Total Synthesis of FR901464: Second Generation.

Motoyoshi, Hajime; Horigome, Masato; Watanabe, Hidenobu; Kitahara, Takeshi

doi:10.1002/chin.200624212

Cited by 4 publications

(12 citation statements)

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“…6 For comparison, the literature contains only one report of an active carbamate PD analogue (2), which is 4-fold less active than pladienolide B. 4 It is noted that despite several very high quality total syntheses, 9,13,14,20,22 the complexity of 1 has hindered development of extensive SAR data, and there have been no reports on the activity of corresponding 1 reference compounds to compare to most of the analogues in Scheme 1. For example, there are no reports on the synthesis, or bioactivity, of carbamate analogues of 1 to directly compare to carbamates 7-10.…”

Section: Resultsmentioning

confidence: 99%

“…Previous work identified some of the structural requirements for activity in 1 and PD analogues, either by modification of the natural products, 4 or by the total synthesis of some modified compounds (Figure 2). 3,10,12,13 Prior studies have shown the orientation of the acetyl group and the presence of the epoxide to be important in conferring activity to 1 analogues 10,13 and that the glycosidic hydroxyl group can be replaced by an alkoxy 14 or a methyl group 9 to give more stable compounds, or as in the latter case more stable and more active compounds 9 (Figure 2). Active analogues of PD also contain functionality similar to that found in 1, 4,5 though less structure-activity information has been reported on these more recently discovered compounds.…”

Section: Introductionmentioning

confidence: 99%

“…Previous work identified some of the structural requirements for activity in 1 and PD analogues, either by modification of the natural products, or by the total synthesis of some modified compounds (Figure ). ,,, Prior studies have shown the orientation of the acetyl group and the presence of the epoxide to be important in conferring activity to 1 analogues , and that the glycosidic hydroxyl group can be replaced by an alkoxy or a methyl group to give more stable compounds, or as in the latter case more stable and more active compounds (Figure ). Active analogues of PD also contain functionality similar to that found in 1 , , though less structure−activity information has been reported on these more recently discovered compounds.…”

Section: Introductionmentioning

confidence: 99%

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Synthetic mRNA Splicing Modulator Compounds with in Vivo Antitumor Activity

Lagisetti¹,

Pourpak²,

Goronga³

et al. 2009

J. Med. Chem.

107

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We report our progress on the development of new synthetic anti-cancer lead compounds that modulate the splicing of mRNA. We also report the synthesis evaluation of new biologically active ester and carbamate analogs. Further, we describe initial animal studies demonstrating the antitumor efficacy of compound 5 in vivo. Additionally, we report the enantioselective and diastereospecific synthesis of a new 1,3-dioxane series of active analogs. We confirm that compound 5 inhibits the splicing of mRNA in both cell-free nuclear extracts and in a cell-based dual-reporter mRNA splicing assay. In summary, we have developed totally synthetic novel spliceosome modulators as therapeutic lead compounds for a number of highly aggressive cancers. Future efforts will be directed toward the more complete optimization of these compounds as potential human therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthetic mRNA Splicing Modulator Compounds with in Vivo Antitumor Activity

Lagisetti¹,

Pourpak²,

Goronga³

et al. 2009

J. Med. Chem.

107

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“…This compound was converted to the corresponding 2-thiobenzthioazole derivative 11 using Mitsunobu conditions17 and subsequently oxidized to the corresponding 2-sulfonylbenzothioazole derivative 12 10. Removal of the BOC group in 12 and coupling of the optically pure (S,Z)-4-(dimethyl- t -butylsilyloxy)pent-2-enoic acid (prepared according to the known procedure)18 gave the desired functionalized amide 13 in excellent overall yield.…”

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confidence: 99%

Antitumor Compounds Based on a Natural Product Consensus Pharmacophore

et al. 2008

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We report the design and highly enantioselective synthesis of a potent analog of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogs. We present results on the in vitro activity for this compound against several tumor cell lines.A novel mechanism of anti-tumor activity was recently elucidated for two structurally distinct fermentation products (see Figure 1) 1 and pladienolide 2 (actually a set of closely related compounds that have been designated pladienolides A-G, isolated from Streptomyces platensis) 3 and FR901464 (isolated from Pseudomonas sp. No 2663). 4-6 These natural products have previously been reported to have a similar novel effect on the cell cycle in mammalian cell lines; cell cycle arrest at the G1 and G2/M phases. 3, 4 . This effect on the cell cycle distinguished these compounds from other anti-tumor agents that also inhibit proliferation in tumors and act at previously identified molecular targets. 3-5 This interaction with the spliceosome leads to the inhibition of mRNA splicing and the translation of unspliced mRNA, which ultimately results in the observed effects on the cell cycle. 2, 7 The first of these natural products to be discovered, FR901464, showed activity in in vivo cancer animal models, but showed a relatively narrow therapeutic window. 4 On the other hand pladienolide-based compounds (first reported in 2004) have shown a very broad therapeutic window. 2 Of the seven pladienolides, pladienolide B was reported to have the most promising anti-cancer activity in vivo, and it has recently been reported that a derivative of pladienolide B has entered human clinical trials for cancer. 2Motivated by the recognition that FR901464 and pladienolide have a very similar (or possibly identical) mechanism of action, we compared overlays of molecular models of the two natural products. Upon inspection of these overlays we recognized that despite the gross dissimilarities *To whom correspondence should be addressed. . E-mail: E-mail: thomas.webb@stjude.org. Supporting Information Available: The supporting information includes the general experimental methods, procedures for the synthesis of 9-13 and 15-18, as well as full experimental methods for the cell cycle analysis and the in vitro cytotoxicity assays. This material is available free of charge via theInternet at http://pubs.acs.org. between FR901464 and pladienolide, both molecules share certain common key features (which are known to be critical to their activity) that can overlap in low energy conformations in three dimensions (see Figure 2). It is known from previous studies that the orientation of the acetyl group and the presence of the epoxide are important in conferring activity to FR901464 analogs, 8, 9 but that the glycosidic hydroxyl group...

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“…2663 and has been shown to inhibit tumour growth in various xenograft models (Nakajima et al, 1996; Nakajima et al, 1996; Nakajima, Sato et al, 1997). FR901464 has been the subject of several successful total synthesis efforts (Thompson et al, 2001; Motoyoshi, et al, 2006; Albert et al, 2007) including the establishment of some structure-activity relationships (SAR) based on the synthesis of new analogs (Thompson et al, 2001; Motoyoshi et al, 2004; Albert et al, 2007; Osman et al, 2011). Most notable among these latter studies was the report of the highly active analogue (meayamycin) by the Koide group (Albert et al, 2007) and their recent very substantial expansion of the SAR work in this area (Osman et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis of antitumor spliceosome modulators

Goronga¹,

Boyd²,

Lagisetti³

et al. 2011

Applied Radiation and Isotopes

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A set of novel antitumor agents (the sudemycins) has recently been described that are analogs of the natural product FR901464. We report the radiosynthesis of two of these antitumor drug lead compounds, using a three step procedure: 1) ester hydrolysis, 2) Lindlar’s catalyst/tritium gas to give a (S,Z)-4-acetoxypent-2-enoic acid derivative, and finally 3) amide bond formation. These labelled analogs are useful in developing a better understanding of the pharmacological properties of this new class of therapeutic lead compounds.

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Total Synthesis of FR901464: Second Generation.

Cited by 4 publications

References 1 publication

Synthetic mRNA Splicing Modulator Compounds with in Vivo Antitumor Activity

Synthetic mRNA Splicing Modulator Compounds with in Vivo Antitumor Activity

Antitumor Compounds Based on a Natural Product Consensus Pharmacophore

Radiosynthesis of antitumor spliceosome modulators

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