Asymmetric Synthesis of Apratoxin E

Mao, Zhuo‐Ya; Si, Chang‐Mei; Liu, Yiwen; Dong, Hanqing; Lin, Guo‐Qiang

doi:10.1021/acs.joc.6b02086

Cited by 10 publications

(2 citation statements)

References 64 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.…”

mentioning

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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“…Total syntheses of apratoxin A ( 1a ) and its analogues have been reported previously. ,,,, Forsyth et al accomplished the first total synthesis of 1a , , and several groups including the present authors have since reported the synthesis and SAR studies of apratoxins and their analogues using solution-phase ,,, or solid-phase syntheses. , However, the syntheses of apratoxins and their analogues require multistep processes and result in very low overall yields. In addition, apratoxins are sensitive to acidic conditions , and have a Michael acceptor in the moCys moiety .…”

Section: Introductionmentioning

confidence: 77%

Conformation-Based Design and Synthesis of Apratoxin A Mimetics Modified at the α,β-Unsaturated Thiazoline Moiety

et al. 2017

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We have demonstrated design, synthesis, and biological evaluation of apratoxin A mimetics. In the first generation, the moCys moiety was replaced with seven simple amino acids as their 3D structures can be similar to that of apratoxin A. Apratoxins M1-M7 were synthesized using solid-phase peptide synthesis and solution-phase macrolactamization. Apratoxin M7, which contains a piperidinecarboxylic acid moiety, exhibited potent cytotoxicity against HCT-116 cells. In the second generation, substitution of each amino acid residue in the tripeptide Tyr(Me)-MeAla-MeIle moiety in apratoxin M7 led to the development of the highly potent apratoxin M16 possessing biphenylalanine (Bph) instead of Tyr(Me), which exhibited an IC value of 1.1 nM against HCT-116 cells. Moreover, compared to apratoxin A, apratoxin M16 exhibited a similarly high level of growth inhibitory activity against various cancer cell lines. The results indicate that apratoxin M16 could be a potential candidate as an anticancer agent.

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Construction of Tetracyclic Core Skeleton of Cephalotaxus Diterpenoids through Diastereoselective Pauson‐Khand Reaction

et al. 2022

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Cephalotaxus diterpenoids represent a class of attractive natural products with diverse chemical structures and valuable biological activities. The Construction of tetracyclic core skeleton plays an important role in synthesizing these compounds. We report here the development of diastereoselective Pauson-Khand reactions as an effective strategy to the core structure, which enabled the total synthesis of (+)-3-deoxyfortalpinoid F, (+)-fortalpinoid A, and (+)-cephinoid H.

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Asymmetric Synthesis of Apratoxin E

Cited by 10 publications

References 64 publications

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

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

Conformation-Based Design and Synthesis of Apratoxin A Mimetics Modified at the α,β-Unsaturated Thiazoline Moiety

Construction of Tetracyclic Core Skeleton of Cephalotaxus Diterpenoids through Diastereoselective Pauson‐Khand Reaction

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