Taketo Uchiyama

L-threonine aldolase in organic synthesis: Preparation of novel β-hydroxy-α-amino acids

The L-threonine aldolase from Candida humicola was used in the synthesis of multifunctional β-hydroxy-α-amino acids. Of many aldehydes with different substituents tested as substrates for reaction with glycine, benzyloxy- and alkoxy-aldehydes are found to be good substrates, providing a new synthetic route to α-amino-β,ω-dihydroxy and α,ω-diamino-β-hydroxy acids. The enzymatic reactions are not stereospecific regarding the new stereocenter formed at the β-carbon, though they all give L-α-amino acids.

An efficient chemo-enzymatic synthesis of α-amino-β-hydroxy-γ-butyrolactone

Abstract The synthesis of ( 2S,3R )-2- amino-3-hydroxybutyrolactone , a precursor of the monobactam antibiotic Carunoman, has been accomplished in three steps involving the use of L-threonine aldolase.

Design and synthesis of C-linked fucosides as inhibitors of E-selectin

Two series of C-linked fucosides as mimetics for the tetrasaccharide sialyl Lewis X have been synthesized and tested as inhibitors of E-Selectin. The fucopeptides have been prepared from three key intermediates, including alpha-C-allyl fucose, natural and unnatural amino acids bearing hydroxyl groups and an alpha, omega-diacid moiety for the imitation of the essential three parts of SLex, i.e., the Fuc, Gal, and NeuAc. The nature and distance of the linkage of the fucose moiety to the amino acids as well as the distance between the amino acids and the terminal carboxylic acid group turned out to be crucial for the biological activity. In addition the necessity of both OH groups (4- and 6-OH) in the Gal part could be confirmed. Conformational NMR study of the most active mimetic supports the structure-activity relationship. A second series of mimetics was prepared, where Fuc and Gal moieties were purely C-linked. In the synthesis of beta-C-allyl galactose an intramolecular 1,2-hydride shift led to an interesting side product. However, the substituted glycosidic oxygens led to a substantial loss of conformational constrain, which could not be compensated and resulted in low activity.

Separation, synthesis and estrogenic activity of 4-nonylphenols: two sets of new diastereomeric isomers in a commercial mixture.

Two sets of new diastereomeric 4-nonylphenol (NP) isomers [4-(3,4-dimethylheptan-4-yl)phenol (344NP, NP-J, L) and 4-(3,4-dimethylheptan-3-yl)phenol (343NP, NP-K, P)] were separated from a commercial NP mixture. The mixture of these diastereomers was synthesized at the same time by a single Friedel-Crafts reaction of 3,4-dimethyl-4-heptanol and phenol, and the mixture was separated into individual NPs by HPLC equipped with Hypercarb column. For the first time, in this study the stereostructure-estrogenic activity relationship of NP diastereomers was investigated. The NP isomers (NP-L and NP-P) having the beta-methyl group over the benzene ring were found to be 2-4 times more estrogenic than their diastereomers (NP-J and NP-K). In the case of the other set of diastereomer [4-(3,5-dimethylheptan-3-yl)phenol, (353NP, NP-E, G)] containing gamma-methyl group in the molecule, the gamma-methyl proton signal (delta 0.49) in the more estrogenic isomer (NP-G) also appeared in a higher field than the corresponding methyl signal (delta 0.76) of the less estrogenic isomer (NP-E).

seco-Adianane-type triterpenoids from Dorstenia brasiliensis (Moraceae).

Two seco-adianane-type triterpenoids, dorstenic acid A and B, were isolated, along with a known isopimarane-type diterpenoid and six coumarins, from the roots of Dorstenia brasiliensis. Their structures were elucidated on the basis of their spectral data. The two triterpenoids showed moderate cytotoxicity against leukemia cells (L-1210 and HL-60).

Terpenoids and phenethyl glucosides from Hyssopus cuspidatus (Labiatae)

Monoterpenoids (3 and 4), sesquiterpenoid (2), diterpenoid (1) and four phenethyl glucosides (5-8), together with fourteen known compounds, were isolated from the whole herb of Hyssopus cuspidatus. Their structures were determined by spectroscopic means. The abietane-type diterpenoids (1, 9, 10), rosmarinic acid (15) and salvigenin (17) inhibited leukotriene (LT) C(4) secretion from primary alveolar cells of Wistar rats.

Sesquiterpene pyridine alkaloids from Hippocratea excelsa

Nineteen sesquiterpene pyridine alkaloids including 17 new compounds have been isolated from the 70% aq. EtOH extract of stem barks of Hippocratea excelsa. The structures of these compounds were elucidated by various spectroscopic means.

Sesquiterpene lactones derived from Saussurea lappa induce apoptosis and inhibit invasion and migration in neuroblastoma cells

Neuroblastoma is among the most fatal of solid tumors in the pediatric age group, even when treated aggressively. Therefore, a new effective therapeutic drug(s) for neuroblastoma is urgently needed. To clarify the anticancer effects of the sesquiterpene lactones dehydrocostus lactone and costunolide, derived from Saussurea lappa, we examined the cytotoxic and migration/invasion-inhibitory effects of these compounds against neuroblastoma cell lines. Both the compounds exerted significant cytotoxicity against the neuroblastoma cell lines IMR-32, NB-39, SK-N-SH, and LA-N-1. Evidence of cellular apoptosis, such as nuclear condensation and membrane inversion, were observed after treatment with these compounds. Both compounds induced caspase-7 activation and PARP cleavage as confirmed by Western blotting. Furthermore, the sesquiterpene lactones also suppressed invasion and migration of the neuroblastoma cells. These results suggest that dehydrocostus lactone and costunolide are promising candidates for being developed into novel anticancer drugs effective against neuroblastoma.

Neuroprotective effect of S-allyl-l-cysteine derivatives against endoplasmic reticulum stress-induced cytotoxicity is independent of calpain inhibition.

S-allyl-l-cysteine (SAC) is known to have neuroprotective properties. We synthesized various SAC derivatives and tested their effects on endoplasmic reticulum stress-induced neurotoxicity in cultured hippocampal neurons (HPNs). Among the compounds tested, S-propyl-l-cysteine (SPC) exhibited the strongest neuroprotective activity in HPNs, followed by S-ethyl-l-cysteine (SEC) and S-methyl-l-cysteine (SMC). Unlike SAC and SMC, SPC and SEC did not have inhibitory activity on μ-calpain, suggesting that the mechanism underlying the protective activity of SPC and SEC differs from that of SAC.

Ferrearin C induces apoptosis via heme oxygenase-1 (HO-1) induction in neuroblastoma

We investigated the cytotoxicity of six neolignans (1–6), which are similar in structure to furanocyclohexenone with an angular allyl group, in human neuroblastoma cell lines (IMR-32, LA-N-1, NB-39, SK-N-SH) and normal cells [human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF)] using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Two neolignans, ferrearin C (1) and 2, showed significant cytotoxicity in neuroblastoma cells. Typical morphologic features of apoptosis were observed for the ferrearin-type neolignans using Hoechst 33342, and apoptotic cytoplasmic membrane inversion was also induced by ferrearin-type neolignans in IMR-32. Furthermore, a Proteome Profiler Array showed that the ferrearin-type neolignans induced the marked expression of heme oxygenase-1 (HO-1). In a western blot analysis, ferrearin C (1) increased the level of Bax and reduced the level of survivin, indicating the activation of the mitochondrial pathway of apoptosis.