Publications by authors named "Koichi Narita"

26 Publications

  • Page 1 of 1

Is branched-chain amino acid nutritional supplementation beneficial or detrimental in heart failure?

World J Cardiol 2021 Jun;13(6):163-169

Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Sarcopenia or cachexia is often complicated in heart failure. Nutritional support, particularly branched-chain amino acid (BCAA) supplementation, is a candidate treatment for improving sarcopenia or cachexia in elderly patients. However, the efficacy of BCAA supplementation in patients with heart failure has not been established, and the issue is comparatively more complex. Indeed, there are conflicting reports on the efficacy of BCAA supplementation. The evidence for including BCAA supplementation in treating patients with heart failure was reviewed, and the complexity of the issue was discussed.
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http://dx.doi.org/10.4330/wjc.v13.i6.163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223699PMC
June 2021

Synthesis and evaluation of trypanocidal activity of derivatives of naturally occurring 2,5-diphenyloxazoles.

Bioorg Med Chem 2021 Jul 12;42:116253. Epub 2021 Jun 12.

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

African trypanosomiasis is a zoonotic protozoan disease affecting the nervous system. Various natural products reportedly exhibit trypanocidal activity. Naturally occurring 2,5-diphenyloxazoles present in Oxytropis lanata, and their derivatives, were synthesized. The trypanocidal activities of the synthesized compounds were evaluated against Trypanosoma brucei brucei, T. b. gambiense, T. b. rhodesiense, T. congolense, and T. evansi. Natural product 1 exhibited trypanocidal activity against all the species/subspecies of trypanosomes, exhibiting half-maximal inhibitory concentrations (IC) of 1.1-13.5 μM. Modification of the oxazole core improved the trypanocidal activity. The 1,3,4-oxadiazole (7) and 2,4-diphenyloxazole (9) analogs exhibited potency superior to that of 1. However, these compounds exhibited cytotoxicity in Madin-Darby bovine kidney cells. The O-methylated analog of 1 (12) was non-cytotoxic and exhibited selective trypanocidal activity against T. congolense (IC = 0.78 µM). Structure-activity relationship studies of the 2,5-diphenyloxazole analogs revealed aspects of the molecular structure critical for maintaining selective trypanocidal activity against T. congolense.
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http://dx.doi.org/10.1016/j.bmc.2021.116253DOI Listing
July 2021

Social and environmental risks as contributors to the clinical course of heart failure.

Heart Fail Rev 2021 May 4. Epub 2021 May 4.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, 113-8655, Tokyo, Japan.

Heart failure is a major contributor to healthcare expenditures. Many clinical risk factors for the development and exacerbation of heart failure had been reported, including diabetes, renal dysfunction, and respiratory disease. In addition to these clinical parameters, the effects of social factors, such as occupation or lifestyle, and environmental factors may have a great impact on disease development and progression of heart failure. However, the current understanding of social and environmental factors as contributors to the clinical course of heart failure is insufficient. To present the knowledge of these factors to date, this comprehensive review of the literature sought to identify the major contributors to heart failure within this context. Social factors for the risk of heart failure included occupation and lifestyle, specifically in terms of the effects of specific occupations, occupational exposure to toxicities, work style, and sleep deprivation. Socioeconomic factors focused on income and education level, social status, the neighborhood environment, and marital status. Environmental factors included traffic and noise, air pollution, and other climate factors. In addition, psychological stress and behavior traits were investigated. The development of heart failure may be closely related to these factors; therefore, these data should be summarized for the context to improve their effects on patients with heart failure. The present study reviews the literature to summarize these influences.
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http://dx.doi.org/10.1007/s10741-021-10116-7DOI Listing
May 2021

Case Report: A Case of Acute Cellular Rejection Due to Atopic Dermatitis Exacerbation 3 Years After Heart Transplantation.

Front Immunol 2021 22;12:630051. Epub 2021 Feb 22.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Little evidence has been presented about the association between previous atopic/allergic disease and graft rejection after solid organ transplantation. Thus, we present a case wherein acute cellular rejection (ACR) after heart transplantation (HTx) was noted along with exacerbation of atopic disease.

Case Summary: A 32-year-old man was admitted at our hospital for regular monitoring of graft rejection. He had undergone heart transplant 3 years prior due to dilated cardiomyopathy. Echocardiogram revealed good biventricular function, and no abnormal findings were found in blood sampling tests. However, biopsy showed moderate ACR [Grade 2R(ISHLT 2004)/3A(ISHLT 1990)], which required twice-repeated steroid pulses with intensified immunosuppression. Meanwhile, his atopic dermatitis, which was diagnosed before having heart failure, was getting worse for the past 6 months. The exacerbation of atopic dermatitis was presumed to be related to the development of the intractable cellular rejection.

Discussion: This case suggested the association of atopic disease and graft rejection after HTx. We examined 76 patients from a cohort of previous studies who underwent HTx at our hospital, which suggested that patients with atopic/allergic disorders such as atopic dermatitis and asthma tended to have a significantly higher frequency of moderate rejection than non-allergic patients. (p = 0.012; Fisher's exact test). Our case also suggests that exacerbation of atopic dermatitis might cause graft rejection of the transplanted organ, so that it is important to carefully evaluate the risk of graft rejection if there is a previous history of atopic/allergic disease.
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http://dx.doi.org/10.3389/fimmu.2021.630051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937951PMC
February 2021

Differences in the prognoses of patients referred to an advanced heart failure center from hospitals with different bed volumes.

Sci Rep 2020 12 3;10(1):21071. Epub 2020 Dec 3.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan.

Few reports have discussed appropriate strategies for patient referrals to advanced heart failure (HF) centers with available left ventricular assist devices (LVADs). We examined the association between the characteristics and prognoses of referred patients with advanced HF and the bed volume of the referring hospitals. This retrospective analysis evaluated 186 patients with advanced HF referred to our center for consultation about the indication of LVAD between January 1, 2015, and August 31, 2018. We divided the patients into two groups according to the bed volume of their referring hospital (high bed volume hospitals (HBHs): ≥ 500 beds in the hospital; low bed volume hospitals (LBHs): < 500 beds). We compared the primary outcome measure, a composite of LVAD implantation and all-cause death, between the patients referred from HBHs and patients referred from LBHs. The 186 patients with advanced HF referred to our hospital, who were referred from 130 hospitals (87 from LBHs and 99 from HBHs), had a mean age of 43.0 ± 12.6 years and a median left ventricular ejection fraction of 22% [15-33%]. The median follow-up duration of the patients was 583 days (119-965 days), and the primary outcome occurred during follow-up in 42 patients (43%) in the HBH group and 20 patients (23%) in the LBH group. Patients referred from HBHs tended to require catecholamine infusion on transfer more often than those referred from LBLs (36.5% (HBH), 20.2% (LBL), P = 0.021). Kaplan-Meier analysis indicates that the occurrence of the primary outcome was significantly higher in the HBH patients than in the LBH patients (log-rank P = 0.0022). Multivariate Cox proportional hazards analysis revealed that catecholamine support on transfer and long disease duration were statistically significant predictors of the primary outcome. Patients from HBHs had a greater risk of the primary outcome. However, the multivariate analysis did not indicate an association between referral from an HBH and the primary outcome. In contrast, catecholamine support on transfer, long duration of disease, and low blood pressure were independent predictors of the primary outcome. Therefore, these should be considered when determining the timing of a referral to an advanced HF center, irrespective of the bed volume of the referring hospital.
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http://dx.doi.org/10.1038/s41598-020-78162-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713124PMC
December 2020

Concise Syntheses of Violaceoids A and C.

Chem Pharm Bull (Tokyo) 2021 Feb 26;69(2):232-235. Epub 2020 Nov 26.

Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University.

The concise syntheses of two alkylated hydroquinone natural products, violaceoids A and C, were accomplished by a protecting-group-free method employing the commercially available 2,5-dihydroxybenzaldehyde as the starting material. The key strategy of the syntheses is the utilization of alkenylboronic acid as both the coupling and temporary protective reagents to efficiently introduce the requisite alkenyl side chain of violaceoid A. Moreover, the synthesis of violaceoid C is reported here for the first time.
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http://dx.doi.org/10.1248/cpb.c20-00816DOI Listing
February 2021

Association between infectious event and de novo malignancy after heart transplantation.

Heart Vessels 2021 Apr 2;36(4):499-508. Epub 2020 Nov 2.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan.

The aim of the study was to investigate the incidence of and risk factors for de novo malignancy after heart transplantation (HTx) in a single center. We assessed 102 consecutive patients who received HTx and were followed-up in our center regularly for > 1 year from June 2006 to May 2018. We investigated the incidence of and risk factors for de novo malignancy. The cumulative incidence of each malignancy type during the follow-up period was one (0.98%) for skin cancer, four (3.92%) for nonskin solid organ cancer, and six (5.88%) for posttransplant lymphoproliferative disorder (PTLD). The percentage of patients with more than one infectious event ≤ 1 year after HTx was higher in the malignancy group than in the non-malignancy group. Furthermore, Kaplan-Meier analysis revealed that the incidence rate of infectious events was higher in patients with malignancies than in those without (log-rank P < 0.001). After dividing malignancies into a PTLD group and a solid organ malignancy group, we found that negative Epstein-Barr virus serostatus, cytomegalovirus-positive antigenemia, and the occurrence of any viral or gastrointestinal infectious event at ≤ 1 year were more frequent in patients with PTLD than in patients without it. The survival rate was significantly lower for patients with solid organ malignancy than for patients without malignancy. In conclusion, there was a correlation between infectious events and de novo malignancy, particularly in patients with PTLD. We should confirm this finding by conducting a larger cohort study.
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http://dx.doi.org/10.1007/s00380-020-01715-9DOI Listing
April 2021

Efficacy and Safety of Direct Oral Anticoagulant for Treatment of Atrial Fibrillation in Cerebral Amyloid Angiopathy.

Cureus 2020 Aug 30;12(8):e10143. Epub 2020 Aug 30.

Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, JPN.

A 75-year-old man with a history of atrial fibrillation (AF) and anticoagulant therapy presented with a headache. Cerebral amyloid angiopathy (CAA) was diagnosed after MRI of the brain revealed cortical superficial siderosis, lobar intracerebral hemorrhage, and lobar microbleeds. Anticoagulant therapy was carefully discontinued. Several years later, he was admitted with sudden onset left upper-extremity weakness. In addition to CAA bleeding lesions, a diffusion-weighted brain MRI showed multiple infarct lesions of high signal intensity. The administration of edoxaban 7.5 mg/day (later increased up to 30 mg/day) prevented ischemic stroke recurrence without exacerbation of cerebral bleeding. This could indicate that CAA patients with AF who had previous adverse effects from warfarin can safely use newer direct oral anticoagulants, such as edoxaban, to prevent ischemic stroke without danger of cerebral hemorrhage. The superiority of edoxaban as compared with warfarin might be due to its antioxidant effect because vascular oxidative stress plays a causal role in CAA-induced cerebrovascular dysfunction, CAA-induced cerebral hemorrhage, and CAA formation itself. We explained the beneficial effect of edoxaban for CAA by the mechanism of oxidative stress in the paper.
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http://dx.doi.org/10.7759/cureus.10143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462646PMC
August 2020

Clinical importance of respiratory muscle fatigue in patients with cardiovascular disease.

Medicine (Baltimore) 2020 Aug;99(34):e21794

Department of Cardiovascular Medicine, Graduate School of Medicine, the University of Tokyo.

Patients with cardiovascular diseases frequently experience exertional dyspnea. However, the relationship between respiratory muscle strength including its fatigue and cardiovascular dysfunctions remains to be clarified.The maximal inspiratory pressure/maximal expiratory pressure (MIP/MEP) before and after cardiopulmonary exercise testing (CPX) in 44 patients with heart failure and ischemic heart disease were measured. Respiratory muscle fatigue was evaluated by calculating MIP (MIPpost/MIPpre) and MEP (MEPpost/MEPpre) changes.The mean MIPpre and MEPpre values were 67.5 ± 29.0 and 61.6 ± 23.8 cm H2O, respectively. After CPX, MIP decreased in 25 patients, and MEP decreased in 22 patients. We evaluated the correlation relationship between respiratory muscle function including respiratory muscle fatigue and exercise capacity evaluated by CPX such as peak VO2 and VE/VCO2 slope. Among MIP, MEP, change in MIP, and change in MEP, only the value of change in MIP had an association with the value of VE/VCO2 slope (R = -0.36, P = .017). In addition, multivariate analysis for determining factor of change in MIP revealed that the association between the change in MIP and eGFR was independent from other confounding parameters (beta, 0.40, P = .017). The patients were divided into 2 groups, with (MIP change < 0.9) and without respiratory muscle fatigue (MIP change > 0.9), and a significant difference in peak VO2 (14.2 ± 3.4 [with fatigue] vs 17.4 ± 4.7 [without fatigue] mL/kg/min; P = .020) was observed between the groups.Respiratory muscle fatigue demonstrated by the change of MIP before and after CPX significantly correlated with exercise capacity and renal function in patients with cardiovascular disease.
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http://dx.doi.org/10.1097/MD.0000000000021794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447364PMC
August 2020

The Efficacy of Lactulose for the Treatment of Hyperammonemic Encephalopathy Due to Severe Heart Failure.

Diagnostics (Basel) 2020 Jan 27;10(2). Epub 2020 Jan 27.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.

Hyperammonemic encephalopathy secondary to heart failure is rare and there had been little reports about effective treatment. Organ hypoperfusion or congestion by heart failure may lead to various organ dysfunctions, and liver and intestinal circulatory impairment might cause ammonia metabolic failure. Here, we report on the case of a patient with hyperammonemic encephalopathy that was secondary to heart failure, which was effectively treated by lactulose.
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http://dx.doi.org/10.3390/diagnostics10020070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168910PMC
January 2020

In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells.

Cancer Med 2019 09 31;8(12):5662-5672. Epub 2019 Jul 31.

Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

Liphagal, isolated from the marine sponge Aka coralliphaga, exhibits phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitory activity and cytotoxic effects in human cancer cells. Siphonodictyal B, the biogenetic precursor of liphagal, also has PI3K inhibitory activity. However, its cytotoxic or antitumor activities have not been evaluated. In this study, we demonstrated that siphonodictyal B inhibits several kinases such as CDK4/6, CDK7, and PIM2 in addition to PI3K in vitro and that siphonodictyal B exhibits more potent cytotoxic effects than liphagal against human colon cancer cell lines. Furthermore, treatment with siphonodictyal B resulted in increased PARP cleavage, a larger sub-G1 fraction, and a larger annexin V-positive cell population, all of which are indicative of apoptosis induction. As a mechanism of apoptosis induction, we found that siphonodictyal B activates the p38 MAPK pathway, leading the upregulation of proapoptotic factors. Moreover, siphonodictyal B increased ROS levels, thus promoting p38 MAPK pathway activation. NAC, an ROS scavenger, almost completely reversed both the cytotoxic and p38 MAPK pathway-activating effects of siphonodictyal B. These results indicate that the p38 MAPK pathway might be involved downstream of ROS signaling as part of the mechanism of siphonodictyal B-induced apoptosis. Finally, siphonodictyal B displayed antitumor effects in a human colon cancer xenograft mouse model and increased p38 phosphorylation in tumor tissue. These results suggest that siphonodictyal B could serve as the basis of a novel anticancer drug.
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http://dx.doi.org/10.1002/cam4.2409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745845PMC
September 2019

A novel approach to oxazole-containing diterpenoid synthesis from plant roots: salviamines E and F.

Org Biomol Chem 2019 01;17(3):655-663

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.

In this study, salviamines E and F, which are structurally unique abietane-type diterpene alkaloids containing an oxazole ring, were efficiently synthesized from a known molecule, 5,7,8-trimethoxy-1-naphthol. The synthetic sequence involves the following crucial steps: (i) the assembly of a carbon skeleton by coupling a six-carbon homoprenyl unit with a naphthalene moiety (Kumada-Tamao-Corriu coupling); (ii) the construction of a tricyclic phenanthrene ring by acid-induced cyclization of a naphthalene derivative with a homoprenyl side chain; (iii) the formation of an oxazole ring by nucleophilic ring closure of a 2-aminophenylene-1,4-diyl-diformate or -diacetate moiety and (iv) Friedel-Crafts acetylation at the C13 position of the tetracyclic intermediates to obtain the two target molecules, salviamines E and F. To the best of our knowledge, salviamine synthesis is reported here for the first time.
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http://dx.doi.org/10.1039/c8ob03030hDOI Listing
January 2019

A novel approach to sesquiterpenoid benzoxazole synthesis from marine sponges: nakijinols A, B and E-G.

Org Biomol Chem 2018 05;16(19):3639-3647

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.

Nakijinols A, B and analogues E through G, which are structurally unique and biologically significant sesquiterpenoid benzoxazoles, can be efficiently obtained in a highly unified manner from the sesquiterpenoid quinone, smenospongine. The starting material is accessible from the (+)-5-methyl Wieland-Miescher ketone. The synthetic method features strategic construction of the requisite dihydroxylated benzoxazole substructure via the ring closure of the N-(2-hydroxyphenyl)-formamide or -acetamide moiety. The synthesis of nakijinols is reported here for the first time. The absolute configurations of nakijinols A and E were also established.
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http://dx.doi.org/10.1039/c8ob00721gDOI Listing
May 2018

Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3-kinase dual inhibitor.

Cancer Sci 2017 Jul 19;108(7):1469-1475. Epub 2017 May 19.

Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors. Subsequently, we identified FK-A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC/PI3K dual inhibitor. In this study, we reveal the in vitro and in vivo efficacy of FK-A11 in HT1080 fibrosarcoma and PC3 prostate cancer cell xenograft mouse models. FK-A11 showed in vivo antitumor activity by both i.v. and i.p. administration in a dose-dependent manner. In both xenograft models, FK-A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with in vitro anti-cell proliferation effects and the potency of HDAC/PI3K dual inhibition. In addition, we showed evidence of HDAC/PI3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of FK-A11 in mice. These findings will be essential for guiding further preclinical and clinical studies.
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http://dx.doi.org/10.1111/cas.13255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497724PMC
July 2017

Total Synthesis of Thailandepsin B, a Potent HDAC Inhibitor Isolated from a Microorganism.

Chem Pharm Bull (Tokyo) 2016 ;64(7):913-7

Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University.

Thailandepsin B, a bicyclic depsipeptide histone deacetylase inhibitor, was efficiently synthesized in 51% overall yield in eight steps, starting from commercially available D-norleucine methyl ester and known (S,E)-3-(4-methoxybenzyloxy)-7-(tritylthio)hept-4-enoic acid. The method features a convergent approach in which the corresponding seco-acid, a key precursor in macrolactonization, is directly assembled through the condensation of a D-allo-isoleucine-D-cysteine-containing segment with a D-norleucine-containing segment.
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http://dx.doi.org/10.1248/cpb.c16-00060DOI Listing
January 2017

Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors.

Eur J Med Chem 2016 Oct 18;121:592-609. Epub 2016 May 18.

Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address:

Novel C4- and C7-modified FK228 analogues were efficiently synthesized in a highly convergent and unified manner. This synthesis features the amide condensation of glycine-d-cysteine-containing segments with d-valine-containing segments for the direct assembly of the corresponding seco-acids, which are key precursors of macrolactones. The HDAC inhibition assay and cell-growth inhibition analysis of the synthesized analogues revealed novel aspects of their structure-activity relationship. This study demonstrated that simple modification at the C4 and C7 side chains in FK228 is effective for improving both HDAC inhibitory activity and isoform selectivity; moreover, potent and highly isoform-selective class I HDAC1 inhibitors were identified.
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http://dx.doi.org/10.1016/j.ejmech.2016.05.031DOI Listing
October 2016

Low-dose spiruchostatin-B, a potent histone deacetylase inhibitor enhances radiation-induced apoptosis in human lymphoma U937 cells via modulation of redox signaling.

Free Radic Res 2016 Jun 24;50(6):596-610. Epub 2016 Apr 24.

a Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan ;

Spiruchostatin B (SP-B), is a potent histone deacetylase (HDAC) inhibitor, in addition to HDAC inhibition, the pharmacological effects of SP-B are also attributed to its ability to produce intracellular reactive oxygen species (ROS), particularly H2O2. In this study, we investigated the effects of low dose (non-toxic) SP-B on radiation-induced apoptosis in human lymphoma U937 cells in vitro. The treatment of cells with low-dose SP-B induced the acetylation of histones, however, does not induce apoptosis. Whereas, the combined treatment with SP-B and radiation significantly enhanced the radiation-induced apoptosis, suggesting the potential role of this combined treatment for future radiation therapy. Interestingly, the enhancement of apoptosis was accompanied by significant increased in the ROS generation. Pre-treatment with an antioxidant, N-acetyl-l-cysteine (NAC) significantly inhibited the enhancement of apoptosis induced by combined treatment, indicating that ROS play an essential role. It was also found that SP-B combined with radiation caused the activation of death receptor and intrinsic apoptotic pathways, via modulation of ROS-mediated signaling. Moreover, SP-B also significantly enhanced the radiation-induced apoptosis in other lymphoma cell lines such as Molt-4 and HL-60. Taken together, our findings suggest that the low-dose SP-B enhances radiation-induced apoptosis via modulation of redox signaling because of its ability to serve as an intracellular ROS generating agent, mainly (H2O2 or [Formula: see text]). This study provides further insights into the mechanism of action of SP-B with radiation and demonstrates that SP-B can be used as a future novel sensitizer for radiation therapy.
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http://dx.doi.org/10.3109/10715762.2015.1115029DOI Listing
June 2016

Biochemical, biological and structural properties of romidepsin (FK228) and its analogs as novel HDAC/PI3K dual inhibitors.

Cancer Sci 2015 Feb 28;106(2):208-15. Epub 2015 Jan 28.

Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

Romidepsin (FK228, depsipeptide) is a potent histone deacetylase (HDAC) inhibitor that has FDA approval for the treatment of cutaneous and peripheral T-cell lymphomas. We have previously reported that FK228 and its analogs have an additional activity as phosphatidylinositol 3-kinase (PI3K) inhibitors, and are defined as HDAC/PI3K dual inhibitors. Because a combination of an HDAC inhibitor and a PI3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an HDAC/PI3K dual inhibitor will provide an attractive novel drug for cancer therapy. Using structure-based optimization of the analogs, FK-A11 was identified as the most potent analog. FK-A11 inhibited phosphorylation of AKT and accelerated histone acetylation at lower concentrations, resulting in stronger cytotoxic effects than FK228 and the other analogs in human cancer cells. In this study, we have characterized the biochemical, biological and structural properties of FK228 analogs as PI3K inhibitors. First, FK-A11 is an ATP competitive PI3K inhibitor. Second, FK-A11 is a pan-p110 isoform inhibitor. Third, FK-A11 selectively inhibits PI3K among 22 common cellular kinases. Fourth, conformational changes of FK228 analogs by reduction of an internal disulfide bond have no effect on PI3K inhibitory activity, unlike HDAC inhibitory activity. Finally, molecular modeling of PI3K-FK228 analogs and analyses of the binding affinities identified the structure that defines potency for PI3K inhibitory activity. These results prove our concept that a series of FK228 analogs are HDAC/PI3K dual inhibitors. These findings should help in the development of FK228 analogs as novel HDAC/PI3K dual inhibitors.
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http://dx.doi.org/10.1111/cas.12585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399029PMC
February 2015

Predicting the structures of complexes between phosphoinositide 3-kinase (PI3K) and romidepsin-related compounds for the drug design of PI3K/histone deacetylase dual inhibitors using computational docking and the ligand-based drug design approach.

J Mol Graph Model 2014 Nov 8;54:46-53. Epub 2014 Sep 8.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Miyagi, Japan.

Predictions of the three-dimensional (3D) structures of the complexes between phosphoinositide 3-kinase (PI3K) and two inhibitors were conducted using computational docking and the ligand-based drug design approach. The obtained structures were refined by structural optimizations and molecular dynamics (MD) simulations. The ligands were located deep inside the ligand binding pocket of the p110α subunit of PI3K, and the hydrogen bond formations and hydrophobic effects of the surrounding amino acids were predicted. Although rough structures were obtained for the PI3K-inhibitor complexes before the MD simulations, the refinement of the structures by these simulations clarified the hydrogen bonding patterns of the complexes.
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http://dx.doi.org/10.1016/j.jmgm.2014.08.007DOI Listing
November 2014

Spiruchostatin A and B, novel histone deacetylase inhibitors, induce apoptosis through reactive oxygen species-mitochondria pathway in human lymphoma U937 cells.

Chem Biol Interact 2014 Sep 29;221:24-34. Epub 2014 Jul 29.

Department of Dermatology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Spiruchostatin A (SP-A) and spiruchostatin B (SP-B) are the potent histone deacetylase inhibitors (HDACi), that has the potential for chemotherapy of leukemia but the exact mechanism of these compounds remains unclear. In the present study, the role of reactive oxygen species (ROS) production and the mechanism involved in the apoptosis was investigated in human lymphoma U937 cell. When the U937 cells were treated with SP-A and SP-B for 24h at different concentrations, evidence of apoptotic features, including increase in DNA fragmentation and changes in nuclear morphology, were obtained. SP-B showed maximum potency to induce apoptosis, while SP-A was less potent. Apoptosis was also determined by increase in the fraction of sub-G1 cells and Annexin V-FITC staining cells. SP-A and SP-B induced apoptosis was accompanied by significant increase in the formation of intracellular reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine (NAC), significantly inhibited the SP-A and SP-B mediated apoptosis, suggesting a vital role of ROS involved in the lethality of both agents. Moreover, SP-A and SP-B treatment resulted in the loss of mitochondrial membrane potential (MMP), and Fas, caspase-8 and caspase-3 activation. In addition Bid activation and the release of cytochrome-c to the cytosol was also observed. In this study, we suggest that a marked induction of intracellular ROS mediated mitochondrial pathway and the Fas plays a role in the SP-A and SP-B induced apoptosis. Taken together, our data provides further insights of the mechanism of action of SP-A and SP-B and their potential application as novel chemotherapeutic agents.
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http://dx.doi.org/10.1016/j.cbi.2014.07.004DOI Listing
September 2014

Total synthesis of burkholdacs A and B and 5,6,20-tri-epi-burkholdac A: HDAC inhibition and antiproliferative activity.

Eur J Med Chem 2014 Apr 18;76:301-13. Epub 2014 Feb 18.

Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address:

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors burkholdacs A and B were efficiently synthesized in a highly convergent and unified manner. The synthesis features the amide coupling of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-methionine-containing segment to directly assemble the corresponding seco-acids, key precursors for macrolactonization. Using the same methodology, 5,6,20-tri-epi-burkholdac A was also synthesized. HDAC inhibitory assays and cell-growth inhibition analyses of the synthesized depsipeptides demonstrated the potency order of this class of bicyclic depsipeptides as compared to the clinically approved depsipeptide FK228 (romidepsin). Novel structure-activity relationships within this class of compounds were also revealed.
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http://dx.doi.org/10.1016/j.ejmech.2014.02.044DOI Listing
April 2014

Enantioselective total synthesis of dysidavarone A, a novel sesquiterpenoid quinone from the marine sponge Dysidea avara.

Chemistry 2014 Feb 30;20(9):2436-9. Epub 2014 Jan 30.

Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558 (Japan), Fax: (+81) 22-727-0135.

Dysidavarone A, a structurally unprecedented sesquiterpenoid quinone, was synthesized in 30 % overall yield in a longest liner sequence of 13 steps from commercially available o-vanillin. A highly strained and bridged eight-membered carbocyclic core was established by the C7-C21 carbon bond formation through a copper enolate mediated Michael addition to the internal quinone ring.
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http://dx.doi.org/10.1002/chem.201304809DOI Listing
February 2014

Total synthesis of bicyclic depsipeptides spiruchostatins C and D and investigation of their histone deacetylase inhibitory and antiproliferative activities.

Eur J Med Chem 2013 Feb 21;60:295-304. Epub 2012 Dec 21.

Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins C and D were synthesized for the first time in a highly convergent and unified manner. The method features the amide coupling of a D-leucine-D-cysteine- or D-valine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids, key precursors of macrolactonization. The HDAC inhibitory assay and cell-growth inhibition analysis of the synthesized depsipeptides determined the order of potency of spiruchostatins A-D in comparison with the clinically approved depsipeptide FK228 (romidepsin). Novel aspects of structure-activity relationships (SAR) were revealed.
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http://dx.doi.org/10.1016/j.ejmech.2012.12.023DOI Listing
February 2013

Incorporation and remodeling of phosphatidylethanolamine containing short acyl residues in yeast.

Biochim Biophys Acta 2010 Jun 20;1801(6):635-45. Epub 2010 Feb 20.

Department of Biotechnology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.

Phosphatidylethanolamine (PE) is one of the essential phospholipids in the yeast Saccharomyces cerevisiae. We have previously shown that a yeast strain, the endogenous PE synthesis of which was controllable, grew in the presence of PE containing decanoyl residues (diC10PE) when PE synthesis was repressed. In this study, we investigated the fate of diC10PE, its uptake and remodeling in yeast. Deletion of the genes encoding Lem3p/Ros3p or P-type ATPases, Dnf1p and Dnf2p, impaired the growth of the mutants in the medium containing diC10PE, suggesting the involvement of these proteins in the uptake of diC10PE. Analysis of the metabolism of deuterium-labeled diC10PE by electrospray ionization tandem mass spectrometry revealed that it was rapidly converted to deuterium-labeled PEs containing C16 or C18 acyl residues. The probable intermediate PEs that contained decanoic acid and C16 or C18 fatty acids as acyl residues were also detected. In addition, a substantial amount of decanoic acid was released into the culture medium during growth in the presence of diC10PE. These results imply that diC10PE was remodeled to PEs with longer acyl residues and used as membrane components. Defects in the remodeling of diC10PE in the deletion mutants of ALE1 and SLC1, products of which were capable of acyl-transfer to the sn-2 position of lyso-phospholipids, suggested their involvement in the introduction of acyl residues to the sn-2 position of lyso-phosphatidylethanolamine in the remodeling reaction of diC10PE. Our results also suggest the presence of a mechanism to maintain the physiological length of PE acyl residues in yeast.
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http://dx.doi.org/10.1016/j.bbalip.2010.02.008DOI Listing
June 2010

Total synthesis of the bicyclic depsipeptide HDAC inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B, FK228 (FR901228) and preliminary evaluation of their biological activity.

Chemistry 2009 Oct;15(42):11174-86

Laboratory of Synthetic Medicinal Chemistry, Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia-Kocienski olefination of a 1,3-propanediol-derived sulfone and a L- or D-malic acid-derived aldehyde to access the most synthetically challenging unit, (3S or 3R,4E)-3-hydroxy-7-mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5'' stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell-growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure-activity relationships. It was also found that unnatural 5''-epi-spiruchostatin B shows extremely high selectivity (ca. 1600-fold) for class I HDAC1 (IC(50)=2.4 nM) over class II HDAC6 (IC(50)=3900 nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC(50) values.
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http://dx.doi.org/10.1002/chem.200901552DOI Listing
October 2009

Total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, from a microorganism.

Chem Commun (Camb) 2008 Apr 5(14):1677-9. Epub 2008 Feb 5.

Laboratory of Synthetic Medicinal Chemistry, Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.

The first total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, was achieved in a convergent manner; the synthesis established stereochemistry at the C5'' position.
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http://dx.doi.org/10.1039/b718310kDOI Listing
April 2008
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