Antitumor activity of trienomycin A on murine tumors.

Komiyama, Kanki; Hirokawa, Yumiko; Yamaguchi, Hiroko; Funayama, Shinji; Masuda, Kazuaki; Anraku, Yumi; Umezawa, Iwao; Ōmura, Satoshi

doi:10.7164/antibiotics.40.1768

Cited by 17 publications

(14 citation statements)

References 5 publications

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“…8 Thus, the unique biological activity manifested by trienomycin A poses this natural product as an attractive lead compound for cancer chemotherapeutic development. Unfortunately, limited structure-activity relationships (SAR) for trienomycin A have been reported and the mechanism of action remains unknown.…”

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confidence: 99%

Monoenomycin: A Simplified Trienomycin A Analogue That Manifests Anticancer Activity

Brandt

Blagg

2011

ACS Med. Chem. Lett.

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Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski’s “rule of 5”, these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.

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confidence: 99%

Monoenomycin: A Simplified Trienomycin A Analogue That Manifests Anticancer Activity

Brandt

Blagg

2011

ACS Med. Chem. Lett.

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“…Members of this subclass, which are produced from various Steptomyces and Bacillus species, include the mycotrienins and mycotrienols,2 the trienomycins3 and the cytotrienins (Figure 1). 4 Whereas the mycotrienins exhibit potent anti-fungal activity,2d,e the trienomycins and cytotrienins display antineoplastic properties 3a,5. For example, cytotrienin A induces apoptosis in human acute promyelocytic leukemia HL-60 cells (ED50 = 7.7 nM) 5c.…”

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confidence: 99%

“…4 Whereas the mycotrienins exhibit potent anti-fungal activity,2d,e the trienomycins and cytotrienins display antineoplastic properties 3a,5. For example, cytotrienin A induces apoptosis in human acute promyelocytic leukemia HL-60 cells (ED50 = 7.7 nM) 5c. Following their stereochemical assignment,6 total syntheses of trienomycins A and F and thiazinotrienomycin E were reported by Smith, 7a–c total syntheses of mycotrienol I and mycotrienin I were reported by Panek7d,e and a total synthesis of cytotrienin A was reported by Hayashi 7f.…”

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confidence: 99%

Synthesis of the Cytotrienin A Core via Metal Catalyzed C−C Coupling

2011

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A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, RCM delivers the cytotrienin core.Beginning with the discovery of the antibacterial rifamycin B, ansamycin antibiotics continue to evoke interest as antibiotic and antineoplastic agents. 1 An important ansamycin subclass is represented by the ansatrienins, which are classified as triene-containing C17-benzene ansamycins. Members of this subclass, which are produced from various Steptomyces and Bacillus species, include the mycotrienins and mycotrienols, 2 the trienomycins 3 and the cytotrienins (Figure 1).4 Whereas the mycotrienins exhibit potent anti-fungal activity,2d,e the trienomycins and cytotrienins display antineoplastic properties. 3a ,5 For example, cytotrienin A induces apoptosis in human acute promyelocytic leukemia HL-60 cells (ED50 = 7.7 nM). 5c Following their stereochemical assignment,6 total syntheses of trienomycins A and F and thiazinotrienomycin E were reported by Smith, 7a-c total syntheses of mycotrienol I and mycotrienin I were reported by Panek7d,e and a total synthesis of cytotrienin A was reported by Hayashi. 7f Finally, Kirschning and Panek reported syntheses of the ansatrienol and cytotrienin cores, respectively. 8 Here, we report initial efforts toward the development of a synthetic approach to triene-containing C17-benzene ansamycins featuring C-C bond forming hydrogenations and transfer hydrogenations developed in our laboratory. 9 Retrosynthetically, it was envisioned that diverse C17-benzene ansamycins may be accessed through modular assembly of fragments A-D. Specifically, Suzuki cross-coupling of vinyl bromide A and the organoboron building block B would deliver an arene-containing C11-C17 substructure. Chelation-controlled pentadienylation of the latent C11-aldehyde employing reagent C followed by reduction of the nitroarene and amidation of the resulting mkrische@mail.utexas.edu. Supporting Information Available. Characterization data for all new compounds ( 1 H NMR, 13 C NMR, IR, HRMS, [α]). This material is available free of charge via the internet at http://pubs.acs.org. High levels of anti-diastereo-and enantioselectivity are obtained using the isolated orthocyclometallated iridium C,O-benzoate precatalyst modified by (S)-SEGPHOS. As efforts toward corresponding syn-diastereoselective processes are underway, 11d the present firstgeneration synthesis requires conversion of the anti-adduct to the syn-diastereomer via Mitsunobu inversion employing p-nitrobenzoic acid 12 to deliver the crystalline pnitrobenzoate 3. Saponification of 3 followed by Williamson ether synthesis p...

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“…AC 654 as an inhibitor of ER stressinduced XBP1 activation. Although many triene-ansamycin antibiotics, such as trienomycins [13], mycotrienins [14], cytotrienins [15], thiazinotrienomycins [16], TMC-135s [17], and UCF116s [18] have been isolated from the cultured broth of Actinomycete strains, they do not have a SCH 3 group in their structures; therefore, trierixin is a new member of the triene-ansamycin family.…”

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confidence: 99%

Trierixin, a Novel Inhibitor of ER Stress-induced XBP1 Activation from Streptomyces sp.

et al. 2007

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In the course of screening for an inhibitor of ER stress-induced XBP1 activation, we isolated a new member of the triene-ansamycin group compound, trierixin, from a culture broth of Streptomyces sp. AC 654. Trierixin was purified by column chromatography on silica gel and by HPLC. The molecular formula of trierixin is C 37 H 52 N 2 O 8 S. Trierixin inhibited thapsigargin-induced XBP1-luciferase activation in HeLa/XBP1-luc cells and endogenous XBP1 splicing in HeLa cells with an IC 50 of 14 ng/ml and 19 ng/ml, respectively. Moreover, in the process of isolating trierixin, we isolated structurally related mycotrienin II and trienomycin A as inhibitors of ER stress-induced XBP1 activation from a culture broth of a trierixin-producing strain. This study provides the first observation that triene-ansamycins have a novel inhibitory effect against XBP1 activation.

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Antitumor activity of trienomycin A on murine tumors.

Cited by 17 publications

References 5 publications

Monoenomycin: A Simplified Trienomycin A Analogue That Manifests Anticancer Activity

Monoenomycin: A Simplified Trienomycin A Analogue That Manifests Anticancer Activity

Synthesis of the Cytotrienin A Core via Metal Catalyzed C−C Coupling

Trierixin, a Novel Inhibitor of ER Stress-induced XBP1 Activation from Streptomyces sp.

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