title: New betulinic acid derivatives as potent proteasome inhibitors.
abstract: In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC(50) values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. kdqian@unc.edu
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Sang-Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hung
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Chin-Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D007249:Inflammation / Q000188:drug therapy; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D053978:Pentacyclic Triterpenes; D061988:Proteasome Inhibitors; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D053978:Pentacyclic Triterpenes; D061988:Proteasome Inhibitors; D014315:Triterpenes; D002918:Chymotrypsin; D000094062:Betulinic Acid