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Papers - Arai, Midori

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Natural Compounds with BMI1 Promoter Inhibitory Activity from Mammea siamensis and Andrographis paniculata

Fujii Kazuki, Hara Yasumasa, Arai Midori A., Sadhu Samir K., Ahmed Firoj, Ishibashi Masami

Chemical and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 70 ( 12 ) 885 - 891 2022.12

ISSN 00092363

A new coumarin derivative (1) and 30 known compounds were isolated from Mammea siamensis and Andrographis paniculata, guided by B cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) promoter inhibitory activity. Among the isolated compounds, 15 compounds showed BMI1 promoter inhibitory activity, and five compounds were found to be cytotoxic. 14-Deoxy-11,12-dehydroandrographolide (18) was highly cytotoxic to DU145 cells with an IC50 value of 25.4 µM. Western blotting analysis of compound 18 in DU145 cells suggested that compound 18 suppresses BMI1 expression.

病原微生物の浸潤進化に学ぶ休眠遺伝子活性化と創薬

荒井緑

上原記念生命科学財団研究報告集 ((公財)上原記念生命科学財団) 36 1 - 5 2022.12

Dihydromaniwamycin E, a Heat-Shock Metabolite from Thermotolerant Streptomyces sp. JA74, Exhibiting Antiviral Activity against Influenza and SARS-CoV-2 Viruses

S Saito, K Funayama, W Kato, M Okuda, M Kawamoto, T Matsubara, ...

Journal of Natural Products 85 (11), 2583-2591 (American Chemical Society (ACS)) 85 ( 11 ) 2583 - 2591 2022.11

ISSN 01633864

Dihydromaniwamycin E (1), a new maniwamycin derivative featuring an azoxy moiety, has been isolated from the culture extract of thermotolerant Streptomyces sp. JA74 along with the known analogue maniwamycin E (2). Compound 1 is produced only by cultivation of strain JA74 at 45 °C, and this type of compound has been previously designated a "heat shock metabolite (HSM)" by our research group. Compound 2 is detected as a production-enhanced metabolite at high temperature. Structures of 1 and 2 are elucidated by NMR and MS spectroscopic analyses. The absolute structure of 1 is determined after the total synthesis of four stereoisomers. Though the absolute structure of 2 has been proposed to be the same as the structure of maniwamycin D, the NMR and the optical rotation value of 2 are in agreement with those of maniwamycin E. Therefore, this study proposes a structural revision of maniwamycins D and E. Compounds 1 and 2 show inhibitory activity against the influenza (H1N1) virus infection of MDCK cells, demonstrating IC50values of 25.7 and 63.2 μM, respectively. Notably, 1 and 2 display antiviral activity against SARS-CoV-2, the causative agent of COVID-19, when used to infect 293TA and VeroE6T cells, with 1 and 2 showing IC50values (for infection of 293TA cells) of 19.7 and 9.7 μM, respectively. The two compounds do not exhibit cytotoxicity in these cell lines at those IC50concentrations.

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Noaoxazole, a new heat shock metabolite produced by thermotolerant Streptomyces sp. HR41

S Saito, S Suzuki, MA Arai

The Journal of Antibiotics 75 (9), 509-513 (Springer Science and Business Media LLC) 75 ( 9 ) 509 - 513 2022.09

ISSN 00218820

The thermotolerant strain Streptomyces sp. HR41 was found to produce compound 1 only in a 45 °C culture, and not at the standard temperature. We previously designated this type of compound as a “heat shock metabolite” (HSM). NMR and MS analytical techniques were used to determine that the chemical structure of 1 comprised a methylated-oxazole ring and a linear chain moiety modified with a terminal amide group. Thus, 1 was shown to be a new curromycin analog, which we have designated noaoxazole (1). Compound 1 weakly activated Notch signal reporter activity without exhibiting cytotoxicity against assay cells at the same concentration.

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Corrrection to “Two Bioactive Compounds, Uniformides A and B, Isolated from a Culture of Nocardia uniformis IFM0856T in the Presence of Animal Cells”

Yasumasa Hara, Keiichiro Watanabe, Akiko Takaya, Itsuki Ebihara, Teruhisa Manome, Midori A. Arai, Takashi Yaguchi, Masami Ishibashi

Organic Letters (American Chemical Society (ACS)) 24 ( 31 ) 5867 - 5867 2022.08

ISSN 1523-7060

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Identification of 1β, 2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity

Y Makita, S Saito, A Tsuchiya, M Ishibashi, MA Arai

Journal of natural medicines 76, 234-243 (Journal of Natural Medicines) 76 ( 1 ) 234 - 243 2022.01

ISSN 13403443

Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development of Notch signaling inhibitors is eagerly awaited. Notch inhibitory activity-guided fractionation of a Spilanthes acmella extract led to the identification of five sesquiterpene lactones: tagitinin A (1), 1β,2α-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2α-hydroxytirotundin (5). 1β,2α-Epoxytagitinin C (2) exhibited Notch signaling inhibition, with an IC50 of 25.6 μM, and was further evaluated for its activity against HPB-ALL, a Notch-activated leukemia cell line. Compound 2 showed potent cytotoxicity against HPB-ALL (IC50 1.7 μM) and arrested the cell cycle at the G2/M phase, but did not induce apoptotic cell death. Notch inhibitory mechanism analysis suggested that compound 2 transcriptionally suppresses Notch1 mRNA. In addition, we found that oxidative stress induction is critical for Notch signaling inhibition and the cytotoxicity of compound 2. This is the first mechanism of small molecule Notch inhibition. Our results demonstrate that 1β,2α-epoxytagitinin C (2) is a potential anti-leukemia agent and further investigation of this compound is warranted. Graphical abstract: [Figure not available: see fulltext.].

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Two Bioactive Compounds, Uniformides A and B, Isolated from a Culture of Nocardia uniformis IFM0856 (T) in the Presence of Animal Cells (vol 24, pg 4998, 2022)

Y Hara, K Watanabe, A Takaya, I Ebihara, T Manome, MA Arai, T Yaguchi, ...

ORGANIC LETTERS 24 (31), 5867-5867 2022

Corrrection to “Two Bioactive Compounds, Uniformides A and B, Isolated from a Culture of Nocardia uniformis IFM0856T in the Presence of Animal Cells”

Y Hara, K Watanabe, A Takaya, I Ebihara, T Manome, MA Arai, T Yaguchi, ...

Organic Letters 24 (31), 5867-5867 2022

Erratum: Corrrection Two Bioactive Compounds, Uniformides A and B, Isolated from a Culture of Nocardia uniformis IFM0856Tin the Presence of Animal Cells (Organic Letters (2022 …

Y Hara, K Watanabe, A Takaya, I Ebihara, T Manome, MA Arai, T Yaguchi, ...

Organic Letters 2022

Evaluation of Naturally Occurring HIF-1 Inhibitors for Pulmonary Arterial Hypertension.

Midori A Arai, Kota Sakuraba, Yoshinori Makita, Yasumasa Hara, Masami Ishibashi

Chembiochem : a European journal of chemical biology (ChemBioChem) 22 ( 18 ) 2799 - 2804 2021.09

ISSN 14394227

Pulmonary arterial hypertension (PAH) is a rare and severe progressive disorder characterized by high pulmonary artery pressure. Chronic hypoxia causes a metabolic disorder and the Warburg effect in pulmonary arterial smooth muscle cells (PASMCs). Pyruvate dehydrogenase kinase 1 (PDK1) is a key enzyme in Warburg effect increased by hypoxia-inducible factor (HIF-1). We constructed a cell-based luciferase assay system for HIF-1 inhibitors. Using this system, six HIF-1 inhibitors were identified. Among these inhibitors, the effect of tagitinin C (1) on PASMC was investigated. Tagitinin C (1) clearly decreased the amount of HIF-1β and the HIF-1 target PDK1. This result indicates that HIF-1 inhibitors effectively decrease PDK1 activity, which is a cause of the metabolic disorder and Warburg effect observed in PASMCs. Identifying naturally occurring HIF-1 inhibitors could provide novel insights into the development of PAH medications.

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Target Protein-Oriented Isolations for Chemical Biology based on Natural Products

Arai Midori A., Ishibashi Masami

Journal of Synthetic Organic Chemistry, Japan (The Society of Synthetic Organic Chemistry, Japan) 79 ( 7 ) 684 - 693 2021.07

ISSN 00379980

Natural products have contributed to development of medicine for a long time. The structures and bioactivities of natural products often exceed the human knowledge and imagination. We have developed target protein-oriented natural products isolation methods to quick find bioactive compounds from natural resources (compounds mixture). This review summarizes our recent results including protein beads methods and protein plate method for neural stem cells differentiation activators and new cancer drug candidates. Isolated compounds accelerated neural stem cells differentiation and/or showed cytotoxicity against cancer cells. Syntheses of isolated compounds were also described. As protein binding ability tightly related bioactivity, protein based natural products isolation would be a powerful way to find new candidate of medicines.

Target Protein-Oriented Isolations for Bioactive Natural Products

MA Arai

Chemical and Pharmaceutical Bulletin 69 (6), 503-515 (The Pharmaceutical Society of Japan) 69 ( 6 ) 503 - 515 2021.06

Accepted, ISSN 00092363

Natural products are very attractive for development of medicine. Their structure and bioactivities are often beyond human knowledge and imagination. We have developed isolation methods for target protein-oriented natural products so as quickly to discover bioactive compounds from natural resources. This review summarizes our recent results including protein beads methods for neural stem cells differentiation activators and new cancer drug candidates. Syntheses of isolated compounds are described. We also developed protein plate method for identification of protein–protein interaction inhibitors. Because protein binding ability is tightly related to bioactivity, protein-based natural products isolation is a powerful means to find new candidate medicines.

Practical Stereoselective Synthesis of C3‐Spirooxindole‐ and C2‐Spiropseudoindoxyl‐Pyrrolidines via Organocatalyzed Pictet‐Spengler Reaction/Oxidative Rearrangement Sequence

Masaru Kondo, Naoki Matsuyama, Tin Z. Aye, Irshad Mattan, Tomoyuki Sato, Yoshinori Makita, Masami Ishibashi, Midori A. Arai, Shinobu Takizawa, Hiroaki Sasai

Advanced Synthesis & Catalysis (Wiley) 363 ( 10 ) 2648 - 2663 2021.05

ISSN 16154150

A stereoselective synthetic route to chiral C3-spirooxindole- and C2-spiropseudoindoxyl-pyrrolidines was accomplished by an enantioselective organocatalyzed Pictet-Spengler reaction of tryptamines and isotryptamines followed by a diastereoselective oxidative rearrangement using eco-friendly oxidants (i. e., NaOCl ⋅ 5H2O and Oxone®). This sequential reaction enables rapid access to chiral C3-spirooxindole- and C2-spiropseudoindoxyl-pyrrolidines in a one-pot process. A Wnt signaling inhibitory assay of the prepared enantioenriched spiro compounds demonstrated that they exhibited moderate activities. (Figure presented.).

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Isolation of nocobactin NAs as Notch signal inhibitors from Nocardia farcinica, a possibility of invasive evolution

MA Arai, I Ebihara, Y Makita, Y Hara, T Yaguchi, M Ishibashi

The Journal of Antibiotics 74 (4), 255-259 (Journal of Antibiotics) 74 ( 4 ) 255 - 259 2021.04

ISSN 00218820

Notch signaling inhibitors with the potential of immune suppressor production by pathogenic bacteria for easy host infection were searched from extracts of Nocardia sp. Nocobactin NA-a (compound 1) and nocobactin NA-b (compound 2), which have been suggested as pathogenesis factors, were isolated from N. farcinica IFM 11523 isolated from the sputum of a Japanese patient with chronic bronchitis. Compounds 1 and 2 showed Notch inhibitory activities with IC50 values of 12.4 and 17.6 μM, respectively. Compound 1 and 2 decreased of Notch1 protein, Notch intracellular domain, and hairy and enhancer of split 1, which is a Notch signaling target protein. In addition, compounds 1 and 2 showed cytotoxicity against mouse macrophage-like cell line RAW264.7 with IC50 values of 18.9 and 21.1 μM, respectively. These results suggested that the Notch inhibitors production by pathogenic bacteria may increase pathogen infectivity.

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Acacienone, a terpenoid-like natural product having an unprecedented C20 framework isolated from Acacia mangium leaves

Y Hara, Y Totsugi, H Ichikawa, S Harada, K Fujii, F Ahmed, SK Sadhu, ...

Journal of natural medicines 75, 99-104 (Journal of Natural Medicines) 75 ( 1 ) 99 - 104 2021.01

ISSN 13403443

A novel C20 natural product, acacienone (1), was isolated from the leaves of Acacia mangium collected in Bangladesh. The structure of compound 1 was elucidated by spectral studies and X-ray crystallographic analysis. Acacienone (1) possesses a terpenoid-related tetracyclic framework containing 20 carbons with biogenetically unusual structural features: (i) vicinal C1-branches at the C-3 and C-4 positions in the A ring, and (ii) a cyclopentenone D ring in an androsterone-like assembly, lacking a methyl group at the C-13 position.

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Isolation of Peptidolipin NA Derivatives From the Culture of Nocardia arthritidis IFM10035T in the Presence of Mouse Macrophage Cells

Y Hara, D Tanimura, T Manome, MA Arai, T Yaguchi, M Ishibashi

Heterocycles 104 (1), 185-190 (Heterocycles) 104 ( 1 ) 185 - 190 2021

ISSN 03855414

We isolated two peptidolipin NA derivatives, L-Val (6) peptidolipin NA and peptidolipin NA, named as compounds 1 and 2, respectively. These compounds were produced in the co-culture extracts of Nocardia arthritidis IFM10035T and the mouse macrophage cell line J774.1, but not in the single culture of N. arthritidis. Among the two compounds along with nocarjamide (3) isolated from the co-culture of N. tenerifensis and J774.1, compounds 1 and 3 showed higher cytotoxicity against J774.1, with IC50 values of 116 μM and 25 μM, respectively. In addition, compound 1 showed a TRAIL-resistance-overcoming activity in the human gastric adenocarcinoma AGS cells.

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Evaluation of Naturally Occurring HIF‐1 Inhibitors for Pulmonary Arterial Hypertension

MA Arai, K Sakuraba, Y Makita, Y Hara, M Ishibashi

ChemBioChem 22 (18), 2799-2804 2021

Practical Stereoselective Synthesis of C3‐Spirooxindole‐ and C2‐Spiropseudoindoxyl‐Pyrrolidines via Organocatalyzed Pictet‐Spengler Reaction/Oxidative …

M Kondo, N Matsuyama, TZ Aye, I Mattan, T Sato, Y Makita, M Ishibashi, ...

Advanced Synthesis & Catalysis 363 (10), 2648-2663 2021

Target protein-oriented isolation of Hes1 dimer inhibitors using protein based methods.

Midori A Arai, Kaori Morita, Haruka Kawano, Yuna Makita, Manami Hashimoto, Akiko Suganami, Yutaka Tamura, Samir K Sadhu, Firoj Ahmed, Masami Ishibashi

Scientific reports (Scientific Reports) 10 ( 1 ) 1381 - 1381 2020.12

Accepted

Natural products isolation using protein based methods is an attractive for obtaining bioactive compounds. To discover neural stem cell (NSC) differentiation activators, we isolated eight inhibitors of Hes1 dimer formation from Psidium guajava using the Hes1-Hes1 interaction fluorescent plate assay and one inhibitor from Terminalia chebula using the Hes1-immobilized beads method. Of the isolated compounds, gallic acid (8) and 4-O-(4"-O-galloyl-α-L-rhamnopyranosyl)ellagic acid (11) showed potent Hes1 dimer formation inhibitory activity, with IC50 values of 10.3 and 2.53 μM, respectively. Compound 11 accelerated the differentiation activity of C17.2 NSC cells dose dependently, increasing the number of neurons with a 125% increase (5 μM) compared to the control.

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Total synthesis of lindbladione, a Hes1 dimerization inhibitor and neural stem cell activator isolated from Lindbladia tubulina.

Midori A Arai, Yuna Makita, Yumi Yamaguchi, Haruka Kawano, Akiko Suganami, Yutaka Tamura, Masami Ishibashi

Scientific reports (Scientific Reports) 10 ( 1 ) 21433 - 21433 2020.12

Lindbladione (1) is a neural stem cell differentiation activator isolated from Lindbladia tubulina by our group. Hes1 dimerization inhibitory activity of lindbladione (1) was discovered using our original fluorescent Hes1 dimer microplate assay. We also found that lindbladione (1) accelerates the differentiation of neural stem cells. We conducted the first total synthesis of lindbladione (1) via Heck reaction of 1-hexene-3-one 7 with iodinated naphthoquinone 12, which was provided by Friedel-Crafts acylation followed by Claisen condensation, in the presence of Pd (II) acetate. Careful deprotection of the benzyl groups of 13 successively provided lindbladione (1). Synthesized lindbladione (1) exhibited potent Hes1 dimer inhibition (IC50 of 2.7 μM) in our previously developed fluorescent Hes1 dimer microplate assay. Synthesized lindbladione (1) also accelerated the differentiation of C17.2 mouse neural stem cells into neurons dose dependently, increasing the number of neurons by 59% (2.5 μM) and 112% (10 μM) compared to the control. These activities are comparable to those of naturally occurring lindbladione (1) isolated from L. tublina.

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