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Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery.

Fontaine SD, DiPasquale AG, Renslo AR - Org. Lett. (2014)

Bottom Line: Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane.In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo.A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitution pattern that enables ferrous iron-dependent drug delivery is reported.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.

ABSTRACT
Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitution pattern that enables ferrous iron-dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a trans relationship between the 3″ substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3″-substituted 4-nitrobenzoate analogue.

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Structure of arterolane(1) and arterolane-inspiredtrioxolane–drug conjugate 2. Free drug is releasedfrom 2 in the presence of ferrous iron.
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fig1: Structure of arterolane(1) and arterolane-inspiredtrioxolane–drug conjugate 2. Free drug is releasedfrom 2 in the presence of ferrous iron.

Mentions: Combination therapy with thesesquiterpene endoperoxide artemisinin is the current standard ofcare for treating uncomplicated malaria. A variety of synthetic moleculesunrelated to artemisinin except for the presence of a hindered peroxidebond have been shown to also exhibit potent antimalarial properties.The 1,2,4-trioxolane arterolane1−3 (1, Figure 1) was the first such synthetic peroxide to be approvedfor clinical use (in India), while a related analogue with improvedproperties (OZ439)4 is currently progressingthrough human clinical trials. While their mechanism of antimalarialaction is still studied and debated,5−16 the prevailing view is that Fenton-type reduction by ferrous ironsources within the parasite is an essential, activating chemical event.Various in vitro studies7,11,13,17 have confirmed the intermediacyof carbon-centered radicals following exposure of arterolane-likemodel systems to inorganic iron(II) salts or iron(II) heme. The concomitantproduction of ketone products in these reactions suggested to us thepossibility of exploiting trioxolane fragmentation chemistry for ferrousiron-dependent and parasite-selective drug delivery.


Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery.

Fontaine SD, DiPasquale AG, Renslo AR - Org. Lett. (2014)

Structure of arterolane(1) and arterolane-inspiredtrioxolane–drug conjugate 2. Free drug is releasedfrom 2 in the presence of ferrous iron.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4227544&req=5

fig1: Structure of arterolane(1) and arterolane-inspiredtrioxolane–drug conjugate 2. Free drug is releasedfrom 2 in the presence of ferrous iron.
Mentions: Combination therapy with thesesquiterpene endoperoxide artemisinin is the current standard ofcare for treating uncomplicated malaria. A variety of synthetic moleculesunrelated to artemisinin except for the presence of a hindered peroxidebond have been shown to also exhibit potent antimalarial properties.The 1,2,4-trioxolane arterolane1−3 (1, Figure 1) was the first such synthetic peroxide to be approvedfor clinical use (in India), while a related analogue with improvedproperties (OZ439)4 is currently progressingthrough human clinical trials. While their mechanism of antimalarialaction is still studied and debated,5−16 the prevailing view is that Fenton-type reduction by ferrous ironsources within the parasite is an essential, activating chemical event.Various in vitro studies7,11,13,17 have confirmed the intermediacyof carbon-centered radicals following exposure of arterolane-likemodel systems to inorganic iron(II) salts or iron(II) heme. The concomitantproduction of ketone products in these reactions suggested to us thepossibility of exploiting trioxolane fragmentation chemistry for ferrousiron-dependent and parasite-selective drug delivery.

Bottom Line: Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane.In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo.A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitution pattern that enables ferrous iron-dependent drug delivery is reported.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.

ABSTRACT
Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitution pattern that enables ferrous iron-dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a trans relationship between the 3″ substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3″-substituted 4-nitrobenzoate analogue.

Show MeSH