Studies on chemical structure modification and structure-activity relationship of derivatives of gambogic acid at C(39).
The natural product gambogic acid exhibits high potency in inhibiting cancer cell lines. Rational medicinal modifications on gambogic acid will improve its physicochemical properties and drug-like characters. To investigate the structure-activity relationship of gambogic acid and also to find rational modification position on its chemical skeleton, we designed, synthesized, and characterized 16 derivatives of gambogic acid that were modified at C(39). The structure-activity relationships (SARs) were discussed. The anti-proliferation data were accquired through MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays of A549, BGC823, U251, HepG2, and MDA-MB-231 cancer cell lines. Most of the synthesized compounds showed strong inhibitory effects. The SAR study revealed that derivatives with aliphatic amino moieties at C(39) were more potent than those with other substituents. The C(39) position can undergo different kinds of chemical modifications without leading to loss of activity. Compounds 4 and 6 can serve as potential lead compounds for further development of new anticancer drugs.
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Hao-Peng
HP
Sun
Zong-Liang
ZL
Liu
Xin
X
Xue
Yuan
Y
Gao
Lei
L
Zhang
Jin-Xin
JX
Wang
Qing-Long
QL
Guo
Qi-Dong
QD
You
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D029760:Garcinia / Q000737:chemistry*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D044004:Xanthones; C052659:gambogic acid