Stereochemical studies of hexylitaconic acid, an inhibitor of p53–HDM2 interaction

Nakahashi, Atsufumi; Miura, Nobuaki; Monde, Kenji; Tsukamoto, Sachiko

doi:10.1016/j.bmcl.2009.04.057

Cited by 34 publications

(24 citation statements)

References 26 publications

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“…produced (3S)-hexylitaconic acid (5). 4,12) Itaconic acid has been found as a metabolite of filamentous fungi such as Aspergillus itaconicus, 13) Helicobasidium mompa, 14) Ustilago zeae, 15) and U. maydis 16) and some yeast belonging to the genus Candida. 17) Whilst alkylated derivatives (alkylitaconic acids) have been isolated from lichens and several fungi.…”

Section: Resultsmentioning

confidence: 99%

Oxygenated Hexylitaconates from a Marine Sponge-Derived Fungus Penicillium sp.

Zhang

Lee

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Although dicarboxylic acids do not occur in appreciable amount as components of animal or vegetal lipids, generally they are important metabolic products of fatty acids. Especially the a,b-dicarboxylic acid and its derivatives, such as itaconic acid 1,2) and citraconic acid derivatives, 3) have been of much interest for their biosynthesis, stereochemistry, and chemical relationship. Furthermore, some of them were reported to exhibit various interesting bioactivities, such as plant growth-stimulation, 4) production of a cellulolytic active oxygen species, inhibition of the iron redox reaction, 5) inhibition of p53-HDM2 interaction which can induce apoptosis in human cancer cells, 6) and anti-trypanosomal activity. 7)In the course of search for bioactive metabolites from marine organisms, five hexylitaconic acid derivatives including four new ones (1-4) were isolated from a sponge-derived fungus Penicillium sp. Herein we describe the structure elucidation and the biological evaluation of the compounds. Results and DiscussionAccurate mass measurement (high resolution (HR)-FAB-MS) of compound 1 (m/z 259.1549 [MϩH] ϩ , Dϩ0.4 mmu) revealed the molecular formula to be C 13 H 22 O 5 with three degrees of unsaturation. Thirteen carbon signals were evident in the 13 C-NMR spectrum (Table 1) and deduced to be three methyl, five methylene, two methine, and three quaternary carbons from the distortionless enhancement by polarization transfer (DEPT)135 spectrum. According to 1 H-and In the course of our search for bioactive metabolites from marine organisms, new hexylitaconic acid derivatives (1-4), along with (3S)-hexylitaconic acid (5), were isolated from a sponge-derived fungus Penicillium sp. Based on the NMR and MS data, the structures of compounds 1-4 were defined as a a,b b-dicarboxylic acid derivatives, such as hexylitaconic acid and tensyuic acids which were previously reported as metabolite of Aspergillus niger, Penicillium striatisporum, or Apiospora montagnei. The isolated compounds were evaluated for cytotoxicity against a panel of five human solid tumor cell lines, and for anti-inflammatory activity gauged by their inhibitory effects on the production of major pro-inflammatory mediators (nitric oxide (NO), interleukin (IL)-6, tumor necrosis factor (TNF)-a a, and IL-1b b) in murine macrophage cells. Compounds 1 and 4 showed weak inhibition of IL-1b b production at the concentration of 200 m mM.

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Section: Resultsmentioning

confidence: 99%

Oxygenated Hexylitaconates from a Marine Sponge-Derived Fungus Penicillium sp.

Zhang

Lee

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The absolute configurations of hexylitaconic acids (+)-263 and (-)-264, inhibitors of p53-HDM2 proteins interaction, of importance in cancer therapy, were confirmed by VCD spectroscopy (302). Enantiomer (+)-263 is found in Nature as a root growth stimulator of lettuce seedlings from cultivated Aspergillus niger, whereas its enantiomeric form (-)-264 is isolated as a metabolite produced by the marine endophytic fungus Apiospora montagnei.…”

Section: Examplementioning

confidence: 88%

Progress in the Chemistry of Organic Natural Products 100

Kinghorn¹,

Falk²,

Kobayashi³

2015

Progress in the Chemistry of Organic Natural Products

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“…Hexylitaconic acid (19) is an itaconic acid derivative isolated from a culture of the marine-derived Arthrinium sp fungi, which was initially separated from a marine sponge from Toyama Bay in the Sea of Japan [210,211]. The compound has been identified as a new inhibitor of the MDM2-p53 interaction by an ELISA assay, blocking MDM2-p53 interaction in a dose-dependent manner, with an IC 50 value of 50 Ag/mL [210].…”

Section: Hexylitaconic Acid and Its Derivativesmentioning

confidence: 98%

Natural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action

Qin

Nag²,

Voruganti³

et al. 2012

CMC

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The mdm2 oncogene has recently been suggested to be a valuable target for cancer therapy and prevention. Overexpression of mdm2 is often seen in various human cancers and correlates with high-grade, late-stage, and more treatment-resistant tumors. The MDM2-p53 auto-regulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main focus of anti-MDM2 drug discovery. Much effort has been expended in the development of small molecule MDM2 antagonists targeting the MDM2-p53 interaction, and a few of these have advanced into clinical trials. However, MDM2 exerts its oncogenic activity through both p53-dependent and -independent mechanisms. Recently, there is an increasing interest in identifying natural MDM2 inhibitors; some of them have been shown to decrease MDM2 expression and activity in vitro and in vivo. These identified natural MDM2 inhibitors include a plethora of diverse chemical frameworks, ranging from flavonoids, steroids, and sesquiterpenes to alkaloids. In addition to a brief review of synthetic MDM2 inhibitors, this review focuses on natural product MDM2 inhibitors, summarizing their biological activities in vitro and in vivo and the underlying molecular mechanisms of action, targeting MDM2 itself, regulators of MDM2, and/or the MDM2-p53 interaction. These MDM2 inhibitors can be used alone or in combination with conventional treatments, improving the prospects for cancer therapy and prevention. Their complex and unique molecular architectures may provide a stimulus for developing synthetic analogs in the future.

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Stereochemical studies of hexylitaconic acid, an inhibitor of p53–HDM2 interaction

Cited by 34 publications

References 26 publications

Oxygenated Hexylitaconates from a Marine Sponge-Derived Fungus Penicillium sp.

Oxygenated Hexylitaconates from a Marine Sponge-Derived Fungus Penicillium sp.

Progress in the Chemistry of Organic Natural Products 100

Natural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action

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