Synthesis, conformational analysis and biological evaluation of the lactam analogue of the cyclodepsipeptide apratoxin A

Yin, Ruwen; Zhang, Wei; Liu, Guoyun; Wu, Ping; Lau, Choiwan; Li, Yingxia

doi:10.1016/j.tet.2016.04.050

Cited by 9 publications

(2 citation statements)

References 21 publications

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“…The synthetic route of 1 is depicted in Scheme . We applied a similar synthetic strategy that we previously developed for the synthesis of apratoxins S4–S9, , which is a modification of other published methods. − Recently, some other papers were published on total syntheses of apratoxins. − The known compounds 2 , 3 , and 7 were synthesized as we established previously . The N -Boc group in 3 was selectively removed with TMSOTf in the presence of 2,6-lutidine, which was subsequently followed by a coupling reaction of deprotected 3 with 2 to afford compound 4 in 92% yield.…”

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confidence: 99%

Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors

Cai

Chen

Dang

et al. 2017

ACS Med. Chem. Lett.

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Renal, hepatocellular, and neuroendocrine carcinomas are known as highly vascularized tumors. Although vascular endothelial growth factor A (VEGF-A)-targeted therapies have shown efficacy in the treatment of these cancers, drug resistance is a major concern and might be mediated by interleukin 6 (IL-6). Furthermore, upon antiangiogenic drug exposure, tumor cells may adapt to survive in a vascular-independent manner. Apratoxins are potent marine-derived cytotoxic in vivo-active agents, preventing cotranslational translocation in the secretory pathway, and show promise to overcome resistance by targeting angiogenesis and tumor growth simultaneously. We designed and synthesized a novel apratoxin analogue, apratoxin S10, with a balanced potency and stability as well as synthetic accessibility and scalability. We showed that apratoxin S10 potently inhibits both angiogenesis in vitro and growth of cancer cells from vascularized tumors. Apratoxin S10 down-regulated vascular endothelial growth factor receptor 2 (VEGFR2) on endothelial cells and blocked the secretion of VEGF-A and IL-6 from cancer cells. It inhibited cancer cell growth through down-regulation of multiple receptor tyrosine kinases (RTKs) and compares favorably to currently approved RTK inhibitors in both angiogenesis and cancer cell growth.

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confidence: 99%

Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors

Cai

Chen

Dang

et al. 2017

ACS Med. Chem. Lett.

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“…All of these isolated marine secondary metabolites show potent in vitro cytotoxicity against LoVo cell lines (IC 50 : 0.36–10.8 nM) and the KB (IC 50 : 0.52–21.3 nM) . Because of their unique scaffolds and striking biological activities, tremendous efforts have been devoted to the asymmetric synthesis of apratoxins A, C, D, F and corresponding analogues, as well as the studies on their mechanism of action and biosynthetic pathways . We demonstrated an asymmetric method for synthesis of dehydroapratoxin A in 2011 .…”

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confidence: 99%

Asymmetric Synthesis of Apratoxin E

Mao

Liu

et al. 2016

J. Org. Chem.

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An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this "from nature to nature" strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl diphenylphosphinate was found to be an efficient condensation reagent for the macrocyclization.

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