Absolute stereochemistry and antitumor activity of iejimalides

Nozawa, Kohei; Tsuda, Masashi; Ishiyama, Haruaki; Sasaki, Takuma; Tsuruo, Takashi; Kobayashi, Jun’ichi

doi:10.1016/j.bmc.2005.09.033

Cited by 34 publications

(18 citation statements)

References 10 publications

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“…IEJLs, unique 24-membered macrolides, were originally isolated as potent antitumor compounds in vitro 11,12) and showed antitumor activity in vivo. 13) Because of their attractive properties, great efforts were made to determine the molecular target, including tumor panel experiments using 39 human cancer cell lines, but there were no standard anticancer drugs with a high correlation coefficient (R < 0:5). So the molecular target(s) of IEJLs remains to be identified.…”

Section: Discussionmentioning

confidence: 99%

“…7,8,15) Because IEJLs ( Fig. 1) also showed antitumor activities in vivo 13) in addition to antiosteoporotic activity ( Fig. 2A and B), we examined the effects on VATPases in mammalian cells and budding yeast.…”

Section: Discussionmentioning

confidence: 99%

“…1). 11,12) Although these compounds exhibit potent cytotoxic activity in vitro and antitumor activity in vivo, 13) their target molecule(s) remain to be identified. Here we report that IEJLs showed antiosteoprotic activity in vitro, and irreversibly inhibited the V-ATPase activity of mammalian and yeast cells.…”

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Iejimalides Show Anti-Osteoclast ActivityviaV-ATPase Inhibition

Kazami

Muroi²,

Kawatani³

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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Iejimalides (IEJLs), 24-membered macrolides, are potent antitumor compounds, but their molecular targets remain to be revealed. In the course of screening, we identified IEJLs as potent osteoclast inhibitors. Since it is known that osteoclasts are sensitive to vacuolar H þ -ATPase (V-ATPase) inhibitor, we investigated the effect of IEJLs on V-ATPases. IEJLs inhibited the V-ATPases of both mammalian and yeast cells in situ, and of yeast V-ATPases in vitro. A bafilomycin-resistant yeast mutant conferred IEJL resistance, suggesting that IEJLs bind a site similar to the bafilomycins/concanamycins-binding site. These results indicate that IEJLs are novel V-ATPase inhibitors, and that antitumor and antiosteporotic activities are exerted via V-ATPase inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Iejimalides Show Anti-Osteoclast ActivityviaV-ATPase Inhibition

Kazami

Muroi²,

Kawatani³

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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“…1), was originally isolated as an agent exhibiting potent cytotoxic activity in vitro 9,10) and antitumor activity in vivo. 11) Here, we showed that compound 3 is a potent V-ATPase inhibitor ( Fig. 2A) by binding a site similar to the bafilomycin-binding site as IEJL-A and -B (Fig.…”

Section: Discussionmentioning

confidence: 75%

“…1). Because these compounds exhibit potent cytotoxic activity in vitro and antitumor activity in vivo, 11) their target molecules and antitumor mechanisms have been attractive subjects for investigation. During the screening of novel inhibitors of osteoclasts, we identified IEJL-A and -B as potent antiosteoporotic compounds.…”

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confidence: 99%

Iejimalide C Is a Potent V-ATPase Inhibitor, and Induces Actin Disorganization

Kazami

Takaine

Itoh

et al. 2014

Biological & Pharmaceutical Bulletin

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Iejimalides (IEJLs) A-D are 24-membered macrolides isolated from a tunicate Eudistoma cf. rigida, and exhibit potent cytotoxicity in vitro and antitumor activity in vivo. We previously reported that the molecular target of IEJL-A and -B was the vacuolar-type H -ATPases (V-ATPases). However IEJL-C and -D, which are sulfonylated IEJL-A and -B, respectively, show more potent antitumor activity, and their molecular targets remain to be discovered. Here, we report that IEJL-C is also a potent V-ATPase inhibitor by binding in a site similar to the bafilomycin-binding site. Two-hour treatment with IEJL-C resulted in the complete disappearance of acidic organelles in HeLa cells. Interestingly, after 24-h treatment, small actin aggregates were observed instead of actin fibers. The same actin reorganization was also observed in cells treated with another V-ATPase inhibitor, bafilomycin A 1 . Because IEJLs did not inhibit actin polymerization in vitro, these results suggest that the primary target of IEJL-C, as well as IEJL-A and -B, is V-ATPase, and actin reorganizations are probably caused by the disruption of pH homeostasis via V-ATPase inhibition.Key words antitumor; cytotoxicity; iejimalide C; V-ATPase; actin cytoskeleton V-ATPases are among the most widely distributed ATPdriven proton pumps in nature, present in all eukaryotic cells and in various bacteria.1,2) Within eukaryotic cells, the structure of these proton pumps is highly conserved from yeast to humans, as a multiple subunit complex with a molecular mass exceeding 850 kDa. The pumps contain at least 13 different subunits with various copy numbers, which are organized into two distinct domains, a peripheral V 1 domain that is the catalytic sector and a transmembrane V 0 domain that constitutes the proton channel. Recently, it has been reported that VATPases are expressed in the plasma membrane of malignant and metastatic tumor cells, and function in the maintenance of intracellular pH.3) Furthermore, it has been found that VATPases are attractive therapeutic targets of tumor cells in vitro 4) and in vivo. 5) These reports strongly suggest that VATPase inhibitors are good candidates for anticancer agents. The mechanism by which such inhibitors interfere with pump function has been investigated in detail. The most potent inhibitors, bafilomycin A 1 6) and the closely related compound concanamycin A, inhibit V-ATPases at nanomolar concentrations and have become important tools for the detection and identification of V-ATPase activity. The site of bafilomycin inhibition has been located to subunit c in the V 0 proton channel. 7,8) Iejimalides (IEJLs) A-D, isolated from the marine tunicate Eudistoma cf. rigida, are unique 24-membered macrolides having two methoxy groups, four diene units, and an N-formyl-L-serine terminus 9,10) ( Fig. 1). Because these compounds exhibit potent cytotoxic activity in vitro and antitumor activity in vivo, 11) their target molecules and antitumor mechanisms have been attractive subjects for investigation. During the screening of novel...

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Ascidians (Tunicates)–1

Kornprobst

2014

Encyclopedia of Marine Natural Products

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Absolute stereochemistry and antitumor activity of iejimalides

Cited by 34 publications

References 10 publications

Iejimalides Show Anti-Osteoclast ActivityviaV-ATPase Inhibition

Iejimalides Show Anti-Osteoclast ActivityviaV-ATPase Inhibition

Iejimalide C Is a Potent V-ATPase Inhibitor, and Induces Actin Disorganization

Ascidians (Tunicates)–1

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