title: An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities.
abstract: We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4) are significantly more potent in inhibiting human cytomegalovirus (CMV) replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574), lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound.
authors: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Ran
authors: R
authors: He
authors: Bryan T
authors: BT
authors: Mott
authors: Andrew S
authors: AS
authors: Rosenthal
authors: Douglas T
authors: DT
authors: Genna
authors: Gary H
authors: GH
authors: Posner
authors: Ravit
authors: R
authors: Arav-Boger
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D037621:Artemisinins