The Discovery of Potent Antitumor Agent C11-Deoxypsymberin/irciniastatin A: Total Synthesis and Biology of Advanced Psymberin Analogs

Huang, Xianhai; Shao, Ning; Huryk, Robert; Palani, Anandan; Aslanian, Robert; Seidel-Dugan, Cynthia

doi:10.1021/ol802772s

Cited by 41 publications

(33 citation statements)

References 17 publications

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“…10–33 The use of copper-catalysis in the formation of C-N, C-O and C-S bonds including aryl and vinyl substituted derivatives covering a broad spectrum of amines, ethers, and thioethers, in good to excellent yields has been reported. 7–8,36 It has now been shown that the formation of vinylic C-N and C-O bonds by a Cu-catalytic method 7 is ineffective with the functionalized ethyliodoacrylate substrates, for both phenols and N -heterocycles as nucleophiles.…”

Section: Resultsmentioning

confidence: 99%

Base-Mediated Stereospecific Synthesis of Aryloxy and Amino Substituted Ethyl Acrylates

et al. 2011

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The stereospecific synthesis of aryloxy and amino substituted E- and Z-ethyl-3-acrylates is of interest because of their potential in the polymer industry and in medicinal chemistry. During work on a copper-catalyzed cross-coupling reaction of E- and Z-ethyl-3-iodo-acrylates with phenols and N-heterocycles, we discovered a very simple (non-metallic) method for the stereospecific synthesis of aryloxy and amino substituted acrylates. To study this long standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of O- and N-substituted nucleophiles was allowed to react with E- and Z-ethyl-3-iodo-acrylates. Screening of different bases indicated that DABCO (1,4-diazabicyclo[2.2.2]octane) afforded successful conversion of E- and Z- ethyl-3-iodoacrylates into aryloxy and amino substituted ethyl acrylates in a stereospecific manner. Herein are the details of this DABCO-mediated stereospecific synthesis of aryloxy and amino substituted E- or Z-acrylates.

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Section: Resultsmentioning

confidence: 99%

Base-Mediated Stereospecific Synthesis of Aryloxy and Amino Substituted Ethyl Acrylates

et al. 2011

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“…11b Based on this observation, we synthesized the C11-deoxypsymberin 91 using a similar synthetic sequence as for natural psymberin starting with the preparation of central piece 92 (Scheme 13). 23 than psymberin across all cancer cell lines tested with IC 50 values in the subnanomolar ranges while epimer 91c showed excellent activity against all cell lines tested with IC 50 value in single digit nanomolar ranges (Table 5).…”

Section: Scheme 12mentioning

confidence: 99%

New Applications of PhI(OAc)2 in Synthesis: Total Synthesis and SAR Development of Potent Antitumor Natural Product Psymberin/Irciniastatin A

Shao¹,

Huang²,

Palani³

et al. 2009

Synthesis

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A novel PhI(OAc) 2 -mediated oxidative cyclization reaction is discovered for the synthesis of a-oxy N-acyl aminals and hemiaminals in good yields from readily synthesized N-acyl enamines. This methodology represents a cascade process to construct the core structure of the pederin family of natural products. The total synthesis of psymberin, a member of the pederin family, is accomplished using this ring-closure reaction as the key step. This new method is further showcased in the preparation of advanced psymberin analogues. The biological data of these analogues are presented.

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“…Despite a broad range of activities and high levels of potency, compounds from the pedrin family have not been extensively developed for therapeutic purposes. However, recent advances in their syntheses 11–14 and a growing literature into structure activity relationships within this family 15,16 provide a framework for future developments. Furthermore, new insights into the biosynthesis of these interesting metabolites open the possibility of their production in large scale through biotechnological approaches 17,18 as well as the development of new analogs through biosynthesis or semisynthesis 19.…”

Section: Introductionmentioning

confidence: 99%

The protein synthesis inhibitors mycalamides A and E have limited susceptibility toward the drug efflux network

Venturi

Davies

Singh

et al. 2011

J Biochem & Molecular Tox

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The mycalamides belong to a family of protein synthesis inhibitors noted for antifungal, antitumour, antiviral, immunosuppressive, and nematocidal activities. Here we report a systematic analysis of the role of drug efflux pumps in mycalamide resistance and the first isolation of mycalamide E. In human cell lines, neither P-glycoprotein overexpression nor the use of efflux pump inhibitors significantly modulated mycalamide A toxicity in the systems tested. In Saccharomyces cerevisiae, it appears that mycalamide A is subject to efflux by the principle mediator of xenobiotic efflux, Pdr5p along with the major facilitator superfamily pump Tpo1p. Mycalamide E showed a similar efflux profile. These results suggest that future drugs based on the mycalamides are likely to be valuable in situations where efflux pump-based resistance leads to failure of other chemotherapeutic approaches, although efflux may be a mediator of resistance in antifungal applications.

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The Discovery of Potent Antitumor Agent C11-Deoxypsymberin/irciniastatin A: Total Synthesis and Biology of Advanced Psymberin Analogs

Cited by 41 publications

References 17 publications

Base-Mediated Stereospecific Synthesis of Aryloxy and Amino Substituted Ethyl Acrylates

Base-Mediated Stereospecific Synthesis of Aryloxy and Amino Substituted Ethyl Acrylates

New Applications of PhI(OAc)2 in Synthesis: Total Synthesis and SAR Development of Potent Antitumor Natural Product Psymberin/Irciniastatin A

The protein synthesis inhibitors mycalamides A and E have limited susceptibility toward the drug efflux network

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