Details of a Researcher - Imoto, Masaya

Papers - Imoto, Masaya

Division display 61 - 80 of about 236 ／ All the affair displays >>

Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase

Magi S., Shitara T., Takemoto Y., Sawada M., Kitagawa M., Tashiro E., Takahashi Y., Imoto M.

Journal of Antibiotics (Journal of Antibiotics) 66 ( 3 ) 165 - 170 2013.03

Research paper (scientific journal), Accepted, ISSN 00218820

In the course of screening for an inhibitor of farnesyl transferase (FTase), we identified two compounds, N-benzyl-aclacinomycin A (ACM) and N-allyl-ACM, which are new derivatives of ACM. N-benzyl-ACM and N-allyl-ACM inhibited FTase activity with IC 50 values of 0.86 and 2.93 μM, respectively. Not only ACM but also C-10 epimers of each ACM derivative failed to inhibit FTase. The inhibition of FTase by N-benzyl-ACM and N-allyl-ACM seems to be specific, because these two compounds did not inhibit geranylgeranyltransferase or geranylgeranyl pyrophosphate (GGPP) synthase up to 100 μM. In cultured A431 cells, N-benzyl-ACM and N-allyl-ACM also blocked both the membrane localization of H-Ras and activation of the H-Ras-dependent PI3K/Akt pathway. In addition, they inhibited epidermal growth factor (EGF)-induced migration of A431 cells. Thus, N-benzyl-ACM and N-allyl-ACM inhibited EGF-induced migration of A431 cells by inhibiting the farnesylation of H-Ras and subsequent H-Ras-dependent activation of the PI3K/Akt pathway. © 2013 Japan Antibiotics Research Association All rights reserved.

Access to Document (DOI)

A chemical genomic study identifying diversity in cell migration signaling in cancer cells

Magi S., Tashiro E., Imoto M.

Scientific Reports (Scientific Reports) 2 823 2012.11

Research paper (scientific journal), Accepted

The aim of this study was to analyze the diversity and consistency of regulatory signaling in cancer cell migration, using a chemical genomic approach. The effects of 34 small molecular compounds were assessed quantitatively by wound healing assay in ten types of migrating cells. Hierarchical clustering was performed on the subsequent migration inhibition profile of the compounds and cancer cell types. The result was that hierarchical clustering accurately classified the compounds according to their targets. Furthermore, the cancer cells tested in this study were classified into three clusters, and the compounds were grouped into four clusters. An inhibitor of JNK suppressed all types of cell migration; however, inhibitors of ROCK, GSK-3 and p38MAPK only inhibited the migration of a subset of cell lines. Thus, our analytical system could easily distinguish between the common and cell type-specific signals responsible for cell migration.

Access to Document (DOI)

[Screening for the drug-seeds of antitumor agents].

Fujimaki T., Imoto M.

Nihon rinsho. Japanese journal of clinical medicine (Nihon rinsho. Japanese journal of clinical medicine) 70 Suppl 8 303 - 307 2012.11

Research paper (scientific journal), Accepted, ISSN 00471852

Synthesis and assignment of the absolute configuration of indenotryptoline bisindole alkaloid BE-54017

Kimura T., Kanagaki S., Matsui Y., Imoto M., Watanabe T., Shibasaki M.

Organic Letters (Organic Letters) 14 ( 17 ) 4418 - 4421 2012.09

Research paper (scientific journal), Accepted, ISSN 15237060

Synthesis of the indenotryptoline bisindole alkaloid, BE-54017, was accomplished using osmium-promoted cis-dihydroxylation of maleimide as a key step. After optical resolution, the absolute configuration of this molecule was determined by comparing its optical rotation and HPLC profile to those obtained for BE-54017 derived from enantiopure cladoniamide A, whose stereochemistry has been reported previously. BE-54017 with the correct absolute stereochemistry induced apoptosis of epidermal growth factor (EGF)-stimulated EGF receptor overexpressing A431 cells and inhibited vacuolar-type H+-ATPase (V-ATPase). © 2012 American Chemical Society.

Access to Document (DOI)

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing

Ri M., Tashiro E., Oikawa D., Shinjo S., Tokuda M., Yokouchi Y., Narita T., Masaki A., Ito A., Ding J., Kusumoto S., Ishida T., Komatsu H., Shiotsu Y., Ueda R., Iwawaki T., Imoto M., Iida S.

Blood Cancer Journal (Blood Cancer Journal) 2 ( 7 ) 2012.07

Research paper (scientific journal), Accepted

The IRE1a-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy. © 2012 Macmillan Publishers Limited All rights reserved.

Access to Document (DOI)

Comprehensive predictions of target proteins based on protein-chemical interaction using virtual screening and experimental verifications

Kobayashi H., Harada H., Nakamura M., Futamura Y., Ito A., Yoshida M., Iemura S., Shin-Ya K., Doi T., Takahashi T., Natsume T., Imoto M., Sakakibara Y.

BMC Chemical Biology (BMC Chemical Biology) 12 2 2012.06

Research paper (scientific journal), Accepted

Background: Identification of the target proteins of bioactive compounds is critical for elucidating the mode of action; however, target identification has been difficult in general, mostly due to the low sensitivity of detection using affinity chromatography followed by CBB staining and MS/MS analysis. Results: We applied our protocol of predicting target proteins combining in silico screening and experimental verification for incednine, which inhibits the anti-apoptotic function of Bcl-xL by an unknown mechanism. One hundred eighty-two target protein candidates were computationally predicted to bind to incednine by the statistical prediction method, and the predictions were verified by in vitro binding of incednine to seven proteins, whose expression can be confirmed in our cell system.As a result, 40% accuracy of the computational predictions was achieved successfully, and we newly found 3 incednine-binding proteins. Conclusions: This study revealed that our proposed protocol of predicting target protein combining in silico screening and experimental verification is useful, and provides new insight into a strategy for identifying target proteins of small molecules. © 2012 Kobayashi et al.; licensee BioMed Central Ltd.

Access to Document (DOI)

Inostamycin enhanced TRAIL-induced apoptosis through DR5 upregulation on the cell surface

Yamamoto K., Makino M., Watanapokasin R., Tashiro E., Imoto M.

Journal of Antibiotics (Journal of Antibiotics) 65 ( 6 ) 295 - 300 2012.06

Research paper (scientific journal), Accepted, ISSN 00218820

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a possible therapeutic agent for cancer treatment. This is because of its selective cytotoxicity against various cancer cells without a detrimental effect on normal cells. However, recent studies have reported that the potential application of TRAIL in cancer therapy is limited, as many cancer cells have been found to be resistant to TRAIL. Therefore, small molecule compounds that potentiate the cytotoxicity of TRAIL would be strategic candidates for therapeutic applications in combination with TRAIL. Here we found that a combined treatment of inostamycin and TRAIL synergistically induced caspase-dependent apoptosis in HCT116 cells. Inostamycin upregulated DR5, and a knockdown of DR5 suppressed the apoptosis that was synergistically induced by co-treatment with inostamycin and TRAIL. Moreover, inostamycin increased the expression of DR5 on the cell surface. Therefore, inostamycin-increased cell surface expression of DR5 may have contributed to the enhancement of TRAIL-induced apoptosis. Our study suggests that combined treatment with inostamycin and TRAIL may offer a strategy to overcome TRAIL resistance in tumor cells. © 2012 Japan Antibiotics Research Association All rights reserved.

Access to Document (DOI)

Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein

Sasazawa Y., Kanagaki S., Tashiro E., Nogawa T., Muroi M., Kondoh Y., Osada H., Imoto M.

ACS Chemical Biology (ACS Chemical Biology) 7 ( 5 ) 892 - 900 2012.05

Research paper (scientific journal), Accepted, ISSN 15548929

Autophagy is a bulk, nonspecific protein degradation pathway that is involved in the pathogenesis of cancer and neurodegenerative disease. Here, we observed that xanthohumol (XN), a prenylated chalcone present in hops (Humulus lupulus L.) and beer, modulates autophagy. By using XN-immobilized beads, valosin-containing protein (VCP) was identified as a XN-binding protein. VCP has been reported to be an essential protein for autophagosome maturation. Using an in vitro pull down assay, we showed that XN bound directly to the N domain, which is known to mediate cofactor and substrate binding to VCP. These data indicated that XN inhibited the function of VCP, thereby allowing the impairment of autophagosome maturation and resulting in the accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II). This is the first report demonstrating XN as a VCP inhibitor that binds directly to the N domain of VCP. Our finding that XN bound to and inactivated VCP not only reveals the molecular mechanism of XN-modulated autophagy but may also explain how XN exhibits various biological activities that have been reported previously. © 2012 American Chemical Society.

Access to Document (DOI)

Napyradiomycin A1, an inhibitor of mitochondrial complexes i and II

Yamamoto K., Tashiro E., Motohashi K., Seto H., Imoto M.

Journal of Antibiotics (Journal of Antibiotics) 65 ( 4 ) 211 - 214 2012.04

Research paper (scientific journal), Accepted, ISSN 00218820

Access to Document (DOI)

Target identification of bioactive compounds

Tashiro E., Imoto M.

Bioorganic and Medicinal Chemistry (Bioorganic and Medicinal Chemistry) 20 ( 6 ) 1910 - 1921 2012.03

Research paper (scientific journal), Accepted, ISSN 09680896

To fully understand the regulation of cellular events, functional analysis of each protein involved in the regulatory systems is required. Among a variety of methods to uncover protein function, chemical genetics is a remarkable approach in which small molecular compounds are used as probes to elucidate protein functions within signaling pathways. However, identifying the target of small molecular bioactive compounds isolated by cell-based assays represents a crucial hurdle that must be overcome before chemical genetic studies can commence. A variety of methods and technologies for identifying target proteins have been reported. This review therefore aims to describe approaches for identifying these molecular targets. © 2011 Elsevier Ltd. All rights reserved.

Access to Document (DOI)

Antitumor effects of novel highly hydrophilic and non-ATP-competitive MEK1/2 inhibitor, SMK-17

Kiga M., Tanzawa F., Iwasaki S., Inaba F., Fujiwara K., Iwadare H., Echigo T., Nakamura Y., Shibata T., Suzuki K., Yasumatsu I., Nakayama A., Sasazawa Y., Tashiro E., Imoto M., Kurakata S.

Anti-Cancer Drugs (Anti-Cancer Drugs) 23 ( 1 ) 119 - 130 2012.01

Research paper (scientific journal), Accepted, ISSN 09594973

The mitogen-activated protein kinase (MAPK) signal pathway plays a central role in regulating tumor cell proliferation, survival, and differentiation. The components of this pathway, Ras/Raf/MEK/ERK, are frequently activated in human cancers. Targeting this pathway is considered to be a promising anticancer strategy. In particular, MEK is an attractive drug target because of its high selectivity to ERK. We can expect potent growth inhibitory and proapoptotic effects by inhibiting MEK. Here, we report derivatives of N-[2-(2-chloro-4-iodo- phenylamino)-3,4-difluorophenyl]-methanesulfonamide as novel MEK1/2 inhibitors. Among these compounds, we found SMK-17 to be a potent MEK1/2 inhibitor with high aqueous solubility. The in-silico docking study suggested that SMK-17 is bound to an allosteric pocket of MEK1. The kinetic study and the kinase profiler analysis confirmed the allosteric nature of SMK-17. SMK-17 inhibited MEK1 kinase activity in a non-ATP-competitive manner and it was highly selective to MEK1 and 2. SMK-17 inhibited the growth of tumor cell lines in vitro. Especially, it seemed that cell lines harboring highly phosphorylated MEK1/2 and ERK1/2 were highly sensitive to SMK-17. Moreover, unlike previously reported MEK inhibitors, PD184352 or U0126, SMK-17 did not inhibit the phosphorylation of ERK5. In vivo, SMK-17 exhibited potent antitumor activity in animal models on oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways, which resulted in significant antitumor efficacy without notable side effects. These findings suggest that SMK-17, an exquisitely selective, orally available MEK1/2 inhibitor, is a useful chemical biology tool for characterizing the function of MEK/MAPK signaling both in vitro and in vivo. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Access to Document (DOI)

Involvement of 14-3-3 proteins in the second epidermal growth factor-induced wave of Rac1 activation in the process of cell migration

Kobayashi H., Ogura Y., Sawada M., Nakayama R., Takano K., Minato Y., Takemoto Y., Tashiro E., Watanabe H., Imoto M.

Journal of Biological Chemistry (Journal of Biological Chemistry) 286 ( 45 ) 39259 - 39268 2011.11

Research paper (scientific journal), Accepted, ISSN 00219258

Immense previous efforts have elucidated the core machinery in cell migration, actin remodeling regulated by Rho family small GTPases including RhoA, Cdc42, and Rac1; however, the spatiotemporal regulation of these molecules remains largely unknown. Here, we report that EGF induces biphasic Rac1 activation in the process of cell migration, and UTKO1, a cell migration inhibitor, inhibits the second EGF-induced wave of Rac1 activation but not the first wave. To address the regulation mechanism and role of the second wave of Rac1 activation, we identified 14-3-3ξ as a target protein of UTKO1 and also showed that UTKO1 abrogated the binding of 14-3-3ξ to Tiam1 that was responsible for the second wave of Rac1 activation, suggesting that the interaction of 14-3-3ξ with Tiam1 is involved in this event. To our knowledge, this is the first report to use a chemical genetic approach to demonstrate the mechanism of temporal activation of Rac1. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Access to Document (DOI)

Molecular design, chemical synthesis, and biological evaluation of agents that selectively photo-degrade the transcription factor estrogen receptor-α

Tsumura K., Suzuki A., Tsuzuki T., Tanimoto S., Kaneko H., Matsumura S., Imoto M., Umezawa K., Takahashi D., Toshima K.

Organic and Biomolecular Chemistry (Organic and Biomolecular Chemistry) 9 ( 18 ) 6357 - 6366 2011.09

Research paper (scientific journal), Accepted, ISSN 14770520

2-Phenylquinoline (1) degraded proteins under photo-irradiation with long-wavelength UV light without additives and under neutral conditions. We designed and synthesized a 2-phenylquinoline-estrogen receptor-α (ER-α) agonist (hybrid 2) and a 2-phenylquinoline-ER-α antagonist (hybrid 3) containing estradiol and 4-hydroxytamoxifen moieties, respectively. These 2-phenylquinoline hybrids effectively and selectively photo-degraded the target transcription factor, ER-α, which has a high affinity for estradiol and 4-hydroxytamoxifen. Target-selective photo-degradation was examined in both glass vessels and MCF-7 breast cancer cells, which are dependent upon ER-α for growth. In addition, 2-phenylquinoline-estradiol hybrid 2 functioned as an agonist of ER-α and promoted growth of MCF-7 in the absence of photo-irradiation, while it inhibited the growth of MCF-7 cells upon photo-irradiation due to the photo-degradation of ER-α. In contrast, 2-phenylquinoline-4-hydroxytamoxifen hybrid 3 inhibited growth of MCF-7 cells in the absence of photo-irradiation due to the antagonist effect of the 4-hydroxytamoxifen moiety against ER-α, and upon photo-irradiation significantly inhibited cell growth due to the dual antagonist effect of the 4-hydroxytamoxifen moiety and photo-degradation of ER-α. © 2011 The Royal Society of Chemistry.

Access to Document (DOI)

Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP

Kawamura T., Matsubara K., Otaka H., Tashiro E., Shindo K., Yanagita R., Irie K., Imoto M.

Bioorganic and Medicinal Chemistry (Bioorganic and Medicinal Chemistry) 19 ( 14 ) 4377 - 4385 2011.07

Research paper (scientific journal), Accepted, ISSN 09680896

Natural products have been utilized for drug discovery. To increase the source diversity, we generated a new chemical library consisting of chemically modified microbial metabolites termed 'Unnatural Natural Products' by chemical conversion of microbial metabolites in crude broth extracts followed by purification of reaction products with the LC-photo diode array-MS system. Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP-suppressed enzymatic activity of caspase-3 in vitro. Furthermore, C38OX6 sensitized cancer cells to anticancer drugs, whereas the unconverted natural product did not. These findings suggest that our library could be a useful source for drug seeds. © 2011 Elsevier Ltd. All rights reserved.

Access to Document (DOI)

Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by pro-inflammatory cytokines

Yamada Y., Tashiro E., Taketani S., Imoto M., Kataoka T.

Journal of Antibiotics (Journal of Antibiotics) 64 ( 5 ) 361 - 366 2011.05

Research paper (scientific journal), Accepted, ISSN 00218820

Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin-1α (IL-1α), trigger the activation of the transcription factor nuclear factor-B, a molecule that induces the expression of a variety of genes, including intercellular adhesion molecule-1 (ICAM-1). Here, we report that mycotrienin II, a member of the triene-ansamycin group, inhibited the cell-surface ICAM-1 expression induced by TNF-α more strongly than that induced by IL-1α in human lung carcinoma A549 cells. Mycotrienin II was found to inhibit protein synthesis in intact living cells, as well as in cell-free translation systems. Among translation inhibitors tested, acetoxycycloheximide and anisomycin, but neither puromycin nor emetine, inhibited the TNF-α-induced ICAM-1 expression at lower concentrations than the IL-1α-induced ICAM-1 expression. Several compounds of the triene-ansamycin group (that is, mycotrienin I, trienomycin A, trierixin, quinotrierixin and quinotrierixin HQ) also inhibited ICAM-1 expression, as well as cell-free translation in a manner similar to mycotrienin II. These results indicate that mycotrienin II is a direct inhibitor of translation, thereby inhibiting ICAM-1 expression induced by pro-inflammatory cytokines. © 2011 Japan Antibiotics Research Association. All rights reserved.

Access to Document (DOI)

A new, convenient cell-based screening method for small-molecule glycolytic inhibitors

Kitagawa M., Misawa M., Ogawa S., Tashiro E., Imoto M.

Bioscience, Biotechnology and Biochemistry (Bioscience, Biotechnology and Biochemistry) 75 ( 2 ) 367 - 369 2011.03

Research paper (scientific journal), Accepted, ISSN 09168451

Access to Document (DOI)

Quinotrierixin inhibited ER stress-induced XBPl mRNA splicing through inhibition of protein synthesis

Yamamoto K., Tashiro E., Imoto M.

Bioscience, Biotechnology and Biochemistry (Bioscience, Biotechnology and Biochemistry) 75 ( 2 ) 284 - 288 2011.03

Research paper (scientific journal), Accepted, ISSN 09168451

Quinotrierixin was isolated from microbes as an inhibitor of ER stress-induced XBPl mRNA splicing, but its mode of action was unclear. We found that quinotrierixin is an inhibitor of protein synthesis, and that the required dose range of quinotrierixin to inhibit ER stress-induced XBPl mRNA splicing was similar to that to inhibit protein synthesis. Furthermore, we also found that quinotrierixin inhibited the ER stress-induced increases of unfolded protein response-related genes such as GRP78, CHOP, EDEM, ERdj4, and p58IPK. Thus, we showed that quinotrierixin inhibited the ER stress-induced unfolded protein response, possibly due to its inhibitory activity of protein synthesis.

Access to Document (DOI)

Synthesis and anti-migrative evaluation of moverastin derivatives

Sawada M., Kubo S., Matsumura K., Takemoto Y., Kobayashi H., Tashiro E., Kitahara T., Watanabe H., Imoto M.

Bioorganic and Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters) 21 ( 5 ) 1385 - 1389 2011.03

Research paper (scientific journal), Accepted, ISSN 0960894X

Cell migration of tumor cells is essential for invasion of the extracellular matrix and for cell dissemination. Inhibition of the cell migration involved in the invasion process represents a potential therapeutic approach to the treatment of tumor metastasis; therefore, a novel series of derivatives of moverastins (moverastins A and B), an inhibitor of tumor cell migration, was designed and chemically synthesized. Among these moverastin derivatives, several compounds showed stronger cell migration inhibitory activity than parental moverastins, and UTKO1 was found to have the most potent inhibitory activity against the migration of human esophageal tumor EC17 cells in a chemotaxis cell chamber assay. Interestingly, although moverastins are considered to inhibit tumor cell migration by inhibiting farnesyltransferase (FTase), UTKO1 did not inhibit FTase, indicating that UTKO1 inhibited tumor cell migration by a mechanism other than the inhibition of FTase. © 2011 Published by Elsevier Ltd.

Access to Document (DOI)

Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition

Saiki S., Sasazawa Y., Imamichi Y., Kawajiri S., Fujimaki T., Tanida I., Kobayashi H., Sato F., Sato S., Ishikawa K., Imoto M., Hattori N.

Autophagy (Autophagy) 7 ( 2 ) 176 - 187 2011.02

Research paper (scientific journal), Accepted, ISSN 15548627

Caffeine is one of the most frequently ingested neuroactive compounds. All known mechanisms of apoptosis induced by caffeine act through cell cycle modulation or p53 induction. It is currently unknown whether caffeine-induced apoptosis is associated with other cell death mechanisms, such as autophagy. Herein we show that caffeine increases both the levels of microtubule-associated protein 1 light chain 3-II and the number of autophagosomes, through the use of western blotting, electron microscopy and immunocytochemistry techniques. Phosphorylated p70 ribosomal protein S6 kinase (Thr389), S6 ribosomal protein (Ser235/236), 4E-BP1 (Thr37/46) and Akt (Ser473) were significantly decreased by caffeine. In contrast, ERK1/2 (Thr202/204) was increased by caffeine, suggesting an inhibition of the Akt/mTOR/p70S6K pathway and activation of the ERK1/2 pathway. Although insulin treatment phosphorylated Akt (Ser473) and led to autophagy suppression, the effect of insulin treatment was completely abolished by caffeine addition. Caffeine-induced autophagy was not completely blocked by inhibition of ERK1/2 by U0126. Caffeine induced reduction of mitochondrial membrane potentials and apoptosis in a dose-dependent manner, which was further attenuated by the inhibition of autophagy with 3-methyladenine or Atg7 siRNA knockdown. Furthermore, there was a reduced number of early apoptotic cells (annexin V positive, propidium iodide negative) among autophagy-deficient mouse embryonic fibroblasts treated with caffeine than in their wild-type counterparts. These results support previous studies on the use of caffeine in the treatment of human tumors and indicate a potential new target in the regulation of apoptosis. © 2011 Landes Bioscience.

Access to Document (DOI)

Total synthesis of incednam, the aglycon of incednine

Ohtani T., Tsukamoto S., Kanda H., Misawa K., Urakawa Y., Fujimaki T., Imoto M., Takahashi Y., Takahashi D., Toshima K.

Organic Letters (Organic Letters) 12 ( 21 ) 5068 - 5071 2010.11

Research paper (scientific journal), Accepted, ISSN 15237060

The first total synthesis of incednam (1), the aglycon of antibiotic incednine (2), is described. Incednine has been reported to exhibit significant inhibitory activity against the antiapoptotic oncoproteins Bcl-2 and Bcl-xL. The synthesis of 1 commenced with the preparation of the C1-C13 subunit 3 and the C14-C23 subunit 4. The construction of the novel 24-membered macrocycle was achieved by the application of a Stille coupling between 3 and 4, followed by macrolactamization. © 2010 American Chemical Society.

Access to Document (DOI)

　 Previous page - Next page 　