Methylene Homologues of Artemisone: An Unexpected Structure-Activity Relationship and a Possible Implication for the Design of C10-Substituted Artemisinins.
We sought to establish if methylene homologues of artemisone are biologically more active and more stable than artemisone. The analogy is drawn with the conversion of natural O- and N-glycosides into more stable C-glycosides that may possess enhanced biological activities and stabilities. Dihydroartemisinin was converted into 10β-cyano-10-deoxyartemisinin that was hydrolyzed to the α-primary amide. Reduction of the β-cyanide and the α-amide provided the respective methylamine epimers that upon treatment with divinyl sulfone gave the β- and α-methylene homologues, respectively, of artemisone. Surprisingly, the compounds were less active in vitro than artemisone against P. falciparum and displayed no appreciable activity against A549, HCT116, and MCF7 tumor cell lines. This loss in activity may be rationalized in terms of one model for the mechanism of action of artemisinins, namely the cofactor model, wherein the presence of a leaving group at C10 assists in driving hydride transfer from reduced flavin cofactors to the peroxide during perturbation of intracellular redox homeostasis by artemisinins. It is noted that the carba analogue of artemether is less active in vitro than the O-glycoside parent toward P. falciparum, although extrapolation of such activity differences to other artemisinins at this stage is not possible. However, literature data coupled with the leaving group rationale suggest that artemisinins bearing an amino group attached directly to C10 are optimal compounds.
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China.
Yuet
Y
Wu
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China.
Ronald Wai Kung
RW
Wu
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China.
Kwan Wing
KW
Cheu
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China.
Ian D
ID
Williams
Centre for Infection, Division of Cellular and Molecular Medicine, St. George's Hospital, University of London, SW17 0RE, UK.
Sanjeev
S
Krishna
Centre for Infection, Division of Cellular and Molecular Medicine, St. George's Hospital, University of London, SW17 0RE, UK.
Ksenija
K
Slavic
Department of Oncology, Division of Cellular and Molecular Medicine, St. George's Hospital, University of London, Jenner Wing, London, SW17 0RE, UK.
Andrew M
AM
Gravett
Department of Oncology, Division of Cellular and Molecular Medicine, St. George's Hospital, University of London, Jenner Wing, London, SW17 0RE, UK.
Wai M
WM
Liu
Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, 2520, South Africa.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China.
Ho Ning
HN
Wong
Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, 2520, South Africa. richard.haynes@nwu.ac.za, haynes@ust.hk.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China. richard.haynes@nwu.ac.za, haynes@ust.hk.
Richard K
RK
Haynes
D000072283:A549 Cells; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D029968:Escherichia coli Proteins / Q000378:metabolism; D038181:FMN Reductase / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000031:analogs & derivatives / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D059565:G2 Phase Cell Cycle Checkpoints; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D029968:Escherichia coli Proteins; D005182:Flavin-Adenine Dinucleotide; C058805:1,5-dihydro-FAD; C514498:artemisone; D038181:FMN Reductase; C540768:Fre protein, E coli
C-glycosides; antimalarial activity; antitumor agents; mechanisms; peroxides