Chemical modification and antitumor activity of herbimycin A. 8,9-epoxide, 7,9-cyclic carbamate, and 17 or 19-amino derivatives.

Ōmura, Satoshi; Miyano, Katsuji; Nakagawa, Akira; Sano, Hiroshi; Komiyama, Kanki; Umezawa, Iwao; Shibata, Kiyoshi; Satsumabayashi, Sadayoshi

doi:10.7164/antibiotics.37.1264

Cited by 20 publications

(10 citation statements)

References 9 publications

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“…Benzoquinonoid ansamycins caused disappearance of the foci induced by a wild-type RSV without affecting the chicken fibroblast cell sheets at concentrations comparable to those discussed above (data not shown). These antibiotics seem to be not only promising candidates as cancer chemotherapeutic agents (25,26,33,34) but also as useful tools for understanding the molecular mechanisms of cell transformation by the src gene.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus.

Uehara¹,

Hori²,

T³

et al. 1986

Mol. Cell. Biol.

196

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Three benzenoid ansamycin antibiotics (herbimycin, macbecin, and geldanamycin) were found to reduce the intracellular phosphorylation of p6osrc at a permissive temperature (33°C) in a rat kidney cell line infected with a temperature-sensitive mutant of Rous sarcoma virus. This effect was accompanied by morphological changes from the transformed to the normal phenotype. The filamentous staining pattern of actin fibers was observed in the cells treated with these antibiotics at 33°C. Removal of the antibiotics allowed the cells to revert to the transformed morphology. Ansamitocin, another benzenoid ansamycin, and naphthalenoid ansamycins such as streptovaricin and rifamycins did not show this effect. Pulse-labeling of the antibiotic-treated cultures with 32P, showed a marked reduction of 32P radioactivity incorporated into p6orc. A parallel experiment with[35S]methionine showed that synthesis of p6tWc was slightly inhibited. The immune complex prepared by mixing the herbimycin-treated cell extracts with antibody against p6tYrc was inactive in vitro in phosphorylating the complex itself. On the contrary, the immune complex derived from untreated cells was active in vitro even in the presence of the antibiotics. These results suggest that benzoquinonoid ansamycins have no direct effect on src kinase but destroy its intracellular environment, resulting in an irreversible alteration of p60src and loss of catalytic activity. Viral oncogenes have been well characterized at the molecular level, and the studies in this field have provided insights into the understanding of neoplastic transformation. In Rous-sarcoma-virus (RSV)-transformed cells, the functional expression of p6Osrc, the src gene product, is required for manifestation of the oncogenic event (1,3,29). The available evidence strongly suggests that the protein kinase activity of p6Osrc is responsible for the phenotypic changes of cells cultured in vitro (6,22,31): morphological transformation, high saturation density of cell growth, enhanced glucose uptake, the lowered requirement for serum concentration, and growth in soft agar (1,4,14,18).As a means of finding potential antitumor antibiotics, we have been screening compounds which inhibit the function of such oncogenes and thereby suppress the expression of transformed phenotypes. As a tester strain, we have been using normal rat kidney (NRK) cells transformed with a mutant of RSV whose src gene product, the tyrosine protein kinase, is temperature sensitive. By using this assay, we recently found a culture broth of a Streptomyces species which was active in converting transformed cell morphology to normal morphology at a permissive temperature and identified the active agent as herbimycin (34). In herbimycintreated cells, intracellular phosphorylation of p6Osrc was inhibited and the cytoplasmic organization of cytoskeletal proteins was rebuilt. Herbimycin did not inhibit the p6Osr,_ associated kinase activity in vitro, however. Two other benzenoid ansamycins, macbecin and geldanamycin, both of

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Section: Discussionmentioning

confidence: 99%

Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus.

Uehara¹,

Hori²,

T³

et al. 1986

Mol. Cell. Biol.

196

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“…79,80 A similar reactivity was found for herbimycin A (11) as the addition of amines also led to 19-aminated benzoquinones. 71,81,82 A 1992 NCI report that had noted 83 an unprecedented pattern of activity for geldanamycin was probably at the source of a renewed interest for this series. 84 More elaborate chemistry on this ring was subsequently reported 80,85-87 but much less on the macrocycle.…”

Section: Geldanamycin Analogues and Related Ansamycinsmentioning

confidence: 91%

“…In this connection, it is noteworthy that the 8-hydroxy-(7-9) cyclic carbamate analogue of herbimycin A (11) was synthesized in 1984 and retains antitumor activity. 71 Moreover, macbecin I (14) has been reported to be crossresistant to ansamitocin P-3, a compound very closely related to maytansine (15). 72 The reactivity of the benzoquinone moiety in the geldanamycin (2), herbimycin A-C (11)(12)(13), and macbecin I (14) series has been studied 60,73-78 in light of the cytotoxicity 61 of 2.…”

Section: Geldanamycin Analogues and Related Ansamycinsmentioning

confidence: 99%

Heat Shock Protein 90 Inhibitors. A Text Book Example of Medicinal Chemistry?

Janin

2005

J. Med. Chem.

127

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“…Thus, Omura et al synthesized HA derivatives with modifications at the 17 and/or 19-amino position incorporating dimethylamines, allylamines, cyclopropylamines, or methylpiperazines [114]. This effort resulted in three distinct series of derivatives using the HA scaffold: (1) Herbimycin A, (2) 8,9-epoxyherbimycin A, and (3) Herbimycin A-7,9-carbamate (Fig.…”

Section: Natural Product Macrocycle Hsp Inhibitorsmentioning

confidence: 99%

“…16). This derivative showed significant antitumor activity with 141 T/C and 2/3 mice surviving treatment, compared to HA with 109 T/C and 0/4 mice surviving treatment [114]. There are ongoing investigations of the general anti-tumor activity of this compound.…”

Section: Natural Product Macrocycle Hsp Inhibitorsmentioning

confidence: 99%

Macrocyclic Inhibitors of Hsp90

Johnson¹,

Singh²,

Nazarova³

et al. 2010

CTMC

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Heat shock proteins (HSP) are a family of highly conserved proteins, whose expression increases in response to stresses that may threaten cell survival. Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer as it plays a vital role in normal cell maturation and acts as a molecular chaperone for proper folding, assembly, and stabilization of many oncogenic proteins. To date, a majority of Hsp90 inhibitors that have been discovered are macrocycles. The relatively rigid conformation provided by the macrocyclic scaffold allows for a selective interaction with a biological target such as Hsp90. This review highlights the discovery and development of nine macro-cycles that inhibit the function of Hsp90, detailing their potency and the client proteins affected by Hsp90 inhibition.

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Chemical modification and antitumor activity of herbimycin A. 8,9-epoxide, 7,9-cyclic carbamate, and 17 or 19-amino derivatives.

Cited by 20 publications

References 9 publications

Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus.

Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus.

Heat Shock Protein 90 Inhibitors. A Text Book Example of Medicinal Chemistry?

Macrocyclic Inhibitors of Hsp90

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