Investigation of novel fumagillin analogues as angiogenesis inhibitors

Pyun, Hyung‐Jung; Fardis, Maria; Tario, James; Yang, Chui‐Ping; Ruckman, Judy; Henninger, Dwight; Jin, Haolun; Kim, Choung U.

doi:10.1016/j.bmcl.2003.10.008

Cited by 24 publications

(9 citation statements)

References 20 publications

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“…The observed regioselectivity can be rationalized from a model of metal-coordinated amino alcohol intermediate 14 , obtained from opening of the more labile spirocyclic epoxide ( Figure 2c ). 37 , 38 The larger La(III) catalyst may more easily accommodate the C6 hydroxyl group simultaneously with C1′ epoxide activation ( cf . 15 ), thereby leading to tridentate coordination to the substrate wherein the amine is positioned closer and at a more optimal trajectory for addition to C1′.…”

Section: Resultsmentioning

confidence: 99%

Remodelling of the natural product fumagillol employing a reaction discovery approach

et al. 2011

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In search for new biologically active molecules, diversity-oriented synthetic (DOS) strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for DOS, wherein stereochemically rich core structures may be reorganized into chemotypes which are distinctly different from the parent structure. Ideally such transformations should be general and involve few steps in order to be suited for library applications. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodeled in several ways utilizing a reaction discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodeled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.

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Section: Resultsmentioning

confidence: 99%

Remodelling of the natural product fumagillol employing a reaction discovery approach

et al. 2011

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“…They have been tested only by in vitro assays, and to date, no clinical trials of these analogues have yet been conducted. 63,64 Since the angiogenic cascade is a multistep process, numerous assays have been developed to study potential angiogenic activity. Some analyze a single step in the pathway, whereas others test the angiogenic cascade as a whole.…”

Section: Role Of the Tumor Microenvironment In Mediating The Responsementioning

confidence: 99%

Targeting Angiogenesis With Integrative Cancer Therapies

2006

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An integrative approach for managing a patient with cancer should target the multiple biochemical and physiological pathways that support tumor development while minimizing normal tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The authors will focus on natural health products (NHPs) that have a high degree of antiangiogenic activity but also describe some of their many other interactions that can inhibit tumor progression and reduce the risk of metastasis. NHPs target various molecular pathways besides angiogenesis, including epidermal growth factor receptor (EGFR), the HER-2/neu gene, the cyclooxygenase-2 enzyme, the NF-kB transcription factor, the protein kinases, Bcl-2 protein, and coagulation pathways. The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are confirming the knowledge that is already documented in traditional texts. The following herbs are traditionally used for anticancer treatment and are antiangiogenic through multiple interdependent processes that include effects on gene expression, signal processing, and enzyme activities: Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (turmeric), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinale (ginger), Panax ginseng, Rabdosia rubescens (rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking on clinical trials. More data are required on dose response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as biological response modifiers and adaptogens, potentially enhancing the efficacy of the so-called conventional therapies. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials might be preferred, smaller studies with appropriate end points and surrogate markers for antiangiogenic response could help prioritize agents for the larger resource-intensive phase 3 trials.

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“…2). Indeed, the development of antiangiogenesis fumagillin analogs with a modified C-6 tail shows that these modifications are tolerated and yield active compounds (45,46). In contrast, the epoxide groups at C-3 and C-4 are buried deep in the active site, where the crowded environment offers limited replacement options.…”

Section: Resultsmentioning

confidence: 99%

Discovery and Preclinical Development of Antigiardiasis Fumagillol Derivatives

Padia¹,

Kulakova

Galkin

et al. 2020

Antimicrob Agents Chemother

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Giardiasis, caused by the intestinal parasite Giardia lamblia, is a severe diarrheal disease, endemic in poverty-stricken regions of the world, and also a common infection in developed countries. The available therapeutic options are associated with adverse effects, and G. lamblia resistance to the standard-of-care drugs is spreading. Fumagillin, an anti-microsporidiosis drug, is a potential giardiasis therapeutic agent. However, it exhibits considerable, albeit reversible, toxicity when used to treat immune-compromised microsporidiosis patients. Fumagillin is also a highly unstable compound. To address these liabilities, we have designed and synthesized stable fumagillol derivatives with lower permeability across polarized epithelial Caco-2 cells and better potency against G. lamblia trophozoites compared with fumagillin. Metronidazole-resistant G. lamblia strains are also susceptible to the new fumagillol derivatives. In addition, these compounds are more potent against the amebiasis causing parasite, E. histolytica compared with fumagillin. Two compounds exhibit better thermal and acid stability than fumagillin, which should prolong drug shelf life and reduce compound degradation in the stomach. Giardiasis mouse model studies with the most stable compound (4-(((((3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl)oxy)carbonyl)amino)benzoic acid; (compound 9) revealed better efficacy (ED) compared with fumagillin both with respect to the fully curative dose, ED100 = 6.6 mg/kg, and ED50 = 0.064 mg/kg. Plasma pharmacokinetics revealed slow absorption of compound 9 through the gut, consistent with the in vitro characterization in Caco-2 cells. An acute dose study yielded a maximum tolerated dose (MTD) of 1500 mg/kg, 227-fold higher than the fully curative dose. Thus, along with improved stability, compound 9 also exhibits an excellent therapeutic window.

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Investigation of novel fumagillin analogues as angiogenesis inhibitors

Cited by 24 publications

References 20 publications

Remodelling of the natural product fumagillol employing a reaction discovery approach

Remodelling of the natural product fumagillol employing a reaction discovery approach

Targeting Angiogenesis With Integrative Cancer Therapies

Discovery and Preclinical Development of Antigiardiasis Fumagillol Derivatives

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