title: Novel esters of glaucarubolone as inducers of terminal differentiation of promyelocytic HL-60 cells and inhibitors of 7,12-dimethylbenz[a]anthracene-induced preneoplastic lesion formation in mouse mammary organ culture.
abstract: In an effort to discover new chemotherapeutic/chemopreventive agents from natural sources, brusatol (1) was found to induce HL-60 cellular differentiation, accompanied by strong antiproliferative and cytotoxic effects. A series of natural and semisynthetic quassinoids (1-48) was designed to effect both antiproliferative and differentiation-inducing properties. Compounds were assessed in vitro using the HL-60 promyelocytic cell model. Changes in activity due to structural modification of the core structure glaucarubolone (24) were consistent with activities reported in other cell systems. However, the following were novel SAR findings: (1) semisynthetic analogues with a hydroxylated ring at the beta-position of the ester side chain at C-15 were able to induce cellular differentiation at concentrations lower than those inducing cell growth arrest, and (2) quassinoids inhibiting DNA synthesis with greater efficacy than reducing cellular viability possessed alkyl substitutions at the alpha-position of the C-15 ester side chain. Analogues from this latter group and brusatol (1) and bruceantin (2) inhibited dimethylbenz(a)anthracene-induced preneoplastic lesion formation in a mouse mammary organ culture. The novel finding of 1 and glaucarubolone analogues as potent inducers of differentiation leads to potential novel applications in the field of cancer.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mata-Greenwood
authors.forename: J F
authors.initials: JF
authors.lastname: Daeuble
authors.forename: P A
authors.initials: PA
authors.lastname: Grieco
authors.forename: J
authors.initials: J
authors.lastname: Dou
authors.forename: J D
authors.initials: JD
authors.lastname: McChesney
authors.forename: R G
authors.initials: RG
authors.lastname: Mehta
authors.forename: A D
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: J M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000037:antagonists & inhibitors*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005900:Glaucarubin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006031:Glycosylation; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D015394:Molecular Structure; D009580:Nitroblue Tetrazolium / Q000494:pharmacology; D009924:Organ Culture Techniques; D010946:Plants, Medicinal / Q000737:chemistry*; D036702:Quassins; D051381:Rats; D029641:Simaroubaceae / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D036702:Quassins; C445800:dehydrobrusatol; C445799:yadanziolide C; C020237:brusatol; C024967:glaucarubolone; D009580:Nitroblue Tetrazolium; D015127:9,10-Dimethyl-1,2-benzanthracene; C020236:bruceoside A; D004247:DNA; D005900:Glaucarubin; C002550:bruceantin