Antitumor Agents 259. Design, Syntheses, and Structure−Activity Relationship Study of Desmosdumotin C Analogs

Desmosdumotin C (1) and its analogs previously showed potent, selective in vitro anticancer activity. To explore structure−activity relationships of 1 and further increase potency and selectivity, 15 novel analogs (7−15 and 21−26) were synthesized and evaluated for cytotoxity against several human tumor cell lines, as well as inhibition of human endothelial (HUVEC) replication. 4-Bromo-3‘,3‘,5‘-tripropyl analog 26 showed significant cytotoxity against A549, A431, 1A9, and HCT-8 with ED₅₀ values of 1.0, 1.2, 0.9, and 1.3 μg/mL, respectively. Compound 26 also strongly inhibited the growth of matched tumor cells, KB-VIN and its parent cell KB. Furthermore, analogs 13 and 21 were over 5-fold more potent against KB-VIN than KB. Bromination of ring-B and tripropyl functionalization of ring-A enhanced activity, while alkylation of ring-B promoted KB-VIN/KB selectivity. 2-Furyl analog 16 showed selective activity against HUVEC, suggesting that it may have potential as a new prototype for angiogenesis inhibition.