Aspects for development of novel antibacterial medicines using a vitamin D decomposition product in Helicobacter pylori infection.

A previous study by our group demonstrated that a vitamin D decomposition product (VDP1) acts as the selective bactericidal substance on Helicobacter pylori. VDP1 is an indene compound modified with a carbonyl and an alkyl. The alkyl of VDP1 turned out to be a mandatory structure to exert effective bactericidal action on H.

A novel role of catalase in cholesterol uptake of Helicobacter pylori.

Helicobacter pylori infection is known to be a significant risk factor for the development of gastric cancers in humans. This pathogen exhibits unique biological characteristics in membrane lipid composition. Specifically, H.

A short review, effect of dimethyl-β-cyclodextrin on the interaction between and steroidal compounds.

The 2,6-di--methyl-β-cyclodextrin (dMβCD) is an amphiphilic annular compound consisting of seven dimethyl-glucose molecules. This compound is well known as a solubilizer of lipophilic compounds. Especially, dMβCD extracts cholesterol from the plasma membrane of mammalian cells and releases the cholesterol to the aqueous solution.

Efficient synthesis of 5-(hydroxymethyl)piperazin-2-ones using automatically prepared chiral bromocarboxylic acid and Garner's aldehyde as versatile building blocks.

An efficient method for the synthesis of substituted 5-(hydroxymethyl)piperazin-2-ones was established by using an automated synthesis process. Thirteen piperazinones were synthesized from chiral α-bromocarboxylic acids and Garner's aldehyde which were prepared by using our originally developed automated synthesizer, ChemKonzert®. The automated method of synthesizing chiral α-bromocarboxylic acids was efficient and safe because the rate of the dropwise addition of the reagent can be controlled using the automated synthesizer.

Antibacterial effect of indene on Helicobacter pylori correlates with specific interaction between its compound and dimyristoyl-phosphatidylethanolamine.

Recent studies by our group have suggested that the vitamin D decomposition product VDP1 [(1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one] confers the potent bactericidal action to Helicobacter pylori by targeting the membranal dimyristoyl-phosphatidylethanolamine (di-14:0 PE). In this study we synthesized a new VDP1 derivative to advance further investigation as for the correlative relationship between VDP1 structure and anti-H. pylori activity or PE vesicle collapse induction activity.

Synthesis of 3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene and Reductive Nucleophilic Attack on a Branched Aliphatic Aldehyde.

3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene, which has a double bond between C-9 and C-11 and a phenylsulfenyl group on the terminus of the side chain, is a potential synthetic intermediate for steroids with 9,11-unsaturation or 9,11-seco skeletons. We describe here the synthesis of the title compound from 17-ethylenedioxy-3-acetoxyandrosta-3,5-dien-11-one. The introduction of an ethylene unit to 3β-tert-butyldimethylsiloxyandrosta-5,9(11)-dien-17-one by the action of ethyltriphenylphosphonium bromide under basic conditions resulted in an inseparable mixture of two stereoisomeric products (5 : 1).

Formal synthesis of englerin A utilizing regio- and diastereoselective [4+3] cycloaddition.

Englerin A, a guaiane sesquiterpene isolated from Phyllanthus engleri, showed highly potent and selective growth inhibitory activities against renal cancer cell lines. We synthesized the key tricyclic intermediate from commercially available 2,2-dimethyl-1,3-dioxan-5-one via regio- and diastereoselective [4+3] cycloaddition between the formyl enol silyl ether and the disubstituted furan, in 4.8% total yield over 10 steps.

Synthesis of enantiomerically enriched drug precursors and an insect pheromone via reduction of ketones using commercially available carbonyl reductase screening kit "Chiralscreen® OH".

Commercially available "Chiralscreen® OH" starter kit containing five types of carbonyl reductases (E001, E007, E031, E039, and E078) was used for the reduction of several aromatic and aliphatic ketones to obtain enantiomerically enriched drug precursors and an insect pheromone. Almost stereochemically pure secondary alcohols, used in the synthesis of drugs such as (R)-rasagiline mesylate, (S)-rivastigmine, (R)-chlorphenesin carbamate, and (R)-mexiletine, and the insect pheromone (4S,5R)-sitophilure, were conveniently obtained. The enzymes worked well with ketones containing at least one non-bulky substituent at the carbonyl group.

Short-step syntheses of naturally occurring polyoxygenated aromatics based on site-selective transformation.

Wogonin and astringin were synthesized from inexpensive chrysin and piceid in short steps. The key feature of these syntheses is site-selective transformation. The target molecules were obtained in 27 and 62% yields from the starting materials, respectively.

Synthesis of Linezolid Metabolites PNU-142300 and PNU-142586 toward the Exploration of Metabolite-Related Events.

Linezolid (1) is an oxazolidinone antibiotic that is partially metabolized in vivo via ring cleavage of its morpholine moiety to mainly form two metabolites, PNU-142300 (2) and PNU-142586 (3). It is supposed that accumulation of 2 and 3 in patients with renal insufficiency may cause thrombocytopenia, one of the adverse effects of linezolid. However, the poor availability of 2 and 3 has hindered further investigation of the clinical significance of the accumulation of these metabolites.

Simple Synthesis of Sakuranetin and Selinone via a Common Intermediate, Utilizing Complementary Regioselectivity in the Deacetylation of Naringenin Triacetate.

Sakuranetin and selinone were successfully synthesized utilizing the regioselective deacetylation of naringenin triacetate. Deacetylation of the latter at C-7 with imidazole in 1,4-dioxane at 40°C furnished the corresponding diacetate in 80% yield. Methylation of the obtained free hydroxy group and subsequent removal of the remaining two acetyl groups gave sakuranetin, which was previously isolated as a phytoalexin against rice blast disease fungus, Pyricularia oryzae, in 71% overall yield.

Development of a novel sulfonate ester-based prodrug strategy.

A self-immolative γ-aminopropylsulfonate linker was investigated for use in the development of prodrugs that are reactive to various chemical or biological stimuli. To demonstrate their utility, a leucine-conjugated prodrug of 5-chloroquinolin-8-ol (5-Cl-8-HQ), which is a potent inhibitor against aminopeptidase from Aeromonas proteolytica (AAP), was synthesized. The sulfonate prodrug was considerably stable under physiological conditions, with only enzyme-mediated hydrolysis of leucine triggering the subsequent intramolecular cyclization to simultaneously release 5-Cl-8-HQ and form γ-sultam.

New synthesis of artepillin C, a prenylated phenol, utilizing lipase-catalyzed regioselective deacetylation as the key step.

We have synthesized artepillin C, a diprenylated p-hydroxycinnamate originally isolated from Brazilian propolis and exhibiting antioxidant and antitumor activities, from 2,6-diallylphenol. Replacement of the terminal vinyl with 2,2-dimethylvinyl group by olefin cross-metathesis and subsequent transformation yielded 2,6-diprenyl-1,4-hydroquinone diacetate. Candida antarctica lipase B-catalyzed deacetylation in 2-propanol regioselectively removed the less hindered acetyl group to give 2,6-diprenyl-1,4-hydroquinone 1-monoacetate.

(-)-Benzyl 2,3-dide-oxy-β-d-erythro-hex-2-eno-pyran-oside.

In the title compound, C13H16O4, the six-membered ring of the sugar moiety shows a half-chair conformation. In the crystal, mol-ecules are connected via O-H⋯O hydrogen bonds, forming columns around twofold screw axes along the b-axis direction. There is a disorder of the benz-yloxy group, which has two possible orientations with the phenyl group lying on a common plane [site-occupancy factors = 0.

Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities.

Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity.

Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously suggested that in addition to cyclooxygenase-inhibition at the gastric mucosa, NSAID-induced gastric mucosal cell death is required for the formation of NSAID-induced gastric lesions in vivo. We showed that celecoxib exhibited the most potent membrane permeabilizing activity among the NSAIDs tested.

Formal synthesis of (+)-madindoline A, a potent IL-6 inhibitor, utilizing enzymatic discrimination of quaternary carbon.

A formal synthesis of (+)-madindoline A was achieved. The Sunazuka's key intermediate, (4R,5S)-(-)-3-butyl-4-(tert-butyldimethylsiloxy)-5-methoxycarbonyl-2,5-dimethyl-2-cyclopentenone, was synthesized from easily available (2S,3S)-3-acetoxy-2-ethenyl-2-methylcyclopentanone. The starting material was reliably supplied by a chemo-enzymatic procedure in enantiomerically pure form.

Synthesis of okicamelliaside, a glucoside of ellagic acid with potent anti-degranulation activity.

Okicamelliaside, a glucoside of ellagic acid with potent anti-degranulation activity, was synthesized from ellagic acid. The regioselectivity, solubility, and high reactivity of the intermediates throughout the synthesis were obtained by the complementary use of triisopropylsilyl (TIPS) and methoxyethoxymethyl (MEM) protective groups on the aglycone skeleton.

Triazoyl-phenyl linker system enhancing the aqueous solubility of a molecular probe and its efficiency in affinity labeling of a target protein for jasmonate glucoside.

In methods employing molecular probes to explore the targets of bioactive small molecules, long or rigid linker moieties are thought to be critical factors for efficient tagging of target protein. We previously reported the synthesis of a jasmonate glucoside probe with a highly rigid linker consisting of a triazoyl-phenyl (TAzP) moiety, and this probe demonstrated effective target tagging. Here we compare the TAzP probe with other rigid or flexible probes with respect to target tagging efficiency, hydrophobic parameters, aqueous solubility, and dihedral angles around the biaryl linkage by a combination of empirical and calculation methods.

A chemo-enzymatic expeditious route to racemic dihexanoyl (2R*,3R*,4R*)-dehydroxymethylepoxyquinomycin (DHMEQ), the precursor for lipase-catalyzed synthesis of the potent nuclear factor-κB inhibitor, (2S,3S,4S)-DHMEQ.

In order to synthesize the potent nuclear factor (NF)-κB inhibitor, (2S,3S,4S)-dehydroxymethylepoxyquinomycin (DHMEQ), in a large scale, a new route for its corresponding racemic precursor, dihexanoyl (2R*,3R*,4R*)-DHMEQ, was developed. By employing both hydroquinone and benzoquinone intermediates, the total yield, reproducibility, and synthetic steps were improved and the synthetic cost was reduced.

Hybrid stereoisomers of a compact molecular probe based on a jasmonic acid glucoside: syntheses and biological evaluations.

12-O-β-D-glucopyranosyl jasmonic acid (JAG) shows unique biological activities, including leaf-closing of Samanea saman. It is expected that the mode of action for such regulation is distinct from that of other jasmonates. We developed high-performance compact molecular probes (CMPs) based on JAG that can be used for the FLAG-tagging of JAG target.

A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma.

Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9.

Chemoenzymatic synthesis of (2R,3R,4R)-dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2.

Dehydroxymethylepoxyquinomicin (DHMEQ, 1a) is a specific and potent inhibitor of NF-κB, and it is now being developed as an anti-inflammatory and anticancer agent. While previously only the (2S,3S,4S)-form had been available from the racemate by using lipase-catalyzed enantioselective resolution, in the present study a new route for production of the (2R,3R,4R)-form was established by use of a chemoenzymatic approach. (1R*,2R*,3R*)-2,3-Epoxy-5-N-[(2-hydroxybenzoyl)amino]-4,4-dimethoxycyclohex-5-en-1-ol (2a) was hexanoylated on both secondary and phenolic hydroxy groups, and subjected to Burkholderia cepacia lipase-catalyzed hydrolysis.

Formal total synthesis of fostriecin by 1,4-asymmetric induction with an alkyne-cobalt complex.

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis-cis-trans-triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary.