Cytoplasmic microtubules are fibrous intracellular organelles found in almost all eukaryotic cells and play an important role in maintenance of cell shape, cell division, axonal transport, secretion and receptor activity. Besides tubulin dimers, microtubule proteins consist of several other components called MAPs which promote microtubule assembly and form long filamentous projection on the surface of the polymer. In mammalian brain, two classes of MAPs have been characterized ; one is structural MAPs including MAP1 (1A and 1B), MAP2 (2A, 2B and 2C) and tau which function in the morphogenesis and maintenance of neural tissues and cells, and the other contains motor MAPs (kinesin and MAP1C) which are related to translocation of vesicles along microtubules in axon and to mitosis. The primary sequences of MAPs have been determined from their cDNAs. The functions of structural MAPs are modulated by their binding to other intracellular components, different expressions of isoforms during brain development and phosphorylation-dephosphorylation by various protein kinases and phosphatases. Biochemical characterization of MAP2 and tau have been well investigated. However, little is known about the function of MAP1 under the biochemical level, because MAP1 is unstable and high sensitive to proteases. We have developed a simple and rapid purification procedure for MAP1 using poly (L-aspartic acid) and taxol, and observed MAP1-F-actin interaction as well as MAP1-microtubules interaction. Recently, we have found that three specific kinases which can phosphorylate MAP1A and 1B are associated with MAP1 preparation and called it MAP1 kinase. Some evidence suggest that one of them is an unknown kinase and others are casein kinase I-and II-like kinases. Further studies to examine MAP1 kinase and phosphorylation of MAP1 provide a valuable insight for understanding thoroughly the microtubule-mediated functions.
Physico-chemical properties of the blood platelets and their membrane were investigated by fluorescence analysis and electron spin resonance spectrometry. Fluorescence analysis using diphenylhexatriene and its ionic derivatives revealed that the inner membrane compartment of the platelets is more fluid than the outer layer of the plasma membrane. Further, the relationship between the increase in membrane fluidity by membrane reactive compounds such as alcohols and their inhibitory effects on platelet function was clarified. These compounds seem to inhibit platelet function due to stimulation of adenylate cyclase, which is mediated by perturbation of the central region of the membrane lipid bilayer. The effects of monovalent cations and anions on platelet function was also examined and their mechanisms were studied. It was indicated that monovalent cations such as alkali metal cations modify platelet aggregation by changing fibrinogen binding. On the other hand, monovalent anions modified platelet function by quite different mechanism. Furthermore, generation of hydroxyl radicals by platelets and its enhancement accompanied with the activation of platelets were revealed. It was inhibited by inhibitors of platelet activation such as forskolin and phenolic antioxidants.
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 prorification 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 skelton (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.
Treatment of the tricarbonyl (η6-o-trimethylsilylbenzaldehyde) chromium (0) complex with cyclic silyl enol ether species under the Mukaiyama condition resulted in highly stereoselective formation of syn-aldol products, whereas the aldol reaction with O-silyl ketene O, S-acetals afforded the corresponding antiproducts in a highly stereoselective manner. The tricarbonyl (η6-o-trimethylsilylbenzaldehyde) chromium (0) complex has also emerged as an excellent substrate for highly regio-and stereoselective construction of cis-3, 5-isoxazolidine derivatives in the 1, 3-dipolar cycloaddition reaction. By taking advantage of our newly developed aldol reaction, we have succeeded in highly stereocontrolled syntheses of some biologically active compounds such as C-13 side chains of taxol and taxotere, the N-terminal amino acid of nikkomycin B and Bx, and antitumor styryllactones : goniofufurone, goniotriol, and goniothalenol.
Nine new naphthalene related compounds (I, IV, V, VII-XII) together with four known compounds (II, III, VI, XIII) were isolated from the root bark of Oroxylum indicum VENT. (Bignoniaceae), one of the Nepalese crude drugs. Their structures were determined based on chemical and physicochemical evidence.
A compound having structures of both vitamines E and C, L-ascorbic acid dl-α-tocopherol phosphoric acid diester potassium salt (EPC-K), which was proven to have both anti-oxidative and moisturizing effects, has been formulated in the quasi drug hair growing products to mainly prevent dandruff and itching which may be one of the causes for the hair loss. Stabilities of EPC-K in 75% ethanolic solutions with various pHs (2-10) were examined extensively by storing them at 50°C for 30d and by sunlight exposure for 30d. Decomposition of EPC-K was only observed under pH 2 at a level of 50% and under sunlight exposure at 25% level. A main decomposition product was identified as tocopheryl phosphate (EP), suggesting that a decomposition route was through hydrolysis. EPC-K was found to decompose by as much as 20% under 30d storage at 50°C when the concentration of the aqueous ethanolic solution was 0-30%. 1H, 13C and 31P-NMR studies in addition to a micelle formation test using pyrene fluorescent probe revealed that EPC-K formed a micelle at such low concentration of ethanol, which was assumed to be a cause for unstableness of EPC-K in that range. Hydrolytic decomposition of EPC-K was found by the reaction rate study to be a pseudo first order reaction with activation energy of 16.98 kcal/mol.
A series of 8H-indeno [1, 2-d] thiazoles containing various N-substituted amino groups at the 2 position were synthesized by the reaction of 2-bromoindanones and N-substituted thioureas. Their anti-ulcerous activity was evaluated. Alkylamino derivatives have a more potent inhibitory behavior on ethanolinduced gastric ulcers compared with arylamino derivatives. We also studied the effect of various substituents on the both benzene and pyridine ring of 2-pyridylamino derivatives on ethanol-induced gastric ulcers. However no clear effects were observed. Among 3-morpholinopropylamino derivatives, 5-isopropyl-(21) and 7-chloro-2-(3-morpholinopropyl) amino-8H-indeno [1, 2-d] thiazole (25) showed a considerably stronger inhibitory behavior on hydrochloric acid-induced gastric ulcers than cetraxate hydrochloride. Furthermore, 3-morpholinopropylamino derivatives have potent inhibitory effects on gastric acid secretion in pylorus ligated rats.
Extracts of Chinese herbs were administered with antitumor agent, cyclophosphamide (CY), and their effects on macrophages and lymphocytes were studied. Number of peritoneal macrophages significantly decreased and their chemotactic activity was suppressed by treatment with CY. Blastogenic responsiveness to Concanavalin A and NK cell activity of spleen lymphocytes were suppressed significantly in CY-treated mice. Extracts of Lithospermi radix, Astragali radix and Glycyrrhizae radix showed protective effects on immunosuppressive mice. The number of macrophages, chemotactic activity of macrophages and blastogenic response of lymphocytes were recovered to the same or more than that of normal levels. An extract of Ginseng radix showed protective effects on the number and functions of macrophages by treatment with CY but did not show any effects on the lymphocytic blastogenesis. On the contrary it showed a strong inhibitory effect on the NK cell activity. These results suggest that Chinese herbs could modulate cellular immune response, espeically in the activation of macrophages and splenic lymphocytes.