Synthesis and biological evaluation of 20(S)-substituted FL118 conjugates as novel antitumor agents

•FL118 coupled with non-steroidal anti-inflammatory drugs (NSAIDs) were synthesized.•The water-insoluble FL118-NSAIDs(6a-6d)) could not release FL118 as prodrugs.•6c could not release FL118, but showed strong inhibition of Topo1 in vitro.•The water-soluble FL118-AA (9a-9j) could release the FL118 as prodrugs.•The antitumor activity in vivo of FL118-AA were consistent with Topo I activity. Fourteen 20(S)-substituted FL118 hybrids coupled with non-steroidal anti-inflammatory drugs (NSAIDs) or amino acids (AA) were synthesized and characterized. Most of them exhibited excellent antitumor activity against the four types of human cancer cell lines (A549, HepG2, HeLa and HCT116). FL118-NSAID derivatives(6a-6d) showed insoluble and lactone increased stability, and could not release FL118 as esterase-triggered prodrugs. FL118-AA (9a-9j) showed better water-soluble and could release the parental compound FL118 as prodrugs in both PBS and human plasma. The antitumor activity in vivo of the FL118-AA 9c, 9i and 9j were consistent with their Topo I inhibitory activity in vitro. The FL118-NSAID 6c could not release FL118, but showed strong inhibition of Topo1 in vitro and low CDOCKER energy with Topo1, the varous formulation of 6c should be try to address the insoluble problem and the drug delivery in the future. [Display omitted]