Malignant melanoma is an aggressive cancer requiring new therapeutic options. Isodonal, a known spirolactone type ent-kauranoid, was obtained in high abundance from Isodon oresbius. Phenotypic screening of isodonal revealed its antiproliferative activity against A375 melanoma cells. In the structural modification to prompt its selection for optimization, we synthesized a focused library of thirty new ester derivatives (8-37) at C-6 position of isodonal. All analogues exhibited enhanced potency (IC50 = 0.73-4.43 mu M) over isodonal, with the C-6 4-fluorocinnamate ester 29 being most potent (IC50 = 0.73 mu M; similar to 10-fold improvement). Structure-activity relationship analysis revealed that conjugated systems (e.g., cinnamoyl) boost activity, and that specific substitutions in benzoate derivatives can modulate selectivity between melanoma and normal cells. Compound 29 was found to suppress proliferation, induce apoptosis and G2/M phase arrest, and elevate ROS levels in A375 cells. This study delivers a potent lead compound and a framework for the natural product-inspired development of anti-melanoma therapeutics.
[1]Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochemistry & Nat Med, Kunming 650201, Peoples R China.
[2]Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
[3]Peking Univ Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Minist Educ, Beijing 100142, Peoples R China.
(8.0+极速模式)