Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities.
Betulinic acid (BA), a pentacyclic triterpene isolated from birch bark and other plants, selectively inhibits the growth of human cancer cell lines. However, the poor potency of BA hinders its clinical development, despite a lack of toxicity in animal studies even at high concentrations. Here, we describe six BA derivatives that are markedly more potent than BA for inhibiting inducible nitric oxide synthase, activating phase 2 cytoprotective enzymes, and inducing apoptosis in cancer cells and in Bax/Bak(-/-) fibroblasts, which lack two key proteins involved in the intrinsic, mitochondrial-dependent apoptotic pathway. Notably, adding a cyano-enone functionality in the A ring of BA enhanced its cytoprotective properties, but replacing the cyano group with a methoxycarbonyl strikingly increased potency in the apoptosis assays. Higher plasma and tissue levels were obtained with the new BA analogues, especially CBA-Im [1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole], compared with BA itself and at concentrations that were active in vitro. These results suggest that BA is a useful platform for drug development, and the enhanced potency and varied biological activities of CBA-Im make it a promising candidate for further chemoprevention or chemotherapeutic studies.
Liby
Karen
K
Dartmouth Medical School, Hanover, NH 03755, USA.
Honda
Tadashi
T
Williams
Charlotte R
CR
Risingsong
Renee
R
Royce
Darlene B
DB
Suh
Nanjoo
N
Dinkova-Kostova
Albena T
AT
Stephenson
Katherine K
KK
Talalay
Paul
P
Sundararajan
Chitra
C
Gribble
Gordon W
GW
Sporn
Michael B
MB
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; D016660:NAD(P)H Dehydrogenase (Quinone); D000094062:Betulinic Acid