Discovery of Spirosnuolides A-D, Type I/III Hybrid Polyketide Spiro-Macrolides for a Chemotherapeutic Lead against Lung Cancer.

Four new macrolides, spirosnuolides A-D (-, respectively), were discovered from the termite nest-derived sp. INHA29. Spirosnuolides A-D are 18-membered macrolides sharing an embedded [6,6]-spiroketal functionality inside the macrocycle and are conjugated with structurally uncommon side chains featuring cyclopentenone, 1,4-benzoquinone, hydroxyfuroic acid, or butenolide moieties.

Antitumor activity of selenopsammaplin A analog (SPA-10091-HCl) via histone methyltransferase DOT1L degradation and apoptosis induction in castration-resistant prostate cancer cells.

Castrate-resistant prostate cancer (CRPC) is one of the most difficult cancers in men and is characterized by a poor prognosis and a high risk of metastasis. The overexpression of the disruptor of telomeric silencing 1-like (DOT1L), which is a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), has been related to poor outcomes in patients with CRPC. Therefore, targeting DOT1L is considered a potential therapeutic approach to overcome the significant medical challenges of CRPC.

Synthesis and evaluation of N-arylindazole-3-carboxamide derivatives as novel antiviral agents against SARS-CoV-2.

N-Arylindazole-3-carboxamide derivatives synthesized from an anti-MERS-CoV hit compound showed potent inhibitory activities against SARS-CoV-2. Among them, 5-chloro-N-(3,5-dichlorophenyl)-1H-indazole-3-carboxamide (4a) exhibited a potent inhibitory effect (EC = 0.69 µM), low cytotoxicity, and satisfactory in vitro PK profiles.

Enantioselective Michael addition of 3-hydroxy-2-pyridone to nitroolefins using cinchona-derived bifunctional organocatalysts.

Despite the extensive use of N-heteroarenes in pharmaceuticals and natural products, efficient methods for selective alkylation at the C-4 position of 2-pyridone are scarce. We developed an enantioselective Michael addition of 3-hydroxy-2-pyridone to nitroolefins at the C-4 position using cinchona-derived bifunctional squaramide organocatalysts, achieving up to 95% yield and >99% ee. This selectivity is driven by the bifunctional organocatalysts' hydrogen bonding interactions with 3-hydroxy-2-pyridone and nitroolefins under mild conditions.

Enantioselective Synthesis of ()-Sitagliptin via Phase-Transfer Catalytic aza-Michael Addition.

The highly enantioselective synthesis of ()-sitagliptin has been achieved through a series of key steps, including the aza-Michael addition and Baeyer-Villiger oxidation. The enantioselective aza-Michael addition involved the reaction of -butyl β-naphthylmethoxycarbamate with ()-1-(4-methoxyphenyl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one, utilizing a quinine-derived C(9)-urea ammonium catalyst under phase-transfer catalytic conditions. The aza-Michael addition successfully introduced chirality to the amine in ()-sitagliptin with 96% ee.

An RORα agonist, ODH-08, inhibits fibrogenic activation of hepatic stellate cells via suppression of SMAD3.

Aims: Hepatic fibrosis is a dynamic process characterized by the net accumulation of an extracellular matrix resulting from chronic liver injury such as nonalcoholic steatohepatitis. Activation of hepatic stellate cells (HSCs) plays a role in transdifferentiation of quiescent cells into fibrogenic myofibroblasts. We aimed to examine the function of retinoic acid receptor-related orphan receptor alpha (RORα) and its novel agonistic ligand, 1-(4-benzyloxybenzyl)-3-(2-dimethylaminoethyl)-thiourea (ODH-08) against activation of HSCs using hepatic fibrosis mouse models.

Synthesis of chiral malonates by α-alkylation of 2,2-diphenylethyl -butyl malonates via enantioselective phase-transfer catalysis.

An efficient synthetic approach for chiral malonates was established via enantioselective phase transfer catalysis. The α-alkylation of 2,2-diphenylethyl tert-butyl α-methylmalonates with (S,S)-3,4,5-trifluorophenyl-NAS bromide as a phase-transfer catalyst under phase-transfer catalytic conditions successfully produced corresponding α-methyl-α-alkylmalonates; these compounds are versatile chiral building blocks containing a quaternary carbon center in high chemical yields (up to 99%) with excellent enantioselectivities (up to 98% ee). α,α-Dialkylmalonates were selectively hydrolyzed to the corresponding chiral malonic monoacids under basic (KOH/MeOH) and acidic conditions (TFA/CHCl), showing the practicality of the method.

Novel SARS-CoV-2 entry inhibitors, 2-anilinoquinazolin-4(3H)-one derivatives, show potency as SARS-CoV-2 antivirals in a human ACE2 transgenic mouse model.

The ongoing COVID-19 has not only caused millions of deaths worldwide, but it has also led to economic recession and the collapse of public health systems. The vaccines and antivirals developed in response to the pandemic have improved the situation markedly; however, the pandemic is still not under control with recurring surges. Thus, it is still necessary to develop therapeutic agents.

Sadopeptins A and B, Sulfoxide- and Piperidone-Containing Cyclic Heptapeptides with Proteasome Inhibitory Activity from a sp.

New sulfur-bearing natural products, sadopeptins A and B ( and ), were discovered from sp. YNK18 based on a targeted search using the characteristic isotopic signature of sulfur in mass spectrometry analysis. Compounds and were determined to be new cyclic heptapeptides, bearing methionine sulfoxide [Met(O)] and 3-amino-6-hydroxy-2-piperidone (Ahp), based on 1D and 2D NMR spectroscopy along with IR, UV, and MS.

Optimization of 2-Aminoquinazolin-4-(3)-one Derivatives as Potent Inhibitors of SARS-CoV-2: Improved Synthesis and Pharmacokinetic Properties.

We previously reported the potent antiviral effect of the 2-aminoquinazolin-4-(3)-one , which shows significant activity (IC = 0.23 μM) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no cytotoxicity. However, it is necessary to improve the in vivo pharmacokinetics of compound because its area under the curve (AUC) and maximum plasma concentration are low.

Inhibition of adhesion and biofilm formation with small-molecule inhibitors of sortase A from .

Background: , an important Gram-positive pathogen in dental caries, uses sortase A (SrtA) to anchor surface proteins to the bacterial cell wall, thereby promoting biofilm formation and attachment to the tooth surface.

Design: Based on activity-guided separation, inhibitors of SrtA were isolated from and identified through combined spectroscopic analysis. Further effects of isolated SrtA inhibitor on were evaluated on bacterial aggregation, adherence and biofilm formation.

Asymmetric Phase-Transfer Catalytic aza-Michael Addition to Cyclic Enone: Highly Enantioselective and Diastereoselective Synthesis of Cyclic 1,3-Aminoalcohols.

The highly enantioselective aza-Michael reaction of -butyl β-naphthylmethoxycarbamate to cyclic enones has been accomplished by using a new alkaloid derived C(9)-urea ammonium catalyst under phase-transfer catalysis conditions with up to 98% ee at 0 °C. The resulting aza-Michael adducts can be converted to versatile intermediates by selective deprotection and the cyclic 1,3-aminoalcohols by diastereoselective reduction with up to 32:1, which have been widely used as important pharmacophores in pharmaceutical development.

Psammocindoles A-C: Isolation, Synthesis, and Bioactivity of Indole-γ-lactams from the Sponge .

Psammocindoles A-C (-), a new class of indole alkaloids, were isolated from a sponge. By combined spectroscopic analyses, the structures of these compounds were determined to be the indole-γ-lactams derived from three amino acid residues. In addition, an enantiomer psammocindole D (), and the -lactam isomers isopsammocindoles A-D (-) were also synthesized.

Synthesis and biological activity of selenopsammaplin A and its analogues as antitumor agents with DOT1L inhibitory activity.

Disruptor of telomeric silencing-1 like (DOT1L) is a histone H3 methyltransferase which specifically catalyzes the methylation of histone H3 lysine-79 residue. Recent findings demonstrate that DOT1L is abnormally overexpressed and the upregulated DOT1L evokes the proliferation and metastasis in human breast cancer cells. Therefore, the DOT1L inhibitor is considered a promising strategy to treat breast cancers.

Enantioselective Total Synthesis of Alkaloids: (+)-Nitramine, (+)-Isonitramine, (-)-Isonitramine, and (-)-Sibirine via Asymmetric Phase-Transfer Catalytic α-Allylations of α-Carboxylactams.

Many optically active 2-azaspirocyclic structures have frequently been found in biologically active natural products. In particular, alkaloids, (+)-nitramine, (+)-isonitramine, (-)-isonitramine, and (-)-sibirine, have stereogenicity on their quaternary carbon of the 2-azaspiro[5,5]undecane-7-ol structure. To synthesize alkaloids, we developed a new enantioselective synthetic method for chiral α-quaternary lactams via the α-alkylation of α--butoxycarbonyl lactams.

Inhibition of DOT1L by Half-Selenopsammaplin A Analogs Suppresses Tumor Growth and EMT-Mediated Metastasis in Triple-Negative Breast Cancer.

Due to a lack of hormone receptors, current treatment strategies for triple-negative breast cancer (TNBC) are limited with frequent disease recurrence and metastasis. Recent findings have suggested that aberrant methylation of histone H3 lysine 79 residue (H3K79me) by the histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is a potential therapeutic target for TNBC clinical management. Therefore, we developed DOT1L inhibitors as potential antitumor agents against TNBC cells.

Enantioselective Synthesis of (+)-Coerulescine by a Phase-Transfer Catalytic Allylation of Diphenylmethyl -Butyl α-(2-Nitrophenyl)Malonate.

A 7-step enantioselective synthetic method for preparing (S)(+)-coerulescine is reported through the use of diphenylmethyl tert-butyl α-(2-nitrophenyl)malonate (16% overall yield, >99% ee). Allylation is the key step under phase-transfer catalytic conditions (86% ee). This synthetic method can be used as a practical route for the synthesis of various derivatives of (S)(+)-coerulescine for analyzing its structure-activity relationships against its biological activities.

Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells.

Chemistry-oriented synthesis (ChOS) and target deconvolution on neuroprotective effect of a novel scaffold, oxaza spiroquinone.

Here we first time report an unprecedented and unnatural six-membered 1,5-oxaza spiroquinone scaffold with structural novelty, a convenient and efficient synthetic route was developed for the synthesis of new 1,5-oxaza spiroquinone derivatives (1a-1r) in high yields from readily available starting materials. The logic of the present work consists of (1) the identification of a promising unprecedented scaffold from privileged scaffolds of biological active molecules through our 'Chemistry-oriented Synthesis' (ChOS) approach, a compensatory strategy for target-based drug discovery, (2) the positioning of the identified 1,5-oxaza spiroquinone scaffold on neuroinflammation and neurodegenerative disease through nitric oxide (NO) inhibitory activity without cytotoxicity in hyper-activated microglia (IC of NO production: 0.07-1.

Anti-cancer effect of GV1001 for prostate cancer: function as a ligand of GnRHR.

GV1001, a 16-amino acid fragment of the human telomerase reverse transcriptase catalytic subunit (hTERT), has been developed as an injectable formulation of cancer vaccine. Here, we revealed for the first time that GV1001 is a novel ligand for gonadotropin-releasing hormone receptor (GnRHR). The docking prediction for GV1001 against GnRHR showed high binding affinity.

Enantioselective Synthesis of Chiral α-Thio-Quaternary Stereogenic Centers via Phase-Transfer-Catalyzed α-Alkylation of α-Acylthiomalonates.

An efficient synthetic method for establishing chiral α-thio-α-quaternary stereogenic center was successfully developed. The enantioselective α-alkylation of α-acylthiomalonates under phase-transfer catalytic conditions [50% aq. KOH, toluene, -20 °C, and (S,S)-3,4,5-trifluorophenyl-NAS bromide] provided the corresponding α-acylthio-α-alkylmalonates in high chemical yields (up to 99%) and high optical yields (up to 98% ee).

Pharmacological use of a novel scaffold, anomeric N,N-diarylamino tetrahydropyran: molecular similarity search, chemocentric target profiling, and experimental evidence.

Rational drug design against a determined target (disease, pathway, or protein) is the main strategy in drug discovery. However, regardless of the main strategy, chemists really wonder how to maximize the utility of their new compounds by drug repositioning them as clinical drug candidates in drug discovery. In this study, we started our drug discovery "from curiosity in the chemical structure of a drug scaffold itself" rather than "for a specific target".

Enantioselective Synthesis of Chiral α-Azido and α-Aryloxy Quaternary Stereogenic Centers via the Phase-Transfer-Catalyzed α-Alkylation of α-Bromomalonates, Followed by S2 Substitution.

A new efficient synthetic method for chiral α-azido-α-alkylmalonates and α-aryloxy-α-alkylmalonates was developed. The enantioselective α-alkylation of diphenylmethyl tert-butyl α-bromomalonate under phase-transfer catalytic conditions [(S,S)-3,4,5-trifluorophenyl-NAS bromide, 50% KOH, toluene, and -40 °C) provided the corresponding α-bromo-α-alkylmalonates in high chemical yields (≤98%) and high optical yields (≤99% ee). The resulting α-alkylated products were converted to α-azido-α-alkylmalonates (≤96%, ≤97% ee) and α-aryloxy-α-alkylmalonates (≤79%, ≤93% ee) by S2 substitution with sodium azide and aryloxides, respectively.

A synthetic Nitraria alkaloid, isonitramine protects pancreatic β-cell and attenuates postprandial hyperglycemia.

Objective: The extracts of Nitraria genus are composed of Nitraria alkaloids and have been used traditionally as a hypoglycemic medicine. However, the efficacy and precise mechanism of Nitraria alkaloids remain largely unknown.

Methods: Previously, we reported the total synthesis of (+)-isonitramine, one of Nitraria alkaloids.