Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity.

Journal of Medicinal Chemistry
Ik-Hyeon PaikGary H Posner

Abstract

In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.

References

Jun 1, 1993·Journal of Natural Products·H J WoerdenbagA W Konings
Mar 7, 2003·Journal of Medicinal Chemistry·Mankil JungSoo Kie Kim
Mar 7, 2003·Journal of Medicinal Chemistry·Gary H PosnerTheresa A Shapiro
Jul 19, 2003·Molecular Pharmacology·Thomas EfferthJens Oliver Funk
Feb 20, 2004·Journal of Medicinal Chemistry·J Prince JeyadevanPaul M O'Neill
Feb 20, 2004·Journal of Medicinal Chemistry·Gary H PosnerBarbara Foster
Jun 3, 2004·Nature Reviews. Drug Discovery·David A FidockSolomon Nwaka
Dec 29, 2005·Bioorganic & Medicinal Chemistry Letters·Mankil JungKwang-Kyun Park

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Citations

Sep 1, 2012·Investigational New Drugs·Henry C LaiTomikazu Sasaki
Nov 4, 2009·Expert Reviews in Molecular Medicine·Gary L Firestone, Shyam N Sundar
Apr 3, 2008·American Journal of Veterinary Research·Kenji HosoyaWilliam C Kisseberth
Dec 10, 2013·Pharmacology & Therapeutics·Wanxing Eugene HoW S Fred Wong
Sep 1, 2007·Current Opinion in Chemical Biology·Michael H Gelb
Jun 18, 2009·International Journal of Cancer. Journal International Du Cancer·Luke H StockwinMaja A Bumke
Jul 20, 2007·The Journal of Pharmacy and Pharmacology·Xiao-Jia HuangEr-Qing Wei
Jul 11, 2006·Toxicology Letters·Stephen Toovey
Mar 25, 2016·Journal of Medicinal Chemistry·Tony FröhlichSvetlana B Tsogoeva
Apr 30, 2016·Cancer Chemotherapy and Pharmacology·Christina D DrenbergSharyn D Baker
Feb 19, 2015·Chemical Communications : Chem Comm·Hai-Jun ChenJian-Dong Huang
Jun 7, 2018·Anais Da Academia Brasileira De Ciências·Luiz C S PinheiroNubia Boechat
Sep 11, 2007·Chemistry, an Asian Journal·Masaki ShimizuTamejiro Hiyama
Oct 19, 2007·Angewandte Chemie·Axel G GriesbeckAngela Raabe
Jan 30, 2010·Chemical Society Reviews·Devdutt ChaturvediParuchuri G Rao
Mar 10, 2020·ChemMedChem·Clinton G L Veale, Ronel Müller
Sep 25, 2014·Journal of the American Animal Hospital Association·Kenji HosoyaJames T Dalton
Dec 13, 2018·Anti-cancer Drugs·Nelson Siukei LamJames C G Doery
Feb 16, 2017·Applied Microbiology and Biotechnology·Jaime A Teixeira da Silva, Tzi Bun Ng
Jul 9, 2020·Parasitology Research·J O AdebayoS O Malomo
Jan 29, 2021·European Journal of Medicinal Chemistry·Om P S PatelLesetja J Legoabe
Jan 10, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Raquel G Soengas, Humberto Rodríguez-Solla
Nov 11, 2008·Organic Letters·Ajit Shankar SinghChandan Singh
Jun 12, 2021·Medicinal Research Reviews·Aysun ÇapcıSvetlana B Tsogoeva

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