Total synthesis of the marine cyanobacterial cyclodepsipeptide apratoxin A

Chen, Jiehao; Forsyth, Craig J.

doi:10.1073/pnas.0402752101

Cited by 57 publications

(34 citation statements)

References 48 publications

(38 reference statements)

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“…3 H]apratoxin A were similar to reported procedures (13)(14)(15)(16)(17)(18)(19)(20). Abbreviated synthetic schemes for [ 3 H]apratoxin A and C.18-epi-apratoxin A are depicted in Supplementary Figs.…”

Section: Compoundssupporting

confidence: 56%

Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61

Huang

Chen

Jiang

et al. 2016

Molecular Cancer Therapeutics

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Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo. Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anticancer drug. Here, we describe a detailed pathologic analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A-treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a 3 H-labeled apratoxin A probe and specific Sec 61a/b antibodies, we identified that the Sec 61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure.

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Section: Compoundssupporting

confidence: 56%

Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61

Huang

Chen

Jiang

et al. 2016

Molecular Cancer Therapeutics

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“…Due to the structural novelty, coupled with the exceptional biological activity of apratoxin A, several synthetic research groups carried out total synthesis of 67 and its analogues (73-76) (Fig. 8) for the purpose of SAR studies (Chen and Forsyth 2003a;b;Chen and Forsyth 2004;Zou et al 2003;Doi et al, 2006;Ma et al 2006;Numajiri et al 2009;Gilles et al 2009). An oxazoline analogue of apratoxin A, oxapratoxin A (73), was found to be slightly lower in potency against HeLa cells when compared with apratoxin A (Table 2; Ma et al 2006).…”

Section: Apratoxins and Analoguesmentioning

confidence: 99%

Filamentous tropical marine cyanobacteria: a rich source of natural products for anticancer drug discovery

2010

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“…The first total synthesis of this cyclodepsipeptide was achieved by Chen and Forsyth. 6) They succeeded in synthesizing thiazoline 3 by the formation of thioester 2, followed by a Staudingeraza-Wittig condensation as a key step. Macrolactamization between proline and N-methylisoleucine residues provided apratoxin A (1) (Chart 1).…”

Section: Apratoxin Amentioning

confidence: 99%

“…to the oxazoline-alanogue of apratoxin A, 7) we had planned macrolactamization between proline and N-methylisoleucine, as reported by Chen and Forsyth. 6) Because it will be suitable to synthesize various analogues of apratoxin A on solid-phase afterwards, synthetically valuable 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid (Dtena) can be introduced at the late stage of the synthesis.…”

Section: Apratoxin Amentioning

confidence: 99%

Synthesis of the Biologically Active Natural Product Cyclodepsipeptides Apratoxin A and Its Analogues

Doi

2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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This paper describes the synthetic studies conducted on a marine natural product, cyclodepsipeptide apratoxin A. Total synthesis of the oxazoline analogue of apratoxin A was achieved. The conversion of oxazoline to thioamide, as well as thioamide formation from a serine-derived compound, were both unsuccessful. However, thiazoline formation from a cysteine-derived compound led to the total synthesis of apratoxin A. An in vivo study on synthetic apratoxin A revealed that it has potent antitumor activity, but with significant toxicity. Solid-phase synthesis of apratoxin A was accomplished using a preformed thiazoline derivative as a coupling unit. This method was used to synthesize several azido-containing analogues as precursors of molecular probes, and these analogues exhibited potent biological activity.

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Total synthesis of the marine cyanobacterial cyclodepsipeptide apratoxin A

Cited by 57 publications

References 48 publications

Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61

Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61

Filamentous tropical marine cyanobacteria: a rich source of natural products for anticancer drug discovery

Synthesis of the Biologically Active Natural Product Cyclodepsipeptides Apratoxin A and Its Analogues

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