Synthesis and evaluation of caged Garcinia xanthones.
Inspired by the combination of unique structure and potent bioactivities exhibited by several family members of the caged Garcinia xanthones, we developed a synthesis of simplified analogues that maintain the overall caged motif. The caged structure of these compounds was constructed via a site-selective Claisen/Diels-Alder reaction cascade. We found that the fully substituted caged structure, in which are included the C18 and C23 geminal methyl groups, is necessary to maintain bioactivity. Analogue had comparable activity to the natural products of this family, such as gambogic acid. These compounds exhibit cytotoxicity in a variety of tumor cell lines at low micromolar concentrations and were found to induce apoptosis in HUVE cells. In addition, studies with HL-60 and HL-60/ADR cells indicate that these compounds are not affected by the mechanisms of multidrug resistance, conferred by P glycoprotein expression, typical of relapsed cancers and thus represent a new and potent pharmacophore.
Batova
Ayse
A
Department of Pediatrics/Hematology-Oncology, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103-8447, USA. abatova@ucsd.edu
Lam
Thanh
T
Wascholowski
Veit
V
Yu
Alice L
AL
Giannis
Athanassios
A
Theodorakis
Emmanuel A
EA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000473:Alkanes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001688:Biological Products / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D029760:Garcinia / Q000737:chemistry*; D018922:HL-60 Cells; D006801:Humans; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000473:Alkanes; D000970:Antineoplastic Agents; D001688:Biological Products; D044004:Xanthones; C052659:gambogic acid