New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure-activity relationships.
Cellular screening of various synthetic triterpenoid compounds formally derived from lupane has identified a number of analogues as potential anticancer drug candidates. Here we describe the synthesis and structure-activity relationships of betulin and betulinic acid derivatives containing an E-ring modified with different oxygen functions. Thus compounds containing the lup-18-en-21-one, lup-18-ene-21,22-dione, 18,19-secolupane, and the highly oxygenated 18,19-secolupane systems, as well as des-E-lupane derivatives, were prepared from the readily available natural pentacyclic triterpene betulin using oxidative procedures. These compounds were named betulinines. We demonstrate that only selected compounds, particularly those containing a lupane E-ring-derived unsaturated ketone or diketone function, possessed in vitro cytotoxic activity against tumor cell lines, suggesting a structure-activity relationship.
Sarek
Jan
J
Department of Organic and Nuclear Chemistry, Charles University in Prague, Hlavova 8, 128 43 Prague 2, Czech Republic.
Klinot
Jirí
J
Dzubák
Petr
P
Klinotová
Eva
E
Nosková
Vera
V
Krecek
Václav
V
Korínková
Gabriela
G
Thomson
Jean Oliver
JO
Janost'áková
Anna
A
Wang
Shudong
S
Parsons
Simon
S
Fischer
Peter M
PM
Zhelev
Nikolai Z
NZ
Hajdúch
Marián
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D000094062:Betulinic Acid
D000970:Antineoplastic Agents; D014315:Triterpenes; C480547:3,28-diacetoxy-18-oxo-19,20,21,29,30-pentanorlupan-22-oic acid; C480546:lupane; D053978:Pentacyclic Triterpenes; C002503:betulin; D000094062:Betulinic Acid