ABSTRACT
Based on biological properties of epoxyquinols from natural sources, bromo and epoxyquinols derived from estrone were synthesized and screened against Fem-X, HeLa and K(562) cell lines. Evidence was found that the bromine atom and the epoxy moiety significantly increase the antiproliferative activity within the series.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bromine/chemistry , Epoxy Compounds/chemistry , Estrone/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Estrone/chemistry , Estrone/pharmacology , HeLa Cells , Humans , K562 Cells , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antimalarials/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cholic Acids/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cholic Acids/chemistry , Cholic Acids/pharmacology , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Plasmodium falciparum/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The synthesis of delta 7,9(11)-lanostadiene derivatives functionalized at C(32) starting from 3 beta-acetoxy-7 alpha,32-epoxylanostan-11-one has been presented. The delta 7,9(11) moiety was efficiently introduced in three steps in 71% yield by the regioselective abstraction of allylic 8 beta hydrogen. The formyl group of the key intermediate, 3 beta-benzoyloxylanosta-7,9(11)-dien-32-al, has been stereoselectively alkylated into (32S) derivative, whereas its oxidation unexpectedly afforded 3 beta-benzoyloxy-7-oxolanost-8-ene-32,11 alpha-lactone and not the corresponding acid. delta 7,9(11)-lanostadienes possessing HC(32)=O, C(32) [symbol: see text] N, HC(32S)CH3OH, H2C(32)OH, as well as some 11-keto lanostenes, were tested in vitro against several purified cholesterogenic enzymes showing moderate activity, with most the active aldehyde 16 having IC50 = 86 microM.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Lanosterol/analogs & derivatives , Lanosterol/metabolism , Animals , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Lanosterol/chemical synthesis , Lanosterol/pharmacology , Male , Microsomes, Liver/enzymology , Molecular Structure , Oxidoreductases/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Sterol 14-DemethylaseABSTRACT
Cholestane-derived gem-dihydroperoxides and tetraoxanes were synthesized starting from 5 alpha- and 5 beta-cholestan-3-ones by acid-catalyzed addition of hydrogen peroxide to the ketone. They were characterized by IR, NMR, and mass spectroscopy analysis aided by molecular mechanics calculations, and, in the instance of 5 beta-cholestane-3 alpha,3 beta-dihydroperoxide (6), by x-ray analysis. The synthesized compounds were tested in vitro against Plasmodium falciparum Sierra Leone (D6) and Indochina (W2) malaria clones. All compounds were inactive to both clones, with the exception of tetraoxane 7a, which exhibited modest activity toward D6 clone with IC50 = 155 nM.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Cholestanes/chemistry , Cholestanes/chemical synthesis , Peroxides/chemistry , Animals , Antimalarials/chemical synthesis , Cholestanes/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Molecular Structure , Peroxides/chemical synthesis , Peroxides/pharmacology , Plasmodium falciparum/drug effects , Steroids/chemistryABSTRACT
The two-phase oxidation of steroidal 5-en-3 beta-ol (via 5-en-3-ones) into corresponding 4-en-3,6-diones in diethyl ether with Jones reagent was investigated. It was found that the system Jones reagent/diethyl ether enables short reaction times and easy isolation of the obtained products. The exclusive abstraction of 4 alpha-hydrogen during oxidation, together with molecular mechanics (MM2), and semiempirical (PM3) calculations, suggest that boat conformation of ring A precedes the formation of corresponding radicals (or cations).
