Structure-activity Relationship for FR901464: A Versatile Method for the Conversion and Preparation of Biologically Active Biotinylated Probes

Motoyoshi, Hajime; Horigome, Masato; Ishigami, Ken; Yoshida, Tadao; Horinouchi, Sueharu; Yoshida, Minoru; Watanabe, Hidenobu; Kitahara, Takeshi

doi:10.1271/bbb.68.2178

Cited by 48 publications

(58 citation statements)

References 10 publications

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“…The replacement of the C1-hydroxy group with either a hydrogen atom 30 or a methoxy group 74 only marginally improved the potency of FR901464. We hypothesized that such increased stability and more desirable van der Waals interaction with target proteins might improve the potency of FR901464.…”

Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 98%

“…Similar to the Jacobsen and Kitahara groups, we also noticed the instability of FR901464 toward acids, even as mild as silica gel. 30,74 However, the sensitivity of FR901464 under physiologically relevant conditions remained unreported, and therefore we decided to determine the half-life of 64 to examine its stability in various phosphate buffers at 37°C as shown in Table 4. Alarmingly, the half-lives of 64 are only 8 and 4 h at pH 7 and 7.4, respectively.…”

Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 99%

“…We did not observe acrolein (by 1 H NMR or HPLC), 91, or 92 via Kitahara's decomposition pathway (b). 74 We also looked for acetate 93 that would be formed by a Grob fragmentation (c) 75,76 but have insufficient evidence to confirm this product formation. Hemiketal 64 exists as a 10:1 equilibrium mixture with linear ketoalcohol 64-open in both CD 2 Cl 2 and D 2 O, in accordance with Jacobsen's observation.…”

Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 99%

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Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue

et al. 2007

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FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4′ stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by -elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI 50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.

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Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 98%

Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 99%

Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 99%

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Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue

et al. 2007

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“…15 Other synthetic efforts provided insights into structure−activity relationships of this class. 16,17 The antitumor potencies and unique mode of action of the spliceostatins prompted us to examine this class of compounds for analogues possessing biological and physicochemical properties suitable for drug lead generation. As a result of our investigation, a group of spliceostatin analogues, 4−12, were isolated from a three-day fermentation broth, and their structures were identified by analysis of spectroscopic data.…”

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confidence: 99%

Cytotoxic Spliceostatins from Burkholderia sp. and Their Semisynthetic Analogues

et al. 2014

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The spliceostatin class of natural products was reported to be potent cytotoxic agents via inhibition of the spliceosome, a key protein complex in the biosynthesis of mature mRNA. As part of an effort to discover novel leads for cancer chemotherapy, we re-examined this class of compounds from several angles, including fermentation of the producing strains, isolation and structure determination of new analogues, and semisynthetic modification. Accordingly, a group of spliceostatins were isolated from a culture broth of Burkholderia sp. FERM BP-3421, and their structures identified by analysis of spectroscopic data. Semisynthesis was performed on the major components 4 and 5 to generate ester and amide derivatives with improved in vitro potency. With their potent activity against tumor cells and unique mode of action, spliceostatins can be considered potential leads for development of cancer drugs.

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“…A more stable, semisynthetic methyl ketal of 4 was later shown to inhibit the spliceosome, and it was thus termed spliceostatin A (Fig. 1A) (11,23). Subsequently, an analog bearing a terminal carboxylic acid (3) was reported from Burkholderia sp.…”

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confidence: 99%

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

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Janso

Ratnayake

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Spliceostatins are bacterial natural products that show promising anticancer activity. Understanding how the bacterium makes spliceostatins will aid efforts toward a sustainable route for their production. Moreover, altering the chemical structure of a natural product is usually necessary to improve its pharmaceutical properties. For example, the parent spliceostatin molecule contains an unstable hemiketal chemical group. Contrary to previous hypotheses, we report on the identification of a dioxygenase enzyme responsible for hemiketal biosynthesis. Deletion of the corresponding dioxygenase gene led to a strain that produces exclusively spliceostatin congeners that are more stable than, and as active as, the parent compound, when derivatized to increase cell permeability. The strain generated in this study will be the basis for future development.

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Structure-activity Relationship for FR901464: A Versatile Method for the Conversion and Preparation of Biologically Active Biotinylated Probes

Cited by 48 publications

References 10 publications

Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue

Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue

Cytotoxic Spliceostatins from Burkholderia sp. and Their Semisynthetic Analogues

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

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