- Ligerin, an antiproliferative chlorinated sesquiterpenoid from a marine-derived penicillium strain
-
A new chlorinated sesquiterpenoid analogue of fumagillin, ligerin (1), was isolated from a marine-derived strain of Penicillium, belonging to the subgenus Penicillium, along with the known compounds penicillic acid (2), orcinol, and orsellinic acid. Chemical structures were established by an interpretation of spectroscopic data including IR, UV, and HRESIMS, together with analyses of 1D and 2D NMR spectra and X-ray analysis for the determination of the absolute configuration. Ligerin (1) displayed strong inhibitory activity against an osteosarcoma cell line. This is the first report of the isolation of a fumagillin analogue from a marine-derived Penicillium strain.
- Vansteelandt, Marieke,Blanchet, Elodie,Egorov, Maxim,Petit, Fabien,Toupet, Loic,Bondon, Arnaud,Monteau, Fabrice,Bizec, Bruno,Thomas, Olivier P.,Pouchus, Yves Francois,Bot, Ronan Le,Grovel, Olivier
-
-
Read Online
- RK-805, an endothelial-cell-growth inhibitor produced by Neosartorya sp., and a docking model with methionine aminopeptidase-2
-
We found that a fungus Neosartorya sp. produced an angiogenesis inhibitor, RK-805. By spectroscopic analyses and semi-synthetic methods from fumagillin, the structure of RK-805 was identified as 6-oxo-6-deoxyfumagillol, which has not been reported as a natural product. RK-805 preferentially inhibited the growth of human umbilical vein endothelial cells (HUVECs) rather than that of human normal fibroblast in cell proliferation assays and blocked endothelial cell migration induced by vascular endothelial growth factor (VEGF). Moreover, RK-805 selectively inhibited methionine aminopeptidase-2 (MetAP2), but not methionine aminopeptidase-1 (MetAP1). The docked structure of RK-805 complexed with human MetAP2 indicated that not only a covalent bond between a nucleophilic imidazole nitrogen atom of His231 and the carbon of the reactive spirocyclic epoxide of RK-805, but also a hydrogen bond between NH (Asn329) and the carbonyl group of RK-805 at C-6 promote close contact in the binding pocket of the enzyme. Taken together, these results suggest that structure activity relationships of RK-805 derivatives at both C-4 and C-6, in comparison with ovalicin and TNP-470, would be useful for development of new angiogenesis inhibitors.
- Asami, Yukihiro,Kakeya, Hideaki,Onose, Rie,Chang, Yie-Hwa,Toi, Masakazu,Osada, Hiroyuki
-
-
Read Online
- PRODRUG COMPOSITIONS, PRODRUG NANOPARTICLES, AND METHODS OF USE THEREOF
-
The present invention encompasses prodrug compositions, nanoparticles comprising one or more prodrugs, and methods of use thereof.
- -
-
Paragraph 00125
(2016/10/17)
-
- FUMAGILLOL DERIVATIVES
-
Disclosed are compounds of Formula (1), stereoisomers thereof and pharmaceutically acceptable salts of the compounds and stereoisomers, wherein R1 and R2 are defined in the specification. This disclosure also relates to materials and
- -
-
Paragraph 0159-0160
(2016/07/05)
-
- Remodeling of fumagillol: Discovery of an oxygen-directed oxidative mannich reaction
-
An efficient, two-step construction of highly complex alkaloid-like compounds from the natural product fumagillol is described. This approach, which mimics a biosynthetic cyclase/oxidase sequence, allows for rapid and efficient structure elaboration of th
- Grenning, Alexander J.,Snyder, John K.,Porco, John A.
-
supporting information
p. 792 - 795
(2014/03/21)
-
- Synthesis and antiproliferative activity of ligerin and new fumagillin analogs against osteosarcoma
-
Ligerin (1) is a natural chlorinated merosesquiterpenoid related to fumagillin (2) exhibiting a selective antiproliferative activity against osteosarcoma cell lines and an in vivo antitumor activity in a murine model. Semisynthesis of ligerin analogs was performed in order to study the effects of the C3-spiroepoxide substitution by a halogenated moiety together with the modulation of the C6 chain. Results showed that all derivatives exhibited an in vitro antiproliferative activity against osteosarcoma cell lines and that chlorohydrin compounds were equally or more active than their spiroepoxy analogs. Among semisynthetic analogs, the parent compound 1 was the best candidate for further studies since it exhibited higher or equivalent activity compared to TNP470 (3) against SaOS2 and MG63 human osteosarcoma cells with a four times weaker toxicity against HFF2 human fibroblasts. Quantitative videomicroscopy analysis was conducted and allowed a better understanding of the mechanism of its antiproliferative activity.
- Blanchet, Elodie,Vansteelandt, Marieke,Le Bot, Ronan,Egorov, Maxim,Guitton, Yann,Pouchus, Yves Fran?ois,Grovel, Olivier
-
p. 244 - 250
(2014/05/06)
-
- OXASPIRO [2.5] OCTANE DERIVATIVES AND ANALOGS
-
The invention provides oxaspiro[2.5]octane derivatives and analogs, methods for preparation thereof, intermediates thereto, pharmaceutical compositions, and uses thereof in the treatment of various disorders and conditions, such as overweight and obesity.
- -
-
Page/Page column 79-80
(2012/09/22)
-
- Effective procedure for the oxidative cleavage of olefins by OsO4-NaIO4
-
Oxidative cleavage of olefins by OsO4-NaIO4 sometimes suffers from low yields due to the formation of side products. It is reported that the addition of pyrimidine can suppress the side reactions and dramatically improve the yield of
- Lee, Hong Woo,Kang, Sung Kwon,Yoo, Choong Leol,Lee, Seung Uk
-
experimental part
p. 1837 - 1846
(2009/12/03)
-
- Antiparasitic activities of novel, orally available fumagillin analogs
-
Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes,
- Arico-Muendel, Christopher,Centrella, Paolo A.,Contonio, Brooke D.,Morgan, Barry A.,O'Donovan, Gary,Paradise, Christopher L.,Skinner, Steven R.,Sluboski, Barbara,Svendsen, Jennifer L.,White, Kerry F.,Debnath, Anjan,Gut, Jiri,Wilson, Nathan,McKerrow, James H.,DeRisi, Joseph L.,Rosenthal, Philip J.,Chiang, Peter K.
-
supporting information; experimental part
p. 5128 - 5131
(2010/03/31)
-
- Carbamate analogues of fumagillin as potent, targeted inhibitors of methionine aminopeptidase-2
-
Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this
- Arico-Muendel, Christopher C.,Benjamin, Dennis R.,Caiazzo, Teresa M.,Centrella, Paolo A.,Contonio, Brooke D.,Cook, Charles M.,Doyle, Elisabeth G.,Hannig, Gerhard,Labenski, Matthew T.,Searle, Lily L.,Lind, Kenneth,Morgan, Barry A.,Olson, Gary,Paradise, Christopher L.,Self, Christopher,Skinner, Steven R.,Sluboski, Barbara,Svendsen, Jennifer L.,Thompson, Charles D.,Westlin, William,White, Kerry F.
-
experimental part
p. 8047 - 8056
(2010/09/07)
-
- Concise enantio- and diastereoselective total syntheses of fumagillol, RK-805, FR65814, ovalicin, and 5-demethylovalicin
-
(Chemical Equation Presented) L-Proline-mediated α-aminoxylation is a key step in the enantio- and diastereoselective total syntheses of fumagillin, ovalicin, and related compounds (see scheme). These compounds contain a cyclohexane ring, two epoxides, an
- Yamaguchi, Junichiro,Toyoshima, Maya,Shoji, Mitsuru,Kakeya, Hideaki,Osada, Hiroyuki,Hayashi, Yujiro
-
p. 789 - 793
(2007/10/03)
-
- A new, ring closing metathesis-based synthesis of (-)-fumagillol
-
(Equation presented) A new strategy to access the fumagillin/fumagillol skeleton is proposed. An Evans aldolization and a RCM involving an enone are used for the preparation of a key cyclohexanone intermediate, which was readily converted to fumagillol. The synthesis also features an efficient preparation of isogeraniol and isogeranic acid.
- Boiteau, Jean-Guy,Van De Weghe, Pierre,Eustache, Jacques
-
p. 2737 - 2740
(2007/10/03)
-
- An asymmetric total synthesis of (-)-fumagillol
-
(-)-Fumagillol (2), a hydrolysis product of fumagillin (1), has been synthesized in a highly stereoselective manner utilizing a glycolate Claisen rearrangement and an intramolecular ester enolate alkylation as key steps starting from carbohydrate-based precursor 5.
- Kim, Deukjoon,Ahn, Soon Kil,Bae, Hoon,Choi, Won Jun,Kim, Hak Sung
-
p. 4437 - 4440
(2007/10/03)
-