Design, synthesis and evaluation of a series of novel fumagillin analogues

Fardis, Maria; Pyun, Hyung‐Jung; Tario, James; Jin, Haolun; Kim, Choung U.; Ruckman, Judy; Lin, Yuqing; Green, Louis; Hicke, Brian J.

doi:10.1016/j.bmc.2003.08.031

Cited by 23 publications

(19 citation statements)

References 15 publications

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“…Fumagillin binds MetAP-2 on His-231, inactivating the enzyme. MetAP-2 removes the N-terminal methionine from most proteins involved in cell cycle regulation as a part of the translocation process, so its inhibition results in cell cycle arrest and apoptosis (Fardis et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Early Genetic Mechanisms Underlying the Inhibitory Effects of Endostatin and Fumagillin on Human Endothelial Cells

et al. 2004

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A tumor needs to initiate angiogenesis in order to develop its own blood supply, to grow, to invade, and to spread. Angiogenesis, under normal conditions, is a tightly regulated balance between endogenous pro- and antiangiogenic factors. In this study, we investigated, by microarray analysis, the effects of two known antiangiogenic agents (endostatin and fumagillin) on the gene expression profiles of human umbilical vein endothelial cells (HUVEC) in order to elucidate pathways common to the effects of these agents. We observed a majority of gene expression changes within 1 and 2 h of treatment. The genes demonstrating these early expression changes are involved in cell proliferation, gene transcription, and a number have unknown functions. We selected four genes (DOC1, KLF4, TC-1, ID1) from the microarray profile that showed a similar pattern of expression for both of the antiangiogenic agents we tested. We then used small interfering RNAs (siRNA) in an attempt to better understand the role of these selected genes in the inhibitory activity of these agents. Because the gene expression changes occurred within 1 and 2 h of treatment, these genes might be involved in the initial pathways of angiogenesis inhibition

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Section: Discussionmentioning

confidence: 99%

Early Genetic Mechanisms Underlying the Inhibitory Effects of Endostatin and Fumagillin on Human Endothelial Cells

et al. 2004

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“…Fumagillol was converted to the diene (E)-6b in 58% yield by a four-step sequence, improving the reported procedure of Liu et al 13,16,20 The E-benzyl oxime moiety, lacking the potentially labile epoxide group, was found to be the best substitute for the C4 side chain of fumagillin. Fumagillin analogues containing 100 103 106 84 ND ND 98 109 107 Hydrolysate ND ND ND 22 103 100 ND ND ND (E)-6c Substrate 100 92 90 18 ND ND 108 75 5 Hydrolysate ND ND ND 77 79 100 ND 21 87 (E)-3c Substrate 100 103 100 10 2 1 106 95 60 Hydrolysate ND ND ND 93 95 100 ND 15 60 (E)-3d Substrate 100 103 102 96 ND ND 110 101 106 Hydrolysate ND ND ND 6 96 100 ND ND ND a Error of this measurements is estimated to be 10-15%.…”

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confidence: 84%

“…Among the compounds tested, the ethylpiperazinyl carbamate, (E)-3d, was found to be as active as fumagillin, TNP-470, and AGM-1883 (4c) in the HUVEC-based proliferation assay. 20 Although a reasonable correlation between MetAP-2 inhibition and the inhibition of BAEC proliferation has been reported, 10 we discovered an apparent lack of correlation between MetAP-2 activity and HUVEC proliferation. Table 2 shows that most compounds of this series exhibited similar stability in cell culture medium (67-75% intact after 20 h).…”

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confidence: 91%

Investigation of novel fumagillin analogues as angiogenesis inhibitors

Pyun

Fardis

Tario

et al. 2004

Bioorganic & Medicinal Chemistry Letters

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“…By analogy with the procedure of Yang and Beattie 30 , addition of 1N aqueous sulphuric acid to a solution of KA (1) in dioxane at room temperature resulted in opening of the epoxyde to provide, after purification, the diol 12 in a 68% yield (Scheme 3). The synthesis of the chlorohydrine 13 was performed by reaction of KA with lithium chloride in acetic acid / tetrahydrofuran media during one day at room temperature 31 . After work-up and HPLC purification, the compound 13 was obtained in a 88% yield.…”

Section: Scheme 1 Semisynthesis Of Amide Derivatives 3 Andmentioning

confidence: 99%