Strategies and Methods for the Synthesis of Anticancer Natural Product Neopeltolide and its Analogs

Bai, Yu; Dai, Mingji

doi:10.2174/1385272819666150119225149

Cited by 23 publications

(5 citation statements)

References 57 publications

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“…Wright and co-workers isolated a marine macrolide neopeltolide ( 1 , Figure 1 ) from a deep-water sponge that belongs to the Neopeltidae family [ 13 ]. This natural product has been an intriguing synthetic target for organic chemists because of its complex structure and potent biological activity [ 14 , 15 ]. According to Wright et al [ 13 ], this natural product potently inhibited in vitro proliferation of human non-small cell lung adenocarcinoma A549 cells, human ovarian sarcoma NCI-ADR-RES cells, and murine leukemia P388 cells at nanomolar concentrations, whereas it showed cytostatic activity against human pancreatic adenocarcinoma PANC-1 cells and colorectal adenocarcinoma DLD-1 cells.…”

Section: Introductionmentioning

confidence: 99%

A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells

Fuwa

Satô

2017

Marine Drugs

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Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.

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Section: Introductionmentioning

confidence: 99%

A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells

Fuwa

Satô

2017

Marine Drugs

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“…While examining the potential routes towards the synthesis of (+)-Neopeltolide and its analogues [64][65][66], we attempted to perform the stereoselective allylation of MOMprotected 3-hydroxylhexanal 3 with (allyl)tributylstannane 2. The aldehyde 3 (ee > 99%) was prepared by following the known procedure [55] (see the Supplementary Materials).…”

Section: Diastereoselective Allylation Of Aldehyde 3 With (Allyl)trib...mentioning

confidence: 99%

Highly Diastereoselective Chelation-Controlled 1,3-anti-Allylation of (S)-3-(Methoxymethyl)hexanal Enabled by Hydrate of Scandium Triflate

2021

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En route to the total synthesis of (+)-Neopeltolide, we explored Lewis acid-assisted diastereoselective allylation of MOM-protected 3-hydroxylhexanal with β-(2,2-diethoxyethyl)-substituted (allyl)tributylstannane. The hydrated form of scandium triflate was found to be essential for attaining high 1,3-anti-diastereoselectivity (d.r. 94:6), while the use of anhydrous catalyst resulted in a modest diastereocontrol (d.r. 76:24). The preferred 1,3-anti-selectivity in this transformation can be rationalized in the framework of the Reetz chelate model of asymmetric induction. The 1,3-anti-configuration of the product was confirmed by its conversion into the known C7-C16 building block of (+)-Neopeltolide. We also report an improved protocol for the synthesis of β-(2,2-diethoxyethyl)-substituted (allyl)tributylstannane, which can be utilized as a cost-efficient bipolar isoprenoid-type C5-building block in the synthesis of natural compounds.

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“…Overall, this one-step transformation accomplishes the formation of two carbon–oxygen bonds, one carbon–carbon bond, and a bridged macrocyclic ring. Its application was further demonstrated by a total synthesis of the 9-demethylneopeltolide, a potent anticancer analog of neopeltolide . When Pd(OAc) 2 was used as catalyst and CuCl 2 as oxidant under a carbon monoxide balloon in 1,2-dichloroethane at room temperature, alkendiol 104 was converted to THP-bridged macrolactone 105 in 58% yield with excellent cis selectivity.…”

Section: Carbonylative Macrocyclizationmentioning

confidence: 99%

Natural Product Synthesis via Palladium-Catalyzed Carbonylation

2017

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Carbon monoxide is an important one-carbon source and can be incorporated in complex molecules via various transition-metal-catalyzed carbonylation reactions. In particular, palladium-catalyzed carbonylation reactions have found broad application in total synthesis of natural products. Examples are presented in this Synopsis to highlight recent progress in this area, including our own work in macrolide and spirocyclic molecule synthesis. In these selected cases, carbon monoxide functions as a one-carbon linchpin to facilitate building structural complexity and improving synthetic efficiency.

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Strategies and Methods for the Synthesis of Anticancer Natural Product Neopeltolide and its Analogs

Cited by 23 publications

References 57 publications

A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells

A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells

Highly Diastereoselective Chelation-Controlled 1,3-anti-Allylation of (S)-3-(Methoxymethyl)hexanal Enabled by Hydrate of Scandium Triflate

Natural Product Synthesis via Palladium-Catalyzed Carbonylation

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