Synthesis of triterpenoid triazine derivatives from allobetulone and betulonic acid with biological activities.
The synthetic transformation and modification of natural products with the aim to improve the biological properties is an area of current interest. The triterpenoids betulin and betulinic acid are very abundant in nature and now are commercially available. In our study, starting from betulin and betulinic acid, we obtained allobetulone and betulonic acid in a few synthetic steps. The ketone function at the A-ring was used as the starting point for the synthesis of a series of 1,2,4-triazine-fused triterpenoids. The alkylation and Liebeskind-Srogl coupling were used for further substitution of 1,2,4-triazines, and the intramolecular hetero Diels-Alder reaction leads to interesting fused thienopyridine derivatives. All new compounds were tested for their cytostatic activities against murine leukemia L1210, human cervix carcinoma HeLa and human lymphoblast CEM tumor cells. The results show that some triterpenoid triazine betulonic acid derivatives have a promising cytostatic activity in vitro and could be used as potential leads for the development of new type of anti-cancer agents. Several compounds were also endowed with anti-HCMV activity in the low micromolar range.
Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
Thuc
T
Dinh Ngoc
Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
Nico
N
Moons
Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
Youngju
Y
Kim
Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
Wim
W
De Borggraeve
Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
Anastassiya
A
Mashentseva
Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Graciela
G
Andrei
Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Robert
R
Snoeck
Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Jan
J
Balzarini
Molecular Design and Synthesis, Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium. Electronic address: wim.dehaen@chem.kuleuven.be.
Wim
W
Dehaen
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004267:DNA Viruses / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D012328:RNA Viruses / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009828:Oleanolic Acid; D014227:Triazines; D014315:Triterpenes; C118308:betulonic acid; D000094062:Betulinic Acid
Cervix carcinoma HeLa; Diels–Alder reaction; Lymphoblast CEM tumor cells; Murine leukemia; Triterpenoid triazine