Asymmetric Total Synthesis of (-)-Lemnalemnane A.

The asymmetric total synthesis of lemnalemnane A, a rare rearranged sesquiterpenoid, has been accomplished in 13 steps from (S)-carvone. The key features of the synthesis are the removal of the isopropenyl group derived from (S)-carvone via a radical intermediate, the formation of the bicyclo[3.3.1]nonane skeleton using the Dieckmann condensation, the stereocontrolled construction of five continuous chiral centers by chemo- and stereoselective reduction and stereoselective introduction of the alkyne group, and the formation of the spirolactone moiety via a hemiacetal intermediate.

Total synthesis of highly oxygenated phomopsol B via acid-induced etherification to construct a bridged structure.

The first total synthesis of phomopsol B has been achieved in a racemic form. The synthesis comprises a deacetylative cyclization to construct a bicyclic skeleton followed by primary alcohol-assisted dihydroxylation, ether cyclization to construct a dioxabicyclo [3.2.1] skeleton and γ-lactone formation based on oxidation by TEMPO.

Total synthesis of applanatumol A.

The first total synthesis of applanatumol A has been achieved in a highly stereocontrolled manner. The synthetic method includes assembly of the contiguous chiral centers by convergent Fráter-Seebach alkylation, construction of the seven-membered ring by intramolecular aldol reaction, and stereoselective tandem cyclization to form the tetracyclic skeleton.

Total Synthesis of Asperaculin A.

The racemic total synthesis of asperaculin A, a sesquiterpenoid lactone with an unprecedented structure, has been accomplished in 17 steps from 3-methyl-2-cyclopentenone. Key features of the synthesis are the construction of a central all-carbon quaternary center using the Johnson-Claisen rearrangement, stereocontrolled introduction of a cyano group, and acid-mediated γ-lactonization.

Total Synthesis of Lucidumone through Convenient One-pot Preparation of the Tetracyclic Skeleton by Claisen Rearrangement and Subsequent Intramolecular Aldol Reaction.

The total synthesis of lucidumone (1), a Ganoderma meroterpenoid, was accomplished in racemic form from easily prepared 6 and 7 in 10 steps as the longest linear sequence. The synthesis was completed through one-pot preparation of the tetracyclic core skeleton by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo [2.2.2] octane skeleton fused to an indanone structure. The enantioselective total synthesis of 1 was also described via a chiral transfer strategy in the Claisen rearrangement.

Total Synthesis of Leptosperol B through Stereocontrolled Intramolecular 1,4-Addition to Construct the Octahydronaphthalene Framework.

Leptosperol B, possessing a unique octahydronaphthalene framework and 5-substituted aromatic ring, was isolated from the leaves of Leptospermum scoparium in 2020. The asymmetric total synthesis of leptosperol B was accomplished in 12 steps from (-)-menthone. The efficient synthetic scheme involves regioselective hydration and stereocontrolled intramolecular 1,4-addition to construct the octahydronaphthalene skeleton, followed by the introduction of the 5-substituted aromatic ring.

Roles of peptidyl prolyl isomerase Pin1 in viral propagation.

Peptidyl-prolyl isomerase (PPIase) is a unique enzyme that promotes cis-trans isomerization of a proline residue of a target protein. Peptidyl-prolyl cis-trans isomerase NIMA (never in mitosis A)-interacting 1 (Pin1) is a PPIase that binds to the pSer/pThr-Pro motif of target proteins and isomerizes their prolines. Pin1 has been reported to be involved in cancer development, obesity, aging, and Alzheimer's disease and has been shown to promote the growth of several viruses including SARS-CoV-2. Pin1 enhances the efficiency of viral infection by promoting uncoating and integration of the human immunodeficiency virus. It has also been shown that Pin1 interacts with hepatitis B virus proteins and participates in viral replication. Furthermore, Pin1 promotes not only viral proliferation but also the progression of virus-induced tumorigenesis. In this review, we focus on the effects of Pin1 on the proliferation of various viruses and discuss the underlying molecular mechanisms.

Prolyl isomerase Pin1 plays an essential role in SARS-CoV-2 proliferation, indicating its possibility as a novel therapeutic target.

Novel coronavirus disease 2019 (COVID-19) has emerged as a global pandemic with far-reaching societal impact. Here we demonstrate that Pin1 is a key cellular molecule necessary for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) propagation. In this study, siRNA-mediated silencing of Pin1 expression markedly suppressed the proliferation of SARS-CoV-2 in VeroE6/TMPRSS2 cells. In addition, several recently generated Pin1 inhibitors showed strong inhibitory effects on SARS-CoV-2 proliferation, measured by both viral mRNA and protein synthesis, and alleviated the cytopathic effect (CPE) on VeroE6/TMPRSS2 cells. One compound, termed H-77, was found to block SARS-CoV-2 proliferation at an EC50 below 5 µM regardless of whether it was added to the culture medium prior to or after SARS-CoV-2 infection. The inhibition of viral N protein mRNA synthesis by H-77 implies that the molecular mechanism underlying SARS-CoV-2 inhibition is likely to be associated with viral gene transcription or earlier steps. Another Pin1 inhibitor, all-trans retinoic acid (ATRA)-a commercially available drug used to treat acute promyelocytic leukemia (APL) and which both activates the retinoic acid receptor and inhibits the activity of Pin1-similarly reduced the proliferation of SARS-CoV-2. Taken together, the results indicate that Pin1 inhibitors could serve as potential therapeutic agents for COVID-19.

Total Synthesis of ent-Callilongisin B.

The first enantioselective total synthesis of tricyclic diterpenoid callilongisin B, which was isolated from Callicarpa longissima, has been achieved. The synthetic method includes a diastereoselective 1,4-addition and Hosomi-Sakurai allylation followed by Wacker oxidation, intramolecular aldol reaction to construct a six-membered ring, and oxidative dearomatization accompanied by diastereoselective δ-lactonization.

Total Synthesis of Nesteretal A.

The enantioselective total synthesis of nesteretal A was achieved in 15 steps via biomimetic cascade hemiacetalizations at the final key step. Other key features of the total synthesis include Sharpless asymmetric dihydroxylation, diastereoselective 1,2-addition, Pd-catalyzed ene-type cyclization, and stereoselective epoxidation to construct a complex structure containing multiple quaternary carbons.

Pathological Role of Pin1 in the Development of DSS-Induced Colitis.

Inflammatory bowel diseases (IBDs) are serious disorders of which the etiologies are not, as yet, fully understood. In this study, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) protein was shown to be dramatically upregulated in the colons of dextran sodium sulfate (DSS)-induced ulcerative colitis model mice. Interestingly, Pin1 knockout (KO) mice exhibited significant attenuation of DSS-induced colitis compared to wild-type (WT) mice, based on various parameters, including body weight, colon length, microscopic observation of the intestinal mucosa, inflammatory cytokine expression, and cleaved caspase-3. In addition, a role of Pin1 in inflammation was suggested because the percentage of M1-type macrophages in the colon was decreased in the Pin1 KO mice while that of M2-type macrophages was increased. Moreover, Pin1 KO mice showed downregulation of both Il17 and Il23a expression in the colon, both of which have been implicated in the development of colitis. Finally, oral administration of Pin1 inhibitor partially but significantly prevented DSS-induced colitis in mice, raising the possibility of Pin1 inhibitors serving as therapeutic agents for IBD.

Total Synthesis of Stachyodin A via One-Pot Suzuki Coupling for Quick Construction of Carbon Skeleton.

Stachyodin A, possessing a unique spirotetrahydrofuran ring system, was isolated from the roots of Indigofera stachyodes in 2018. The first total synthesis of racemic stachyodin A was accomplished in 14 steps. The efficient stereoselective synthetic route involved one-pot Suzuki coupling and stereocontrolled epoxidation followed by reductive opening and spirocyclization.

Enantioselective Total Synthesis of Mollebenzylanol A.

Mollebenzylanol A is a tyrosine phosphatase 1B inhibitor isolated from the leaves of Rhododendron molle in 2018 that has a highly functionalized structure. The first enantioselective total synthesis of mollebenzylanol A was achieved in 13 steps from a known chiral starting material. An efficient and practical synthetic scheme was disclosed in a stereocontrolled manner, including stereo/regioselective epoxidation, Eschenmoser-Claisen rearrangement, and stereocontrolled dihydroxylation.

Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice.

Pelizaeus-Merzbacher disease (PMD) is characterized as a congenital hypomyelinating disorder in oligodendrocytes, myelin-forming glial cells in the central nervous system (CNS). The responsible gene of PMD is plp1, whose multiplication, deletion, or mutation is associated with PMD. We previously reported that primary oligodendrocytes overexpressing proteolipid protein 1 (PLP1) do not have the ability to differentiate morphologically, whereas inhibition of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) by its cognate siRNA or chemical inhibitor reverses their undifferentiated phenotypes. Here, we show that oligodendrocyte-specific expression of kinase-deficient dominant-inhibitory mutant (MEK2K101A) of MAPK/ERK kinase 2 (MEK2), as the direct upstream molecule of MAPK/ERK in PMD model mice, promotes myelination in CNS tissues. Expression of MEK2K101A in PMD model mice also improves Rotor-rod test performance, which is often used to assess motor coordination in a rodent model with neuropathy. These results suggest that in PMD model mice, MEK2K101A can ameliorate impairments of myelination and motor function and that the signaling through MAPK/ERK may involve potential therapeutic target molecules of PMD in vivo.

Highly stereocontrolled total synthesis of secodolastane diterpenoid isolinearol.

The first asymmetric total synthesis of isolinearol has been achieved with high stereoselectively. The synthetic method includes enatio- and diastereoselective reductive desymmetrization, stereocontrolled introduction of the methallyl group, regio- and stereocontrolled allylation and introduction of the side chain carbonyl group using olefin cross-metathesis with a pinacol vinyl boronic ester.

Development of Pin1 Inhibitors and their Potential as Therapeutic Agents.

The prolyl isomerase Pin1 is a unique enzyme, which isomerizes the cis-trans conformation between pSer/pThr and proline and thereby regulates the function, stability and/or subcellular distribution of its target proteins. Such regulations by Pin1 are involved in numerous physiological functions as well as the pathogenic mechanisms underlying various diseases. Notably, Pin1 deficiency or inactivation is a potential cause of Alzheimer's disease, since Pin1 induces the degradation of Tau. In contrast, Pin1 overexpression is highly correlated with the degree of malignancy of cancers, as Pin1 controls a number of oncogenes and tumor suppressors. Accordingly, Pin1 inhibitors as anti-cancer drugs have been developed. Interestingly, recent intensive studies have demonstrated Pin1 to be responsible for the onset or development of nonalcoholic steatosis, obesity, atherosclerosis, lung fibrosis, heart failure and so on, all of which have been experimentally induced in Pin1 deficient mice. In this review, we discuss the possible applications of Pin1 inhibitors to a variety of diseases including malignant tumors and also introduce the recent advances in Pin1 inhibitor research, which have been reported.

Total Synthesis of Applanatumol B.

The first total synthesis of the tricyclic meroterpenoid applanatumol B, isolated from Ganoderma applanatum, was accomplished in 14 steps from 2,5-dimethoxybenzaldehyde and 4-pentyn-1-ol. The synthetic features include an intramolecular Morita-Baylis-Hillman reaction, a stereoselective Michael addition, and efficient construction of the tricyclic skeleton under acidic conditions involving epimerization at the α-position of the ketone.

Enantioselective Total Synthesis of Diocollettines A.

The first enantioselective total synthesis of diocollettines A was accomplished in only six steps from a known compound. A short and practical synthetic route was disclosed, featuring an intensive investigation of the stereoselective aldol reaction as a key step using an easily prepared aldehyde moiety and an enone derivative. The synthetic scheme also includes the efficient stereocontrolled construction of the tricyclic skeleton of diocollettines A by intramolecular acetal formation, stereoselective dihydroxylation, and intramolecular ether cyclization.

Asymmetric Synthesis and Structure Revision of Guignardone H and I: Development of a Chiral 1,3-Diketone Possessing C2 Symmetry.

A novel chiral 1,3-diketone possessing C2 symmetry was synthesized and utilized in the asymmetric synthesis of guignardone H and I by employing sequential condensation-6π-electrocyclization reactions with the novel 1,3-diketone followed by stereoselective hydrogenation as key steps. Although the synthetic compounds differed from natural guignardone H and I, we realized that the C4-epimers of the proposed structures for guignardone H and I were the actual structures.

Total synthesis of (±)-chondrosterin I using a desymmetric aldol reaction.

The first total synthesis of racemic chondrosterin I was accomplished. The synthetic features include a Michael addition to incorporate a nitro alkane moiety, an oxidative Nef reaction, intramolecular cyclization of the γ-ketoester derivative, and a desymmetric intramolecular aldol reaction of the meso diketoester compound. The present strategy will be applicable to the synthesis of an optically active form by asymmetric desymmetrization.