Dihydroartemisinin

Dihydroartemisinin
IUPAC name (3R,5aS,6R,8aS,9R,12S,12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-ol
Other names DHA
Identifiers
CAS number	71939-50-9 N
PubChem	107770
ChemSpider	96929 Y
UNII	6A9O50735X Y
ChEMBL	CHEMBL25164 N
Beilstein Reference	4185848
Jmol-3D images	Image 1 Image 2
SMILES C[C@@H]1CC[C@H]2[C@H](C(O[C@H]3[C@@]24[C@H]1CC[C@](O3)(OO4)C)O)C O1[C@H](O)[C@@H](C4CC[C@@H](C)[C@H]3[C@@]42OOC(O[C@@H]12)(C)CC3)C
InChI InChI=1S/C15H24O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-13,16H,4-7H2,1-3H3/t8-,9-,10+,11?,12+,13-,14?,15-/m1/s1 Y Key: BJDCWCLMFKKGEE-KWWHLYHASA-N Y InChI=1/C15H24O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-13,16H,4-7H2,1-3H3/t8-,9-,10+,11?,12+,13-,14?,15-/m1/s1 Key: BJDCWCLMFKKGEE-KWWHLYHABU
Properties
Molecular formula	C15H24O5
Molar mass	284.35 g mol−1
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Dihydroartemisinin (or dihydroqinghaosu or artenimol) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs.^[1]It is sold commercially in combination with piperaquine and has been shown to be equivalent to artemether/lumefantrine.^[2]

Chemistry

The lactone of artemisinin could selectively be reduced with mild hydride-reducing agents, such as sodium borohydride, potassium borohydride, and lithium borohydride to dihydroartemisinin (a lactol) in over 90% yield. It is a novel reduction, because normally lactone cannot be reduced with sodium borohydride under the same reaction conditions (0-5 ˚C in methanol). Reduction with LiAlH4 leads to some rearranged products. It was surprising to find that the lactone was reduced, but that the peroxy group survived. However, the lactone of deoxyartemisinin resisted reduction with sodium borohydride and could only be reduced with diisobutylaluminium hydride to the lactol deoxydihydroartimisinin. These results show that the peroxy group assists the reduction of lactone with sodium borohydride to a lactol, but not to the alcohol which is the over-reduction product. No clear evidence for this reduction process exists.^{[citation needed]}

Dosing

Dihydroartemisinin is available as a fixed drug combination with piperaquine (each tablet contains 40 mg of dihydroartemisinin and 320 mg of piperaquine; trade name Artekin, manufactured by Holleykin Pharmaceuticals).

The adult dose is 1.6/12.8 mg/kg per dose (rounded up or down to the nearest half tablet) given at 0 h, 8 h, 24 h, and 48 h. Alternatively, the same total dose may be given once daily for three days.^[3]

Dihydroartemisinin is also sold in Africa as Cotecxin in 60 mg tablets, which is manufactured by Zhejiang Holley Nanhu Pharmaceutical Co., Ltd., in China.

Activity as experimental cancer chemotherapeutic

Accumulative research suggests that dihydroartemisinin and other artemisinin-based endoperoxide compounds may display activity as experimental cancer chemotherapeutics.^[4] Recent pharmacological evidence demonstrates that dihydroartemisinin targets human metastatic melanoma cells with induction of NOXA-dependent mitochondrial apoptosis that occurs downstream of iron-dependent generation of cytotoxic oxidative stress.^[5]

Commercial preparations

In combination with piperaquine:

• Duocotecxin (Holley Pharm)
• Artekin (Holleykin)

References

1. ^ Soon Hyung Woo, Michael H. Parker, Poonsakdi Ploypradith, John Northrop and Gary H. Posner (1998). "Direct conversion of pyranose anomeric OH→F→R in the artemisinin family of antimalarial trioxanes". Tetrahedron Letters 39 (12): 1533–1536. doi:10.1016/S0040-4039(98)00132-4. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6THS-3SHKHRD-P&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=30b29298d7f7d7c8f81b87e3491376ae. 
2. ^ Arinaitwe E, Sandison TG, Wanzira H, et al. (2009). "Artemether‐lumefantrine versus dihydroartemisinin‐piperaquine for falciparum malaria: A longitudinal, randomized trial in young Ugandan children". Clin Infect Dis 49 (11): 1629–1637. doi:10.1086/647946. PMID 19877969. 
3. ^ Ashley EA, McGready R, Hutagalung R, et al. (2005). "A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria" (– ^{Scholar search}). Clin Infect Dis 41 (4): 425–32. doi:10.1086/432011. PMID 16028147. http://www.journals.uchicago.edu/CID/journal/issues/v41n4/36148/36148.html. ^{[dead link]}
4. ^ Efferth T (2006). "Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells". Curr. Drug Targets 7 (4): 407–21. doi:10.2174/138945006776359412. PMID 16611029. http://www.ncbi.nlm.nih.gov/pubmed/16611029. 
5. ^ Cabello CM, Lamore SD, Bair WB 3rd, Qiao S, Azimian S, Lesson JL, Wondrak GT (2011). "The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis". Invest. New Drugs. doi:10.1007/s10637-011-9676-7. PMID 21547369. http://www.ncbi.nlm.nih.gov/pubmed/21547369.