JRA-003

Sixty novel allogibberic acid derivatives containing 1,2,3-triazole pharmacophore were designed and synthesized. The key chemical processes include aromatization of the A ring in gibberellins, formation of allogibberic azides and its copper mediated Huisgen 1,3-dipolar cycloaddition with alkynes. A number of hybrids containing α,β-unsaturated ketone moiety exhibited excellent in vitro cytotoxic activities. Some of the hybrids were more selective to MCF-7 and SW480 cell lines with IC₅₀ values at least 8-fold more cytotoxic than cisplatin (DDP). The most potent compounds C43 and C45 are more cytotoxic than cisplatin (DDP) against all tested five tumor cell lines, with IC₅₀ values of 0.25-1.72 µM. Mechanism of action studies indicated that allogibberic-triazole derivative C45 could induce the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.

Me esters I (R = Me, R¹ = OH, R² = H) and II (R = Me, R¹ = OH, R² = H) of 3-epi-GA ₃ and 3-epi-GA₁ were efficiently prepared from Me esters I (R = Me, R¹ = H, R² = OH) and II (R = Me, R¹ = H, R² = OH) of GA₃ and GA₁, resp., by highly selective epimerization of the 3-hydroxyl function with a base in a low-polar aprotic medium.