ACS Medicinal Chemistry Letters
LETTER
Table 2. Additional Alkoxydioxolanes
Funding Sources
This work was supported by the Medicines for Malaria Venture
and the Nebraska Research Initiative and conducted in facilities
remodeled with support from the NIH (RR0116544-01). NMR
spectra were acquired, in part, on spectrometers purchased with
NSF support (MRI 0079750 and CHE 0091975). We thank
Dr. Xuejun Liu for initial preparation of several dioxolanes, Tony
Lloyd for technical assistance, and Prof. Jonathan Vennerstrom
(University of Nebraska Medical Center) for helpful discussions.
’ REFERENCES
(1) World Health Organization Malaria Report 2008.
(2) White, N. J. Qinghaosu (Artemisinin): The Price of Success.
Science 2008, 320, 330–334.
(3) Moon, D. K.; Singhal, V.; Kumar, N.; Shapiro, T. A.; Posner,
G. H. Antimalarial preclinical drug development: A single oral dose of a
5-carbon-linked trioxane dimer plus mefloquine cures malaria-infected
mice. Drug Dev. Res. 2010, 71, 76–81.
(4) Walsh, J. J.; Coughlan, D.; Heneghan, N.; Gaynor, C.; Bell, A. A
novel artemisinin-quinine hybrid with potent antimalarial activity.
Bioorg. Med. Chem. Lett. 2007, 17, 3599–3602.
(5) Li, Y.; Zhu, Y.-M.; Jiang, H.-J.; Pan, J.-P.; Wu, G.-S.; Wu, J.-M.;
Shi, Y.-L.; Yang, J.-D.; Wu, B.-A. Synthesis and antimalarial activity of
artemisinin derivatives containing an amino group. J. Med. Chem. 2000,
43, 1635–1640.
(6) O'Neill, P. M.; Pugh, M.; Stachulski, A. V.; Ward, S. A.; Davies, J.;
Park, B. K. Optimisation of the allylsilane approach to C-10 deoxo carba
analogues of dihydroartemisinin: synthesis and in vitro antimalarial
activity of new, metabolically stable C-10 analogues. J. Chem. Soc., Perkin
Trans. 1 2001, 2682–2689.
(7) Lin, A. J.; Li, L. Q.; Andersen, S. L.; Klayman, D. L. Antimalarial
activity of new dihydroartemisinin derivatives. J. Med. Chem. 1992, 35,
1639–1642.
(8) Noedl, H.; Se, Y.; Schaecher, K.; Smith, B. L.; Socheat, D.;
Fukuda, M. M. Evidence of artemisinin-resistant malaria in western
Cambodia. N. Engl. J. Med. 2008, 359, 2619–2620.
a NF54 strain of P. falciparum (refs 29 and 30). b Solvent.
(9) For an overview, see Tang, Y.; Dong, Y.; Vennerstrom, J. L.
Synthetic peroxides as antimalarials. Med. Res. Rev. 2004, 24, 425–448.
(10) 1,2,4,5-Tetraoxanes: O'Neill, P.; Amewu, R.; Nixon, G. L; El
Garah, F. B; Mungthin, M.; Chadwick, J.; Shone, A. E.; Vivas, L.; Lander,
H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.; Park, B. K.;
Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K.; Ward, S. A. Identification
of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate
(RKA 182) with Superior Properties to the Semisynthetic Artemisinins.
Angew. Chem., Int. Ed. 2010, 49, 5693–5697.
(11) Spiroperoxyketals: Ghorai, P.; Dussault, P. H.; Hu, C. H.
Synthesis of Spiro-bisperoxy ketals. Org. Lett. 2008, 10, 2401–2404.
(12) 1,2,4-Trioxanes: Posner, G. H; Oh, C. H.; Wang, D.; Gerena,
L.; Milhous, W. K.; Meshnick, S. R.; Asawamadhasadka, W. Mechanism-
Based Design, Synthesis, and in vitro Antimalarial Testing of New
4-Methylated Trioxanes Structurally Related to Artemisinin. J. Med.
Chem. 1994, 37, 1256–1258.
(13) 1,2,4-Trioxolanes: Dong, Y.; Wittlin, S.; Sriraghavan, K.;
Chollet, J.; Charman, S. A.; Charman, W. N.; Scheurer, C.; Urwyler,
H.; Santo Tomas, J.; Snyder, C.; Creek, D. J.; Morizzi, J.; Koltun, M.;
Matile, H.; Wang, X.; Padmanilayam, M.; Tang, Y.; Dorn, A.; Brun, R.;
Vennerstrom, J. L. The Structure-Activity Relationship of the Anti-
malarial Ozonide Arterolane (OZ277). J. Med. Chem. 2010, 53, 481–91.
(14) Fugi, M. A.; Wittlin, S.; Dong, Y.; Vennerstrom, J. L. Probing
the antimalarial mechanism of artemisinin and OZ277 (arterolane) with
nonperoxidic isosteres and nitroxyl radicals. Antimicrob. Agents Chemo-
ther. 2010, 54, 1042–1046.
with either a bulky C3 alkyl substituent or a large C3 alkoxide
displayed IC50 values below 10 nM.
Finally, we were interested in investigating the Fe(II) reactiv-
ity of the alkoxydioxolanes, and, in particular, the extent of
cleavage of the derived alkoxy radicals (see Scheme 1). Alkoxy-
dioxolane 25, one of our most active of our initial leads, under-
went reaction with FeBr2 to furnish the corresponding 3-hydro-
xyester in 80% yield (reaction illustrated in Scheme 1),
supporting the postulated formation and fragmentation of an
alkoxy-substituted alkoxy radical.15,16 Similar results have been
reported for a monocyclic alkoxydioxolane.23
In conclusion, we have developed new and expanded routes to
1,2-dioxolan-3-ols and 3-alkoxy-1,2-dioxolanes. The latter are
demonstrated to provide a highly promising platform for devel-
opment of a new family of antimalarial peroxides.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures and characterization data; 1H and 13C NMR spectra for all
compounds. This material is available free of charge via the
(15) Posner, G. H.; O'Neill, P. M. Knowledge of the Proposed
Chemical Mechanism of Action and Cytochrome P450 Metabolism of
Antimalarial Trioxanes Like Artemisinin Allows Rational Design of
New Antimalarial Peroxides. Acc. Chem. Res. 2004, 37, 397–404.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 402-472-6951. E-mail: pdussault1@unl.edu.
318
dx.doi.org/10.1021/ml100308d |ACS Med. Chem. Lett. 2011, 2, 316–319