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E Kawachi

Publications and source records attributed to E Kawachi.

At least 37 records · Page 2Linked to original sources
PubMed1994

Retinobenzoic acids. 6. Retinoid antagonists with a heterocyclic ring.

Several candidate retinoid antagonists were designed on the basis of the ligand superfamily concept and synthesized. Retinoidal activities of these benzimidazole and benzodiazepine derivatives were examined by assay of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. The parent benzimidazole derivative, 4-(5,6,7,8-tetrahydro-5,5,8,8- tetramethylnaphth-[2,3-d]imidazol-2-yl)benzoic acid (7a), and related compounds with a small alkyl group instead of the hydrogen on the nitrogen (1N) atom of the imidazole ring exhibited retinoidal activity, and the potency strongly depended on the bulkiness of the substituent. The compounds having a phenyl or benzyl group on the nitrogen lacked differentiation-inducing activity on HL-60 cells and acted as antagonists to the potent retinoid 4-[(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (Am80). Among the compounds possessing a seven-membered heterocyclic ring as a linking group, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10- pentamethylbenzo[e]- naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid (16) also exhibited the antagonistic activity. The binding abilities of these compounds to retinoic acid receptors alpha and beta were consistent with their potency for the inhibition of HL-60 cell differentiation induced by the retinoid Am80.

Benzimidazoles↗
PubMed1994

Synthesis and biological activity of carboxyphenylquinolines and related compounds as new potent retinoids. Retinobenzoic acids. VII.

A series of new quinoline, quinolone, and quinazolinedione derivatives was synthesized and tested for retinoid activity in the human promyelocytic cell line HL-60 differentiation assay. All the quinoline compounds exhibited significant activity, depending on the substituent on the heterocycle. However, the quinolone and quinazolinedione derivatives were poor inducers of the differentiation of the HL-60 cells, the activity depending strongly on the polarity of the molecule.

Benzoates↗
PubMed1993

Cytokinin-specific binding protein in etiolated mung bean seedlings.

We have found that a synthetic urea derivative, N-(2-chloro-4-pyridyl)-N'-phenylurea (4PU30, forchlorfenuron), has even higher cytokinin activity than N6-benzyladenine (BA). Using [3H]4PU30 (2.83 TBq/mmol) as a probe, we confirmed chromatographically the presence of a high-affinity cytokinin-specific binding protein (CSBP) in whole-cell extract from etiolated mung bean seedlings. The apparent molecular weight of CSBP was estimated to be 21 kDa. The association constants (Ka's) of CSBP for 4PU30 and BA were calculated to be 4 x 10(10) M-1 and 3 x 10(9) M-1, respectively. Various active cytokinins showed mutually competitive binding to CSBP, and their affinities for CSBP corresponded well to their cytokinin activities at the tissue level.

Arabidopsis Proteins↗
PubMed1992

Differentiation-inducing activity of retinoic acid isomers and their oxidized analogs on human promyelocytic leukemia HL-60 cells.

Retinoidal activity of retinoic acid isomers [all-trans-retinoic acid (ATRA), 9-cis-retinoic acid (9CRA) and 13-cis-retinoic acid (13CRA)] and their oxidized derivatives [19-hydroxy and 19-oxo derivatives of ATRA (19-hydroxy-ATRA and 19-oxo-ATRA), 19-oxo derivative of 9CRA (19-oxo-9CRA), and 19-hydroxy derivative of 13CRA (19-hydroxy-13CRA)] was evaluated by means of a human promyelocytic leukemia HL-60 cell differentiation induction assay. All the compounds examined showed this activity with ED50 values of 2-30 nM, which are in accordance with their binding activity to nuclear retinoic acid receptors (RARs).

Binding, Competitive↗
PubMed1992

Base-catalyzed isomerization of retinoic acid. Synthesis and differentiation-inducing activities of 14-alkylated all-trans-, 13-cis-, and 20,14-retro-retinoic acids.

Retinoic acid (1) is isomerized regioselectively by excess amounts of lithium diisopropylamide (LDA) to give 20,14-retro-retinoic acid (3). Alkylation of the intermediate dianion of retinoic acid gave 14-alkylated derivatives of 3. By isomerization of the alkylated retro isomers under basic conditions, several 14-alkyl-all-trans- and -13-cis-retinoic acids were synthesized. The retinoidal activities of these derivatives were examined, based on the ability to induce differentiation of human promyelocytic leukemia cell line HL-60. 20,14-retro-Retinoic acid (3) is 1/50 as active as retinoic acid (1). Although 14-methyl-20,14-retro-retinoic acid (4) is as active as 3, the introduction of a 14-methyl group into all-trans- and 13-cis-retinoic acid resulted in decreased activity. Introduction of bulkier alkyl groups at the C-14 position caused the disappearance of the activity.

Alkylation↗
PubMed1990

Retinobenzoic acids. 5. Retinoidal activities of compounds having a trimethylsilyl or trimethylgermyl group(s) in human promyelocytic leukemia cells HL-60.

The retinoidal activities of trimethylsilyl or trimethylgermyl-containing retinobenzoic acids are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. Compounds with a trimethylsilyl or trimethylgermyl group at the meta position of the generic formula 2 have more potent activities than the corresponding retinobenzoic acids with a m-tert-butyl group. Compounds having two m-trimethylsilyl or -trimethylgermyl groups also have strong activities, and (E)-4-[3-[3,5-bis(trimethylsilyl)phenyl]-3-oxo-1-propenyl]benzoic acid (22, Ch55S) and (E)-4-[3-[3,5-bis(trimethylgermyl)phenyl]-3-oxo-1- propenyl]benzoic acid (35, Ch55G) are more active than retinoic acid by 1 order of magnitude. However, in the para-substituted chalcone derivatives, the replacement of a tert-butyl group (49, Ch40) with a trimethylsilyl (27, Ch40S) or a trimethylgermyl (30, Ch40G) group caused the disappearance of the activity.

Antineoplastic Agents↗
PubMed1989

Retinobenzoic acids. 2. Structure-activity relationships of chalcone-4-carboxylic acids and flavone-4'-carboxylic acids.

The structure-activity relationships of (E)-chalcone-4-carboxylic acids, which are retinoidal benzoic acids represented by R-Ph-X-Ph-COOH (4, X = -COCH = CH-), are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. The activity was increased by the substitution of a bulky alkyl group(s) (R), and among such compounds, (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid (Ch55) and (E)-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 -propenyl]benzoic acid (Ch80) are several times more active than retinoic acid. Though the stable conformer of chalcone derivatives is linear (s-cis form), the conformationally restricted analogue 4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-4H-4-oxonaphtho[2,3-b]py ran-2-yl)benzoic acid (Fv80) is more active than Ch80. While the effect of introduction of an oxygen atom varied, 4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2 - naphthalenyl)-1-propenyl]benzoic acid (Re80), regarded as a derivative of Ch80 with two additional hydroxyl groups, has very strong activity.

Carboxylic Acids↗
PubMed1989

Retinobenzoic acids. 3. Structure-activity relationships of retinoidal azobenzene-4-carboxylic acids and stilbene-4-carboxylic acids.

Alkyl-substituted azobenzene-4-carboxylic acids are potent differentiation inducers of human promyelocytic leukemia cell line HL-60 to mature granulocytes. Their structure-activity relationships are very similar to those of other retinoidal benzoic acids which are generally represented by 4 and named retinobenzoic acids. The structure-activity relationships of azobenzenecarboxylic acids can also be applied to the known retinoid TTNPB (3). Thus, (E)-4-[2-(3,4-diisopropylphenyl)-1-propenyl]benzoic acid (St30 (28] and (E)-4-[2-(3-tert-butylphenyl)ethenyl]benzoic acid (St40 (29], the acyclic alkyl analogues of TTNPB, are nearly as active as retinoic acid. Among the oxidatively derived compounds (Az90, Ep series and Ox series) of azobenzene- or stilbenecarboxylic acids, Az90 (71) and Ep80 (61) have strong activities. However, all the bishydroxylated derivatives of TTNPB are inactive, while a diketo analogue Ox580 (69) has only weak potency. The activities of conformationally restricted compounds of TTNPB offer some information on the stereochemistry of the active form of these retinoidal compounds.

Benzoates↗
PubMed1989

Retinobenzoic acids. 4. Conformation of aromatic amides with retinoidal activity. Importance of trans-amide structure for the activity.

N-Methylation of two retinoidal amide compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (3, Am80) and 4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)carbonyl]amino]benzoic acid (5, Am580), resulted in the disappearance of their potent differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. Studies with 1H NMR and UV spectroscopy indicated that large conformational differences exist between the active secondary amides and the inactive N-methyl amides. From a comparison of the spectroscopic results of these amides with those of stilbene derivatives, the conformations of the active amides are expected to resemble that of (E)-stilbene, whereas the inactive amides resemble the Z isomer: 3 (Am80) and 5 (Am580) have a trans-amide bond and their whole structures are elongated, while the N-methylated compounds [4 (Am90) and 6 (Am590)] have a cis-amide bond, resulting in the folding of the two benzene rings. These structures in the crystals were related to those in solution by 13C NMR spectroscopic comparison between the two phases (solid and solution).

Amides↗
PubMed1988

Affinity gels for purification of retinoid-specific binding protein (RSBP).

Retinoids are defined as compounds which elicit specific biological effects such as control of cell growth and cell differentiation by binding to a specific receptor. Recently, we demonstrated the presence of a protein (RSBP) which satisfies the criteria for the retinoid receptor. For purification of RSBP, we prepared two types of affinity gels with retinoidal ligands (Gel-Am and Gel-Ch) based on synthetic retinobenzoic acids which possess very potent retinoidal activities. RSBP in the crude fraction extracted from cultured cells could be purified about 300-fold by affinity column chromatography using these affinity gels.

Binding, Competitive↗
PubMed1988

Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity.

Two types of aromatic amides, terephthalic monoanilides and (arylcarboxamido)benzoic acids, have been shown to possess potent retinoidal activities and can be classified as retinoids. The structure-activity relationships of these amides are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. In generic formula 4 (X = NHCO or CONH), the necessary factors to elicit the retinoidal activities are a medium-sized alkyl group (isopropyl, tert-butyl, etc.) at the meta position and a carboxyl group at the para position of the other benzene ring. The bonding of the amide structure can be reversed, this moiety apparently having the role of locating the two benzene rings at suitable positions with respect to each other. Substitution at the ring position ortho to the amide group or N-methylation of the amide group caused loss of activity, presumably owing to the resultant change of conformation. It is clear that the mutual orientation of the benzylic methyl group(s) and the carboxyl group and their distance apart are essential factors determining the retinoidal activity. Among the synthesized compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (Am80) and 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido] benzoic acid (Am580) were several times more active than retinoic acid in the assay. They are structurally related to retinoic acid, as is clear from the biological activity of the hybrid compounds (M2 and R2).

Amides↗
PubMed1988

Specific uptake of retinoids into human promyelocytic leukemia cells HL-60 by retinoid-specific binding protein: possibly the true retinoid receptor.

The uptake of all-trans-retinoic acid (RA) and two new retinoids [4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl )benzoic acid (Am80) and (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid (Ch55)] by HL-60 human promyelocytic leukemia cells was investigated. For the investigation, [3H]RA and [3H]Am80 with high specific radioactivities (more than 50 Ci/mmol) were used. [3H]Am80 was prepared by hydrogenolysis of the corresponding chlorinated derivative of Am80 with tritium gas. The retinoids RA, Am80 and Ch55 were efficiently taken up by HL-60 cells, and induced differentiation of the cells into mature granulocytes. The specific bindings (uptake) of RA, Am80 and Ch55 (the bindings inhibited competitively by the other two retinoids) by HL-60 cells were due to a newly detected binding protein. The protein that bound specifically to RA appeared identical to that which bound specifically to Am80 by high-performance liquid chromatography (HPLC), and was named retinoid-specific binding protein (RSBP). One HL-60 cell was found to contain about 1500 molecules of RSBP distributed between the nuclear fraction and cytosolic fraction in proportions of about 4:1. The bindings of the three retinoids (RA, Am80 and Ch55) to RSBP (i.e., formation of retinoid-RSBP complexes) greatly enhanced the affinity of RSBP for the nuclei. The apparent molecular weight of RSBP was estimated to be 95,000 daltons by size exclusion HPLC. The association constants (Ka) of RSBP were calculated to be 2.4 X 10(10) M-1 for RA and 4.4 X 10(10) M-1 for Am80 from Scatchard plots. The bindings of RA, Am80 and Ch55 to RSBP were mutually competitive, indicating that the binding sites for RA, Am80 and Ch55 were identical. The very high affinities of these retinoids for RSBP (Ka's of the order of 10(10) M-1) correspond to the effective concentrations of these retinoids in HL-60 cell culture medium for induction of differentiation of the cells. The mutually competitive bindings of these retinoids strongly support the idea that RSBP is the true receptor of retinoids.

Benzoates↗
PubMed1988

[Recent advances in retinoids studies].

Retinoids are defined as the compounds which elicit the specific biological responses through binding or activating the specific receptor(s). Retinoids modulate the cellular differentiation and proliferation in many types of cells. A series of retinoidal benzoic acids, named retinobenzoic acids, have potent activities on human promyelocytic leukemia cells, HL-60, and other assay systems. Among them, Am80, AM580 and Ch55 are more active than retinoic acid in most cases. As these compounds possess quite different structures or physicochemical properties from retinoic acid or conventional retinoids, they are expected to be applied clinically for the treatments of the diseases in oncology and dermatology. Recently, progresses on the mechanistic studies on retinoidal actions have been reported. One of them is isolation and cloning of human retinoic acid-receptors and the mechanism of retinoidal action was concluded that the retinoid-receptor complex interact directly with DNA to regulate the expression of the gene, like steroid hormone. The other is the establishment of the presence of the retinoid-specific-binding protein (RSBP) by the use of our retinobenzoic acids as the probe.

Animals↗
PubMed1987

Transforming activity of human c-Ha-ras-1 proto-oncogene generated by the binding of 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole and 4-nitroquinoline N-oxide: direct evidence of cellular transformation by chemically modified DNA.

An activity that transforms NIH 3T3 cells was generated by the in vitro modification of plasmids containing the human c-Ha-ras-1 proto-oncogene with the synthesized ultimate carcinogen, 2-acetoxyamino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole (N-OAc-Glu-P-1). DNAs isolated from the transformed cells were analyzed by restriction fragment length polymorphism (RFLP) assay using the restriction enzyme Msp I. Of fourteen transformants studied, six contained a mutation in the region of the CCGG sequence of the eleventh and the twelfth codons, in which GG corresponds to the first two nucleotides of the twelfth codon. Transforming activity was also generated by the chemical modification of the plasmids with 4-acetoxyaminoquinoline N-oxide (N-OAc-4AQO). The results clearly indicate that formation of DNA adducts with N-OAc-Glu-P-1 or N-OAc-4AQO causes the induction of transformation of mammalian cells.

4-Nitroquinoline-1-oxide↗
PubMed1986

[Regulation of cell growth by retinoids and gene expression].

Retinoids are compounds that can elicit specific biological responses by virtue of their binding to and activating a specific receptor or a set of receptors. Retinoids produce various specific biological effects, including induction of terminal differentiation, regulation of cell proliferation, regulation of gene expression and regulation of the activity of specific enzymes in cells. In this article, the effects of retinoids on gene expression are reviewed. Among these effects suppression of myc expression and induction of EGF-receptor mRNA expression are considered to be closely related to regulation of cell proliferation. The effects of retinoids on cell growth are discussed on the basis of these two actions: myc mRNA suppression and EGFR mRNA induction. The mode of retinoidal action seems to be similar to that of steroids, as many investigators suggest. The molecular mechanism of retinoidal action is considered to be the formation of a retinoid-receptor complex and its interaction with regulatory elements of DNA. The possibility of application of the methodology used in the investigation of steroidal action to the study of retinoidal action is also discussed.

Animals↗
PubMed1986

Activation of c-Ha-ras proto-oncogene by in vitro chemical modification with 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 4-nitroquinoline N-oxide (4NQO).

Chemical modification of a plasmid containing the human c-Ha-ras proto-oncogene (pSVMBras-gpt) in vitro with the ultimate carcinogens N-acetoxy-2-amino-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (N-OAc-Glu-P-1) and N-acetoxy-4-aminoquinoline N-oxide (N-OAc-4AQO) generated an activated oncogene that transformed NIH3T3 cells. As DNA is only cellular macromolecule present in the reactions, the results clearly show that the chemical modification of DNA with carcinogens alone can cause the induction of transformation of mammalian cells.

4-Nitroquinoline-1-oxide↗