Search PubMed⌕ Search

Biomedical subjects

K Shudo

Publications and source records attributed to K Shudo.

At least 91 records · Page 5Linked to original sources
PubMed1994

Synthesis of oxygenated cholesterols as structural mimics of phorbol ester-type tumor promoters.

We designed several oxygenated steroids in which functional groups including a hydrophobic group are arranged analogously to those of phorbol ester (12-O-tetradecanoylphorbol-13-acetate, TPA), with the aim of finding compounds with TPA-like activity, but having a different skeleton and a rigid conformation. The designed steroids, 1 beta,5 alpha-dihydroxy-3 beta-hydroxymethylcholestan-6-one (4), 3 beta,5 alpha-dihydroxycholestan-6-one (5), 3 beta-hydroxymethylcholestan-5 alpha-ol-6-one (6) and 1 beta,3 beta,5 alpha-trihydroxycholestan-6-one (7), were synthesized. A related oxygenated steroid isolated from soft coral, cholestane-1 beta,3 beta-5 alpha,6 beta-tetrol (8), was also synthesized. Among these analogs, compound 7 showed weak TPA-like activities in three biological tests: inhibition to protein kinase C and to cytosolic-nuclear tumor promoter-binding protein (CN-TPBP), and induction of differentiation of human promyelocytic leukemia cells (HL-60) to monocyte-like cells. On the other hand, compound 5 was found to be a specific ligand for CN-TPBP, but lacked the other TPA-like activities.

Animals↗
PubMed1994

[Stereochemistry of benzanilides and N-methylbenzanilides].

Conformations of benzanilide , N-methylbenzanilide and those with a methyl group(s) ortho to the amide bond in solution and in the crystal have been studied. N-Methylbenzanilide exists in cis-amide (E) form in the crystal. In CDCl3 solution, cis-amide form is also predominant (99%), while benzanilide exists in trans-amide (Z) form in the crystal and in solution. In the crystal, all the methyl-substituted benzanilides exist in trans-amide conformation and the introduction of an ortho-methyl group(s) makes the interplanar angles of the aromatic rings and the amide group (Aramide) larger. N-Methylbenzanilides exist in cis form in the crystal except the compound which has four methyl groups ortho to the amide bond. For the N-methylbenzanilides, the effects of introduction of one or two ortho-methyl groups on the dihedral angles of Ar-amide are smaller than that for the secondary benzanilides. In solution, benzanilides exist exclusively in trans conformation except for the compound 12 which has a minor cis conformer (3%) in CDCl3, whereas N-methylbenzanilides exist in equilibrium between the major cis-form and the minor trans-form. The tetramethyl derivative exists in trans conformation in solution as observed in the crystal. For N-methylbenzanilides, an introduction of a methyl group(s) ortho to the amide bond seems to destabilize the cis-amide conformation in solution, resulting in an increased ratio of the trans-amide conformation.

Anilides↗
PubMed1994

[The active conformation of teleocidins: design and synthesis of new active molecules].

This review deals with structure-activity relationships, conformational analysis of teleocidins and creation of new active compounds for the determination of active conformation of teleocidins. Phorbol esters containing 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidins which are classified as TPA-type tumor promoters exhibit potent tumor-promoting activity as well as many important biological activities connected with cell prolification and cell differentiation. Teleocidins are known to exist in an equilibrium between two conformational states in solution, the twist and the sofa forms. The low energy barrier between the two conformers makes it difficult to identify the mode of interaction of these promoters with common macromolecular targets. Design and synthesis of molecules having a new skeleton (benzolactams) and producing two conformations of teleocidins solve the problem. Benzolactams become the simplest molecule reproducing the conformation and activity of teleocidin, and will be a useful tool for the study of tumor-promotion and cell differentiation.

Animals↗
PubMed1994

[Phenoxenium ions: generations and reactions].

The acid-catalyzed reaction of N-acyl- and N-sulfonylhydroxylamines with benzene proceeded smoothly to give C-C products; 2- and 4-hydroxybiphenyls. The reaction and the thermolysis of N-aryloxypyridinium salts involve common intermediates. The results of product analysis, the orientation of the reaction, effects of substituents on the nitrogen atom and on the phenyl ring suggested a mechanism involving a phenoxenium ion. The positive charge of the phenoxenium ion localized not on the oxygen atom but on the ortho and para carbons of the benzene ring. C-O product: diphenylethers are formed when the heterolysis of the N-O bonds is slow and the aromatic solvent has high nucleophilicity, suggesting an SN2-like reaction on the oxygen atom. The phenoxenium ions are also concerned with a rearrangement of O-arylhydroxylamine to 2-aminophenol. An ion-molecule pair involving phenoxenium ion and ammonia as an intermediate of the intramolecular ortho rearrangement.

Catalysis↗
PubMed1994

[Cytokinins].

Cytokinins which promote cell division and cell differentiation of plants are structurally classified into two groups: purine-type cytokinins and phenylurea-type cytokinins. Structural modification of the two types led a potent cytokinin, N-(2-chloro-4-pyridyl)-N'-phenylurea (forchlorfenuron). Structure-activity relationship was discussed. The mode of the two types of cytokinins was studied, and a putative receptor which is common to both types was detected using a highly-labelled synthetic cytokinin. Examples of horticultural application of the compound were illustrated.

Cell Differentiation↗
PubMed1994

Transcription from the P2 promoter of human protooncogene myc is suppressed by retinoic acid through an interaction between the E2F element and its binding proteins.

When human promyelocytic leukemia cell line HL60 was treated with retinoic acid (RA), considerable suppression of protooncogene myc expression was achieved before granulocytic differentiation became evident. From transient transfection experiments using the reporter plasmid containing exon 1 and its 2.3 kilobases upstream of the c-myc gene fused to the chloramphenicol acetyltransferase gene, it was indicated that this suppression was mainly attributable to the level of transcription initiation. Deletion down to 95 base pairs upstream of the P2 promoter did not change the suppressive effect of RA on c-myc gene expression. Mobility shift assays with respect to the P2 promoter region revealed that the 15-base pair fragment located between P1 and P2 promoters was responsive to the RA treatment. This fragment included the E2F binding site in the c-myc P2 promoter region, and a difference of shifted bands between RA-treated and untreated HL60 cells was due to complex formation of E2F and retinoblastoma protein. The present results suggest that E2F plays an important role in the process of cell differentiation by RA and that a change of the E2F binding pattern induced by RA contributes to the suppression of c-myc gene expression preceding granulocytic differentiation.

Base Sequence↗
PubMed1993

Three novel synthetic retinoids, Re 80, Am 580 and Am 80, all exhibit anti-angiogenic activity in vivo.

In a previous study, we demonstrated that retinoic acid or a synthetic retinoid, Ch 55 ((E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid), significantly affects in vivo angiogenesis, on the basis of our working hypothesis that a cell differentiation modulator could also exhibit anti-angiogenic activity. In the present study, three novel synthetic retinoids, Re 80 (4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl- 2- naphthalenyl)-1-propenyl]benzoic acid), Am 580 (4-[(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid) and Am 80 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl] benzoic acid), whose cell differentiation-modulating effects are roughly comparable to or more potent than that of Ch 55, which was the most effective angiostatic retinoid identified previously, were examined. Their anti-angiogenic effects were tested in an in vivo assay system involving chorioallantoic membranes of growing chick embryos. They were all found to exert dose-dependent anti-angiogenic effects in the picomolar range. Their rank order for inhibitory potency was Re 80 > Am 580 > Am 80, the ID50 values being 6.3, 23 and 28 pmol/egg, respectively. These results indicate that treatment involving these three novel synthetic retinoids might have potential therapeutic efficacy in various angiogenesis-dependent disorders, including solid tumors, psoriasis, rheumatoid arthritis and diabetic retinopathy.

Animals↗
PubMed1993

Oxygenated cholesterols as ligands for cytosolic-nuclear tumor promoter binding protein: yakkasteroids.

Several oxygenated cholesterols and their derivatives (yakkasteroids) were prepared as candidate ligands for cytosolic-nuclear tumor promoter binding protein (CN-TPBP). Among the compounds, a possible natural substance, 3 beta,5 alpha-dihydroxycholestan-6-one (yakkasterone), showed the highest binding affinity to CN-TPBP. It also showed high specificity for binding to CN-TPBP: it does not bind to protein kinase C. Investigation of the structure-activity relationships of yakkasteroids revealed that the structure of the side chain at the 20-position is important for the binding activity to CN-TPBP.

Binding, Competitive↗
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↗
PubMed1993

Expression of the ligand-binding domain-containing region of retinoic acid receptors alpha, beta and gamma in Escherichia coli and evaluation of ligand-binding selectivity.

The complete molecule or the ligand-binding domain-containing region of each of the three subtypes of human retinoic acid receptors (hRAR alpha, hRAR beta and hRAR gamma) was expressed in Escherichia coli. The expressed recombinant RARs (rRARs: rRAR alpha/E, rRAR beta/E and rRAR gamma) showed nearly the same magnitude of binding affinity toward [3H]retinoic acid (RA) as hRARs extracted from human cells (Ka values: 6.0 x 10(9) M-1 for rRAR alpha/E and 2.7 x 10(10) M-1 for both rRAR beta/E and rRAR gamma). Therefore, the ligand-binding selectivity of the rRARs toward RA and synthetic retinoids (4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl )benzoic acid (Am80), (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid (Ch55)) was examined. Am80 bound rRAR alpha/E preferentially and showed no binding activity toward rRAR gamma, which is consistent with the case of hRAR gamma. Ch55 bound all three subtypes of rRARs, preferentially rRAR beta/E. These results suggest that the intrinsic nature of the binding of each retinoid can be investigated by usage of the rRARs. However, rRARs show quantitatively different ligand-selectivity from that of hRARs: RA showed higher binding affinity toward rRARs than both Am80 and Ch55, but Ch55 binds all three subtypes of hRARs stronger than RA and Am80, which binds hRAR beta stronger than RA.

Base Sequence↗
PubMed1993

Inhibitory effects of 2'-deoxy-L-thymidine 5'-triphosphate on human immunodeficiency virus reverse transcriptase and eukaryotic DNA polymerases.

Inhibitory effects of 2'-deoxy-L-thymidine 5'-triphosphate (L-dTTP) which is an enantiomer of the natural substrate (D-dTTP) on the activity of mammalian DNA polymerases, Escherichia coli DNA polymerase I and HIV-1 reverse transcriptase were examined. Interestingly, L-dTTP showed remarkable inhibitory effect on HIV-1 reverse transcriptase in competitive fashion with respect to the substrate dTTP. In contrast, eukaryotic cell nuclear DNA polymerases alpha and beta were not or slightly inhibited by L-dTTP.

DNA Polymerase I↗
PubMed1993

Meso-oligodeoxyribonucleotides.

Meso-DNAs, containing L-sugar and D-sugar in an alternate sequence as the backbone [Fig. 1, designated as LD-(dN)n], were prepared as a modificated oligonucleotides of natural- and enantio-DNA. The characteristics of meso-DNAs were analyzed, focusing on LD-(dA)n and LD-(dT)n. These L-sugar containing oligomers show resistancy to phosphodiesterases. Though both LD-(dA)n and LD-(dT)n bound their corresponding complementary homopolymers, apparent differences of the interaction mode between these two meso-DNAs were observed: [1] Concerning the complex formation with the complementary homopolymers, LD-(dA)n favors a triplex formation while LD-(dT)n forms only duplex, and [2] Concerning DNA/RNA selectivity for the complex formation, LD-(dA)n interacted with poly U more strongly than poly dT (RNA-selective), while LD-(dT)n showed stronger interaction with poly dA than poly A (DNA-selective). The similarities in CD-spectra of LD-oligomer/natural polymer complexes to natural complexes suggest that the conformation possesses a structure close to a natural right-handed helix conformation.

Adenine↗
PubMed1993

[Retinoid signalling pathways].

Retinoids, all-trans-retinoic acid (AT-RA) and its bioisters, exert diverse and profound effects on the growth and differentiation of normal and malignant cells, vertebrate development, and homeostasis. Since their nuclear receptors (RARs: alpha, beta and gamma) were cloned, extensive studies on retinoid signalling at molecular level have elucidated its elaborate mechanisms, by which the expression of a variety of retinoid responsive genes are regulated. Furthermore, discoveries of the second receptor system of retinoid (RXRs: alpha, beta and gamma) and their substantial ligand, 9-cis-retinoic acid (9C-RA), were recently reported. The heterodimer formation between RXR and RAR or other members of the steroid/thyroid hormone receptor superfamily gave us a new aspect of hormonal gene control including retinoids, thyroid hormone, vitamin D3 and others. These heterodimers were showed to bind specific response elements consisted of the direct repeat of consensus sequence (AGATTC) or its related sequences. Differential regulation of retinoid responsive gene by RARs or/and RXRs in vivo is an ongoing subject and the combinatory outcome of subtypes or isotypes of receptors, natural response elements, natural ligands (AT-RA, 9C-RA, or their metabolites) owing to pleiotropic effects of retinoids is being revealed. The anti-malignant effect of retinoids is another important theme. The report of prominent therapeutic effect of AT-RA against APL patients was sensational. In many APL patients, translocation between RAR alpha gene and an oncogenic gene, PML, can be detected, although the roles of their fusion products (RAR alpha-PML and PML-RAR alpha) in APL induction have not been understood. Furthermore, the cross-talk between RAR and AP-1 is thought to give an explanation for the suppressive effects of retinoids against tumor promoters (TPA and others). In those contexts, synthetic retinoids specific for each subtype of RAR or RXR, which will be useful reagents for biological studies and/or excellent therapeutic agents, are being developed. Some RAR subtype-selective compounds including antagonists have been already reported.

Animals↗
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

Active conformation of a tumor promoter, teleocidin. A molecular dynamics study.

Telecidins are potent tumor promoters, having a nine-membered lactam structure. Teleocidins and their small-molecular-sized active congeners (indolactams) are known to exist in an equilibrium between at least two conformational states, the twist and the sofa form. Molecular dynamics (MD) calculations were performed on four indolactams, in order to examine the relationships between preferred ring conformations and the biological activities. It was shown that the tumor-promoting activities are closely related with the existence ratio of the sofa form among 10 possible conformations. This implies that the sofa form is the active ring conformation, which is compatible with the previous result obtained independently from the superposition of teleocidin and phorbol ester. The predicted ratios of conformers for each indolactam were in good agreement with those observed by NMR spectral analysis. The high-temperature MD method proved to be very useful for predicting the preferred structures of these cyclic compounds, in which the overall stabilities are strongly influenced by the conformations of substituent groups on the ring.

Carcinogens↗
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↗
PubMed1992

[A case report of a massive pulmonary tumor embolism occurring during surgery for renal cell carcinoma].

A 59-year-old man, who suffered a massive pulmonary tumor embolism during surgery for renal cell carcinoma with vena caval invasion, was treated by emergency pulmonary embolectomy using cardiopulmonary bypass. Renal cell carcinoma occasionally extends into the inferior vena cava (IVC) as a tumor thrombus. In such patients, removal of the tumor thrombus from the IVC has to be performed in addition to radical nephrectomy. However, the massive pulmonary tumor embolism is a major potential hazard during radical surgical resection. To prevent intraoperative pulmonary embolisms from occurring, scheduled use of cardiopulmonary bypass with the cooperation of cardiovascular surgeons is recommended.

Carcinoma, Renal Cell↗