retinoid synergistic activities in HL-60 cell differentiation assay. N-Alkylation of 5 caused decrease or loss of differentiation-inducing activity, but enhanced the synergistic activity with a synthetic retinoid Am80 (2), as reflected in the potent synergistic EC50 (SEC50) values of DA023 (11, 1.6 x 10(-10) M) and DA113 (14, 1.4 x 10(-10) M) in the presence of 1.0 x 10(-10) M Am80 (2).

Cell Differentiation↗

PubMed1998

Novel thiazolidinedione derivatives with retinoid synergistic activity.

Several arylmethylidene thiazolidinediones were synthesized and their retinoidal activities were examined. TZ181 (7a), having a benzanilide skeleton, exhibited differentiation-inducing activity in HL-60 cell assay, while TZ191 (7b), the N-methylated analog of TZ181 (7a), TZ245 (9) and TZ335 (10) acted as retinoid synergists like the RXR-selective ligand, LGD1069 (5).

Cell Differentiation↗

PubMed1997

Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.

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.

Azepines↗