title: Cholic acid derivatives as 1,2,4,5-tetraoxane carriers: structure and antimalarial and antiproliferative activity.
abstract: Cholic acid-derived 1,2,4,5-tetraoxanes were synthesized in order to explore the influence of steroid carrier on its antimalarial and antiproliferative activity in vitro. Starting with chiral ketones, cis and trans series of diastereomeric tetraoxanes were obtained, and the cis series was found to be approximately 2 times as active as the trans against Plasmodium falciparum D6 and W2 clones. The same tendency was observed against human melanoma (Fem-X) and human cervix carcinoma (HeLa) cell lines. The amide C(24) termini, for the first time introduced into the carrier molecule of a tetraoxane pharmacophore, significantly enhanced both antimalarial and antiproliferative activity, as compared to the corresponding methyl esters, with cis-bis(N-propylamide) being most efficient against the chloroquine-susceptible D6 clone (IC(50) = 9.29 nM). cis- and trans-bis(N-propylamides) were also screened against PBMC, and PHA-stimulated PBMC, showing a cytotoxicity/antimalarial potency ratio of 1/10 000.
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, Belgrade, Yugoslavia.
authors.forename: D
authors.initials: D
authors.lastname: Opsenica
authors.forename: G
authors.initials: G
authors.lastname: Pocsfalvi
authors.forename: Z
authors.initials: Z
authors.lastname: Juranic
authors.forename: B
authors.initials: B
authors.lastname: Tinant
authors.forename: J P
authors.initials: JP
authors.lastname: Declercq
authors.forename: D E
authors.initials: DE
authors.lastname: Kyle
authors.forename: W K
authors.initials: WK
authors.lastname: Milhous
authors.forename: B A
authors.initials: BA
authors.lastname: Solaja
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002793:Cholic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D002793:Cholic Acids; D013141:Spiro Compounds