Concise syntheses of (-)-habiterpenol and (+)-2,3--habiterpenol redox radical cyclization of alkenylsilane.

The concise syntheses of (-)-habiterpenol and (+)-2,3--habiterpenol from (3a)-(+)-sclareolide and 6-methoxyindanone in 11 and 12 steps, respectively, were enabled by the regioselective addition of the TMS-indenyl anion and the facile stereoselective metal hydride hydrogen atom transfer (MHAT)-initiated redox radical cyclization of alkenylsilane.

[Comprehensive Studies on the Synthetic Organic Chemistry of Unique Bioactive Natural Products; Total Synthesis, Drug Discovery, and Development of New Reactions].

Research on natural product chemistry via organic chemistry ranges from isolation and structural elucidation to total synthesis, drug discovery, and chemical biology. Discoveries in organic chemistry, such as novel reactions and synthetic strategies, are enabled by the studies of total synthesis. Thus, organic (synthetic) chemistry and natural product chemistry are correlated.

Synthesis and Evaluation of Habiterpenol Analogs.

Habiterpenol is a G2 checkpoint inhibitor isolated from the culture broth of Phytohabitans sp. 3787_5. Here, we report the synthesis of new habiterpenol analogs through the total synthesis process of habiterpenol and evaluating the analogs for G2 checkpoint inhibitory activity.

Mixture of clopidogrel bisulfate and magnesium oxide tablets reduces clopidogrel dose administered through a feeding tube.

Background: In clinical practice, a mixed suspension of clopidogrel bisulfate and magnesium oxide (MgO) tablets is administered frequently via a feeding tube. However, there is no report on the changes occurring when suspensions of these two drugs are combined, including the effects or potential decrease in dose following tube administration. Thus, the purpose of our study was to investigate the (i) changes caused by mixing clopidogrel bisulfate (ion form) and MgO tablets and (ii) effects on the administered clopidogrel dose after passing through a feeding tube.

One-Pot γ-Lactonization of Homopropargyl Alcohols via Intramolecular Ketene Trapping.

A one-pot γ-lactonization of homopropargyl alcohols via an alkyne deprotonation/boronation/oxidation sequence has been developed. Oxidation of the generated alkynyl boronate affords the corresponding ketene intermediate, which is trapped by the adjacent hydroxy group to furnish the γ-lactone. We have optimized the conditions as well as examined the substrate scope and synthetic applications of this efficient one-pot lactonization.

Synthetic, Mechanistic, and Biological Interrogation of Chemical Space En Route to (-)-Bilobalide.

Here we interrogate the structurally dense (1.64 mcbits/Å) GABA receptor antagonist bilobalide, intermediates en route to its synthesis, and related mechanistic questions. C isotope labeling identifies an unexpected bromine migration en route to an α-selective, catalytic asymmetric Reformatsky reaction, ruling out an asymmetric allylation pathway.

Repair of DNA damage induced by the novel nucleoside analogue CNDAG through homologous recombination.

Purpose: We postulate that the deoxyguanosine analogue CNDAG [9-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)guanine] likely causes a single-strand break after incorporation into DNA, similar to the action of its cytosine congener CNDAC, and that subsequent DNA replication across the unrepaired nick would generate a double-strand break. This study aimed at identifying cellular responses and repair mechanisms for CNDAG prodrugs, 2-amino-9-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)-6-methoxy purine (6-OMe) and 9-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)-2,6-diaminopurine (6-NH). Each compound is a substrate for adenosine deaminase, the action of which generates CNDAG.

Concise asymmetric synthesis of (-)-bilobalide.

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood. Antagonism of γ-aminobutyric acid A receptors (GABARs) by bilobalide has been linked to the rescue of cognitive deficits in mouse models of Down syndrome. A lack of convulsant activity coupled with neuroprotective effects have led some to postulate an alternative, unidentified target; however, steric congestion and the instability of bilobalide have prevented pull-down of biological targets other than the GABARs.

Total Synthesis and Absolute Configuration of Simpotentin, a Potentiator of Amphotericin B Activity.

The total synthesis of simpotentin (), a new potentiator of amphotericin B activity against , was achieved. Our research results enabled the access of all stereoisomers of and the elucidation of the unknown absolute configuration of . Furthermore, one of the stereoisomers is a better amphotericin B potentiator than and is an excellent lead compound for the development of a novel amphotericin B potentiator.

Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors.

Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO-1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O-acyltransferase 2 (SOAT2). To aid in the development of new cholesterol-lowering or anti-atherosclerotic agents, new A-ring simplified pyripyropene A analogues have been designed and synthesized based on total synthesis, and the results of structure-activity relationship studies of pyripyropene A. Among the analogues, two A-ring simplified pyripyropene A analogues exhibited equally efficient SOAT2 inhibitory activity to that of natural pyripyropene A.

Scopranones with Two Atypical Scooplike Moieties Produced by Streptomyces sp. BYK-11038.

Three new compounds, designated scopranones A-C, were isolated from the culture broth of a soil isolate, Streptomyces sp. BYK-11038, and shown to be inhibitors of bone morphogenetic protein (BMP) induced alkaline phosphatase activity in a BMP receptor mutant cell line. The structures were elucidated using NMR and other spectral data.

Synthesis of (-)-11-O-Debenzoyltashironin: Neurotrophic Sesquiterpenes Cause Hyperexcitation.

11-O-Debenzoyltashironin (1) is a member of the neurotrophic sesquiterpenes, trace plant metabolites that enhance neurite outgrowth in cultured neurons. We report its synthesis in six steps from a butenolide heterodimer via its likely biosynthetic precursor, 3,6-dideoxy-10-hydroxypseudoanisatin, here identified as the chain tautomer of 1. Access to the tashironin chemotype fills a gap in a comparison set of convulsive and neurotrophic sesquiterpenes, which we hypothesized to share a common target.

Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor.

Nafuredin-γ, obtained from natural nafuredin, has demonstrated a potent and selective inhibitory activity against nematode complex I. However, nafuredin-γ is unstable in air since its conjugated dienes are oxygen-labile. The instability in air was naturally solved by the synthesis of structure-simplified nafuredin-γ analogs without conjugated dienes.

Synthesis and Structural Revision of Cyslabdan.

Cyslabdan was isolated from the culture broth of Streptomyces sp. K04-0144 as a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus. We accomplished the synthesis of cyslabdan according to a previously reported structure.

Simplifungin and Valsafungins, Antifungal Antibiotics of Fungal Origin.

The targets of antifungal antibiotics in clinical use are more limited than those of antibacterial antibiotics. Therefore, new antifungal antibiotics with different mechanisms of action are desired. In the course of our screening for antifungal antibiotics of microbial origins, new antifungal antibiotics, simplifungin (1) and valsafungins A (2) and B (3), were isolated from cultures of the fungal strains Simplicillium minatense FKI-4981 and Valsaceae sp.

New pyripyropene A derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse models.

Sterol O-acyltransferase 2 (SOAT2; also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA: 1,7,11-triacyl type), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA.

Design, synthesis, and biological evaluation of air-stable nafuredin-γ analogs as complex I inhibitors.

Nafuredin-γ (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conjugated dienes are oxygen-labile. To address this, we designed and synthesized air-stable nafuredin-γ analogs.

Synthesis and biological activity of 5-(4-methoxyphenyl)-oxazole derivatives.

5-(4'-Methoxyphenyl)-oxazole (MPO), originally reported as a synthetic compound, was isolated from fungal culture broth as an inhibitor of hatch and growth of Caenorhabditis elegans. Nineteen MPO derivatives were chemically synthesized, but showed no effect on C. elegans hatch and growth.

In vitro metabolism of pyripyropene A and ACAT inhibitory activity of its metabolites.

Pyripyropene A (PPPA, 1) of fungal origin, a selective inhibitor of acyl-CoA:cholesterol acyltransferase 2 (ACAT2), proved orally active in atherogenic mouse models. The in vitro metabolites of 1 in liver microsomes and plasma of human, rabbit, rat and mouse were analyzed by ultra fast liquid chromatography and liquid chromatography/tandem mass spectrometry. In the liver microsomes from all species, successive hydrolysis occurred at the 1-O-acetyl residue, then at the 11-O-acetyl residue of 1, while the 7-O-acetyl residue was resistant to hydrolysis.

Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 3.

In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on pyripyropene A (PPPA, 1). In particular, we investigated the possibility of introducing appropriate 1,11-O-benzylidene and 7-O-substituted benzoyl moieties into PPPA (1). The new o-substituted benzylidene derivatives showed higher selectivity for ACAT2 than PPPA (1).

Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 2.

Synthesis and structure-activity relationships of 7-O-p-cyanobenzoyl pyripyropene A derivatives with modification at C1 and 11 are described. Regioselective mono-deprotection of di-tert-butylsilylene acetal was critical in their synthesis.

Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 1.

In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on pyripyropene A (PPPA, 1). We have successfully developed novel PPPA derivatives with a 7-O-substituted benzoyl substituent that significantly exhibit more potent ACAT2 inhibitory activity and higher ACAT2 isozyme selectivity than 1.

Stereoselective total synthesis of atpenins a4 and b, harzianopyridone, and NBRI23477 B.

The stereoselective total synthesis of atpenins A4 (2) and B (3), harzianopyridone (4), and NBRI23477 B (5) have been developed using a convergent approach involving the coupling reaction of a common iodopyridine with an aldehyde corresponding to the appropriate side chain of the desired compound. Furthermore, the absolute configurations of atpenin B (3), harzianopyridone (4), and NBRI23477 B (5) have been unambiguously determined.

Potentiation of bleomycin in Jurkat cells by fungal pycnidione.

Most cancer cells have mutations in genes at the G1 checkpoint and repair DNA only in the G2 phase; therefore, the G2 checkpoint is a potential target to develop novel therapy. In the course of screening, a known compound, pycnidione, was isolated from the fungal culture broth of Gloeotinia sp. FKI-3416.