Synthesis and anticancer activity of geldanamycin derivatives derived from biosynthetically generated metabolites

Lee, Kyeong; Ryu, Jung Su; Jin, Yinglan; Kim, Won-Cheol; Kaur, Navneet; Chung, Sang J.; Jeon, Yong-Jin; Park, Joon-Tae; Bang, Ji S.; Lee, Hong S.; Kim, Tae Y.; Lee, Jung J.; Hong, Young‐Soo

doi:10.1039/b713407j

Cited by 34 publications

(26 citation statements)

References 35 publications

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“…Compound 6 did not demonstrate antiproliferation activity within the experimental concentration ranges used in this study. This lack of activity might have been caused by the bulkiness of the glycosylation at the C-11 position, which is consistent with our previous results (18). Other structural modifications at the C-11 position, with an ester and Nmethylcarbamate, failed to improve antiproliferative activities (18).…”

Section: Resultssupporting

confidence: 81%

“…The anomeric configuration of compounds 6 and 7 was determined to be ␤ on the basis of the large coupling constant values of the anomeric protons at ␦ H 4.19 (J ϭ 8.0 Hz) for compound 6 and ␦ H 4.64 (J ϭ 6.8 Hz) for compound 7 (see Table S1 in the supplemental material).Theantiproliferativeactivitiesofglucosidecompounds6and7 (IC 50 s of more than 100 M and 19 M in SK-Br3 breast cancer cells, respectively) were found to be weaker than that of the original nonbenzoquinone GM (13.0 and 9.4 M, respectively). Thus, the unfavorable antiproliferative activity of glucoside compound 6 might have been a consequence of the bulkiness of glycosylation at the C-11 position, which is consistent with our previous results (18). Also, glucoside compound 7, which has a glucose group at the C-17 hydroxyl group in the benzene ring, showed less activity than aglycone.…”

Section: Discussionsupporting

confidence: 82%

“…This lack of activity might have been caused by the bulkiness of the glycosylation at the C-11 position, which is consistent with our previous results (18). Other structural modifications at the C-11 position, with an ester and Nmethylcarbamate, failed to improve antiproliferative activities (18). In addition to the antiproliferation activity studies, we further examined whether Her2, Akt, and c-Raf, which are well-documented clients of Hsp90, were degraded by compound 7.…”

Section: Resultssupporting

confidence: 70%

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Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

Jang

Woo

et al. 2012

Appl Environ Microbiol

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c Geldanamycin (GM) is a naturally occurring anticancer agent isolated from several strains of Streptomyces hygroscopicus. However, its potential clinical utility is compromised by its severe toxicity and poor water solubility. For this reason, considerable efforts are under way to make new derivatives that have both good clinical efficacy and high water solubility. On the other hand, glycosylation is often a step that improves the water solubility and/or biological activity in many natural products of biosynthesis. Here, we report the facile production of glucose-conjugated nonbenzoquinone GM analogs using the Bacillus UDP-glycosyltransferase BL-C. Five aglycon substrates containing nonbenzoquinone aromatic rings were chosen to validate the in vitro glycosylation reaction. Putative glucoside compounds were determined through the presence of a product peak(s) and were also verified using LC/MS analyses. Further, the chemical structures of new glucoside compounds 6 and 7 were elucidated using spectroscopy data. These glucoside compounds showed a dramatic improvement in water solubility compared with that of the original aglycon, nonbenzoquinone GM.

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Section: Resultssupporting

confidence: 81%

Section: Discussionsupporting

confidence: 82%

Section: Resultssupporting

confidence: 70%

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Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

Jang

Woo

et al. 2012

Appl Environ Microbiol

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“…The reason for this discrepancy between ATPase inhibition activity and anti-proliferative activities is not clear. But, we expect that further development of semi-synthetic derivatives with more diverse residues, such as diaminoalky functionality introduced at the benzene ring and/or C15-position, 20 may exhibit improved cellular potency over 4 or 5.…”

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confidence: 99%

New non-quinone geldanamycin analogs from genetically engineered Streptomyces hygroscopicus

Moon

Jang

et al. 2011

J Antibiot

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Heat shock protein 90 (Hsp90) is emerging as an important target in cancer therapeutics and several other diseases. 1,2 Hsp90 is an abundant and ubiquitously expressed molecular chaperone that is involved in the maturation of multiple client proteins, many of which are involved in regulating cell signaling, proliferation and survival. 3,4 Client proteins of Hsp90 include Her-2, Akt, Src, Abl, c-Met and Raf-1, which are currently being targeted for intervention within oncology drug discovery or in clinical development. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors display remarkable selectivity for cancer cells as compared with normal cells. 5,6 Hsp90 is effectively inhibited by benzoquinone ansamycins such as geldanamycin (GM, 1), herbimycin, macbecin and many of their derivatives, which bind to the ATP-binding site in the N-terminal domain. 7,8 However, the development of 1 as a clinical agent has so far been limited by its toxicity, especially liver toxicity. 9 However, the promising antitumor properties of 1 have spurred initiatives to develop biologically active derivatives. 10,11 17-Allylamino-17-demethoxyGM (17-AAG) has reduced toxicity compared with 1 and is the most advanced Hsp90 inhibitor in clinical development (Phase II/III). 12 17-AAG and its benzoquinone analogs conjugate with glutathione, leading to cellular depletion. This conjugation with sulfur-containing nucleophiles may contribute to the dose-limiting hepatotoxicity of these quinone-containing compounds. 13,14 For these reasons, new non-quinone 1 analogs with improved pharmacological profiles are needed. 15,16 Recently, we reported the development of non-quinone 1 analogs by a mutasynthetic approach and directed biosynthetic method. 16,17 Of these non-quinone 1 analogs, DHQ3 (3), a 15-hydroxyl-17-demethoxy non-quinone analog, was found to inhibit Hsp90 ATPase activity more than 1. 16 Moreover, during these studies, novel tricyclic 1 analogs were prepared from a genetically engineered strain (AC15) of Streptomyces hygroscopicus. 18 Presently, we describe the fermentation of mutant AC15, and the isolation, structural determination and bioactivity of new non-quinone 1 analogs produced by the mutant: DHQ7 (4) and DHQ8 (5).AC15 was constructed by a combinational mutation with site-directed mutagenesis of the first dehydratase domain of the geldanamycin polyketide synthase (PKS) gene (gelA) and a post-PKS modification gene (gel7) of S. hygroscopicus JCM4427, as previously reported. 16 The seed medium and production medium (YEME) consisted of sucrose 103.0 g, yeast extract 3.0 g, peptone (Difco, Sparks, MD, USA) 5.0 g, malt extract (Difco) 3.0 g, glucose 10.0 g and MgCl 2 Á6H 2 O 1.0 g in 1.0 l of distilled water. Spores that developed during growth on ISP4 medium were harvested and inoculated into 300 ml of YEME in a 1.0 l baffled flask and cultured for 3 days at 28 1C. Equal volumes of the seed culture were inoculated into 25 baffled flasks containing 300 ml of YEME medium. Fermentation was subsequently carried out for 7 days ...

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“…Currently, there are over 20 clinical trials in progress for the treatment several cancer types with derivatives of geldanamycin. Geldanamycin biosynthetic engineering has generated biologically active analogues that are difficult to synthesize chemically (Kim et al, , 2009Lee et al, 2008). However, dose limiting hepatotoxicity has been observed in several clinical trials.…”

Section: Introductionmentioning

confidence: 99%

6-alkylsalicylic acid analogues inhibit in vitro ATPase activity of heat shock protein 90

Moon

Choi

et al. 2010

Arch. Pharm. Res.

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The molecular chaperone heat shock protein 90 (Hsp90) is responsible for maintaining the correct folding and stability of many signaling proteins. It is a promising target of cancer therapeutics and several other diseases, including neurodegenerative disease, nerve injuries, inflammation, and infection. In an effort to identify new Hsp90 inhibitors from natural sources using an in vitro ATPase inhibition assay, two 6-alkylsalicylic acid analogues, salaceyin A and B were identified from the culture extract of Streptomyces. Salaceyin A and B exhibited moderate ATPase inhibitory activities with IC(50) values of 68.3 and 65.2 μM, respectively. Binding of salaceyins to human Hsp90α was examined by competition binding experiments with ATP-Sepharose beads. However, the compounds exhibited no degradation activity of Hsp90 client proteins, Her2, c-Raf, or Akt.

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Synthesis and anticancer activity of geldanamycin derivatives derived from biosynthetically generated metabolites

Cited by 34 publications

References 35 publications

Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

New non-quinone geldanamycin analogs from genetically engineered Streptomyces hygroscopicus

6-alkylsalicylic acid analogues inhibit in vitro ATPase activity of heat shock protein 90

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