Desmosdumotin C (
1) and its analogs previously showed potent, selective in vitro anticancer activity. Toexplore 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 showedsignificant cytotoxity against A549, A431, 1A9, and HCT-8 with ED
50 values of 1.0, 1.2, 0.9, and 1.3
g/mL, respectively. Compound
26 also strongly inhibited the growth of matched tumor cells, KB-VIN andits 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-Bpromoted KB-VIN/KB selectivity. 2-Furyl analog
16 showed selective activity against HUVEC, suggestingthat it may have potential as a new prototype for angiogenesis inhibition.