Structure-activity-relationship studies on dihydrofuran-fused perhydrophenanthrenes as an anti-Alzheimer's disease agent.

As an extended study on development of anti-Alzheimer's disease agent, we newly synthesized various dihydrofuran-fused perhydrophenanthrenes via o-quinodimethane chemistry. This study revealed that the introduction of carbon side-chain on 8-position or removal of the acetal moiety on 3-position arose a cytotoxicity on rat cortical neurons. On the other hand, the ethereal or thio-ethereal substituent on 8-position enhanced the elongation effect on Aβ-damaged neurons.

Efficient approach to 1,2-diazepines via formal diazomethylene insertion into the C-C bond of cyclobutenones.

Efficient monocyclic 1,2-diazepine formation via a tandem electrocyclization reaction of cyclobutenones with lithiodiazoacetate is demonstrated. The reaction proceeds through an oxy anion-accelerated 4π-ring opening of cyclobutene followed by an 8π-ring closure of the resultant oxy anion-substituted diazo-diene under mild conditions to furnish a 1,2-diazepine via formal diazomethylene insertion into the C-C bond of cyclobutenone.

Synthesis and biological evaluation of pyrethroid insecticide-derivatives as a chemical inducer for Bdnf mRNA expression in neurons.

Brain-derived neurotrophic factor (BDNF) plays a fundamental role in neuronal synaptic plasticity. A decrease of plasticity in the brain may be related to the pathogenesis of neurodegenerative or psychiatric disorders. Pyrethroid insecticides, which affect sodium channels in neurons, are widely used to control insect pests in agriculture and in the home.

Synthesis of dihydrofuran-fused perhydrophenanthrenes having a phenolic hydroxyl group as a novel anti-Alzheimer's disease agent.

As a part of our research program on developing novel anti-Alzheimer's disease medicines, several dihydrofuran-fused perhydrophenanthrenes (DFs) possessing a phenolic hydroxyl group were found to exhibit potent dendritic and axonal regeneration activities. Introduction of a methoxy group into the perhydrophenanthrene skeleton was successfully achieved via a PhI(OAc)(2)-mediated phenolic oxidation of a benzocyclobutene nucleus and subsequent tandem intramolecular electrocyclic reactions based on o-quinodimethane chemistry. We could reveal that a new methoxy derivative having a phenolic hydroxyl group exerted the most significant effects on the dendritic and axonal extensions in the damaged neurons, among DFs examined in this study.

Synthesis and anti-influenza virus activity of dihydrofuran-fused perhydrophenanthrenes with a benzyloxy-type side-chain.

As one of our ongoing research project concerning development of a novel anti-influenza virus agent, dihydrofuran-fused perhydrophenanthrenes were derivatized by means of Williamson ether synthesis and Suzuki-Miyaura cross coupling reactions. Newly synthesized compounds were subjected to evaluation of anti-influenza virus activity using influenza A/Aichi/2/68 (H3N2 subtype) virus strain by a plaque titration method. These investigations revealed that incorporation of benzyl-type ether substituents was effective for exerting the inhibition activity of influenza virus proliferation.

Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice.

Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD.

Synthesis of sominone and its derivatives based on an RCM strategy: discovery of a novel anti-Alzheimer's disease medicine candidate "denosomin".

Synthesis of sominone was achieved starting from dehydroepiandrosterone on the basis of an RCM strategy for the construction of a delta-lactone side chain. This synthetic protocol was applied for the synthesis of several analogous derivatives including 1-deoxy-24-norsominone (denosomin), which was revealed to exhibit notable bioactivities for new antidementia chemotherapy, exceeding the original natural compound sominone.

Efficient enantio- and diastereodivergent synthesis of poison-frog alkaloids 251O and trans-223B.

An efficient and flexible synthesis of poison-frog alkaloids 251O and trans-223B has been achieved by using for both alkaloids an enantiodivergent process starting from the common lactam 1. The relative stereochemistry of 251O and trans-223B was determined to be 7 (R = n-C(7)H(15), R' = n-Pr) and 14 by the present enantioselective synthesis.

Design, synthesis, and biological evaluation of artificial macrosphelides in the search for new apoptosis-inducing agents.

Various artificial macrosphelides were designed and synthesized, including ring-enlarged analogues and epothilone-hybrid compounds. Syntheses were accomplished in an efficient manner by using a ring-closing metathesis (RCM) strategy in a key macrocyclization step. Biological evaluation of these new macrosphelide-based derivatives revealed that several epothilone hybrids, in which a thiazole-containing side chain was incorporated, exhibited potent apoptosis-inducing activity toward human lymphoma cells.

Novel 3,4-diazabenzotropone compounds (2,3-benzodiazepin-5-ones): synthesis, unique reactivity, and biological evaluation.

Efficient synthesis of 3,4-diazabenzo[b]tropone was first achieved utilizing 4pi-8pi sequential electrocyclic reactions of functionalized benzocyclobutenone derivatives. These compounds are highly electron deficient and readily form amine adducts at ambient temperature. Furthermore, gentle heating resulted in quantitative nitrogen extrusion to produce indenone derivatives.

Mechanism of apoptosis induced by a newly synthesized derivative of macrosphelides with a thiazole side chain.

The apoptosis-inducing ability of hybrid compounds composed of macrosphelide and thiazole-containing side chain of epothilones was investigated. Among the tested series of hybrid compounds the one containing thiazole side chain at C15 (MSt-2) showed the maximum potency to induce apoptosis, while another containing thiazole side chain at C3 (MSt-6) was less potent. MSt-2 was found to induce apoptosis in human lymphoma (U937) cells in a dose- and time-dependent manner as confirmed by DNA fragmentation analysis.

Enantioselective syntheses of (-)- and (+)-monomorine I.

A concise enantioselective total synthesis of unnatural (-)-monomorine I has been achieved starting from lactam 2 in 54% overall yield. Natural (+)-monomorine I was also synthesized.

Kinetically controlled ring-closing metathesis: synthesis of a potential scaffold for 12-membered salicylic macrolides.

For the synthesis of a 12-membered salicylic macrolide scaffold, ring-closing metathesis (RCM) of a omega-diene compound was planned. The stereochemical outcome of the RCM reaction changed depending on the type of Ru catalyst that was used; a "first-generation" Grubbs catalyst produced exclusively the E isomer and "second-generation" catalysts provided a mixture of the E and Z isomers under kinetic control (not thermodynamic control). Considerations for the E/Z selectivity are described.

Evidence for separate involvement of different mu-opioid receptor subtypes in itch and analgesia induced by supraspinal action of opioids.

The common adverse effect of centrally-injected mu-opioid receptor (mu-OR) agonists is pruritus. This study was conducted using mice to examine whether different subtypes of mu-OR would be responsible for pruritus and analgesia. Intracisternal injections of morphine and morphine-6beta-glucronide (M6G), but not M3G, produced an antinociceptive effect.

Three-component coupling reaction and cyclization of N-tosylimines and TMS-substituted propiolate mediated by DABCO.

A new three-component coupling reaction of methyl 3-trimethylsilylpropiolate, N-tosylimine, and tosylamide mediated by DABCO was developed. This reaction was based on the consecutive alpha- and beta-activation method of propiolate involving intramolecular silyl migration previously developed by our group. On the basis of these results, a new cyclization reaction was designed to find a chromene-forming reaction utilizing salicyl N-tosylimine as a bifunctional substrate.

Enhancement of hyperthermia-induced apoptosis by a new synthesized class of benzocycloalkene compounds.

The aim of this study was to examine whether, a new synthesized class of benzocycloalkene derivatives (BCs), enhances apoptosis induced by hyperthermia. The combined effects of hyperthermia (44 degrees C, 20 min) and BCs on apoptosis in human lymphoma U937 cells were investigated. Among the tested compounds (BC1 approximately 9), the combined treatment of 10 muM BC2 or BC4 and hyperthermia showed the largest potency to induce DNA fragmentation at 6 h after hyperthermia.

Flexible synthetic routes to poison-frog alkaloids of the 5,8-disubstituted indolizidine-class I: synthesis of common lactam chiral building blocks and application to the synthesis of (-)-203A, (-)-205A, and (-)-219F.

Background: The 5,8-disubstituted indolizidines are the largest class of poison-frog alkaloids found in anuran skin, and are of considerable interest because of their inhibitory effects on the neuronal nicotinic acetylcholine receptors. Many synthetic strategies for the construction of this nucleus have been reported: however, a flexible route has not been reported to date.

Results: Synthesis of lactam chiral building blocks for the flexible synthesis of the title alkaloids has been achieved using a Michael-type conjugate addition reaction to a chiral cyclic enamine ester as the key step in constructing the trisubstituted piperidine ring system.

Synthesis of poison-frog alkaloids 233A, 235U, and 251AA and their inhibitory effects on neuronal nicotinic acetylcholine receptors.

We previously reported that the synthetic quinolizidine 1-epi-207I is a relatively selective blocker of alpha7 nicotinic acetylcholine receptors. We now synthesized the analogous poison frog alkaloids 233A, 235U, and 251AA, and investigated the biological activities at two major types of neuronal nicotinic receptors. Electrophysiological study showed that the alkaloid 233A blocked alpha7 and alpha4beta2 currents with similar potencies.

Rapid and transient intracellular oxidative stress due to novel macrosphelides trigger apoptosis via Fas/caspase-8-dependent pathway in human lymphoma U937 cells.

The ability of the derivatives of macrosphelides (MS) core (simplified 16-membered core structure of natural MS) to induce apoptosis in human lymphoma U937 cells was investigated. Of the five compounds examined, MS core with ketones at 8 and 14 positions (MS5) showed the highest potency to induce apoptosis, while another, MS3 with one ketone, was minimal potent. MS5 was found to induce apoptosis in the U937 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis.

OSW-1 analogues: modification of the carbohydrate moiety.

4 OSW-1 analogues featuring modified carbohydrate moieties were prepared. The purpose of these modifications was to assess the importance of certain chemical functions with respect to biological activity. The synthesis and biological activity of the target molecules are shown.

Synthetic organic chemistry based on small ring compounds.

Small ring systems are important topics in both organic and inorganic chemistry, and draw considerable attention from both theoretical and preparative perspectives. This review intends to summarize the studies, focusing on the preparative aspects, that have been carried out in our laboratory. Namely, synthesis of (+)- and (-)-alpha-cuparenone, (+)-ipomeamarone, (+)-epiipomeamarone, (-)-ngaione, (-)-alpha-bisabolol, (-)-aplysin, (-)-debromoaplysin, (-)-mesembrine, (-)-filiformin, (-)-debromofiliformin, and (-)-4-deoxyverrucarol via successive asymmetric epoxidation and enantiospecific ring expansion of cyclopropylidenes, (+)-equilenin via successive ring expansion-insertion reaction, estrone, estradiol, chenodeoxycholic acid, 19-norspironolactone, 19-nordeoxycorticosterone, cortisone, adrenosterone, 11-oxoprogesterone, and 1alpha,25-dihydroxyvitamin D3 via intramolecular cycloaddition reaction of o-quinodimethanes.

Enhancement of hyperthermia-induced apoptosis by a new synthesized class of furan-fused tetracyclic compounds.

The combined effects of hyperthermia (44 degrees C, 20 min) or X-rays (10 Gy) and a new class of furan-fused tetracyclic synthesized compounds (DFs), on apoptosis in human lymphoma U937 cells were investigated. Among the tested compounds (DF1 approximately 6), the combined treatment of 10 microM DF with TIPS (triisopropylsilyloxy) (Designated #3 DF3) and hyperthermia showed the largest potency to induce DNA fragmentation at 6 h after hyperthermia but no enhancement was observed if it was combined with X-rays. Enhancement of hyperthermia-induced apoptosis by DF3 in a dose-dependent manner was observed.

Flexible synthesis of poison-frog alkaloids of the 5,8-disubstituted indolizidine-class. II: Synthesis of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors.

Background: The 5,8-disubstituted indolizidines constitute the largest class of poison-frog alkaloids. Some alkaloids have been shown to act as noncompetitive blockers at nicotinic acetylcholine receptors but the proposed structures and the biological activities of most of the 5,8-disubstituted indolizidines have not been determined because of limited supplies of the natural products. We have therefore conducted experiments to confirm proposed structures and determine biological activities using synthetic compounds.

Synthesis and anti-tumor activity of a fluorinated analog of medroxyprogesterone acetate (MPA), 9alpha-fluoromedroxyprogesterone acetate (FMPA).

We synthesized 9alpha-fluoromedroxyprogesterone acetate (FMPA) in order to test whether it is a more potent anti-angiogenic agent than medroxyprogesterone acetate (MPA), which has been widely used as a therapeutic agent for breast and endometrium cancers. FMPA was previously synthesized in 10 steps (total yield: 1%). An efficient synthesis of FMPA has been achieved in 6 steps (total yield: 12%).

Synthesis and biological evaluation of dihydrofuran-fused perhydrophenanthrenes as a new anti-influenza agent having novel structural characteristic.

Dihydrofuran-fused perhydrophenanthrenes were synthesized by means of o-quinodimethane chemistry with high generality and stereoselectivity, and found to exhibit potent anti-influenza activity. These compounds exerted an inhibitory effect on various strains of influenza virus growth, including influenza A and B, with a concentration dependent manner, and direct cytotoxicity was low. Several biological experiments suggested that these new drugs affected a virus replication process before mRNA synthesis stage.