Novel securinine derivatives as topoisomerase I based antitumor agents

Novel bivalent securinine mimetics as topoisomerase I inhibitors

“…Presumably it is this direct binding of mimetic R2 to Topo I that prevents the normal interaction of the enzyme with DNA, an effect observed during the course of our previously reported studies of the activities of monomeric securinine derivatives. 6 In addition, compound R2 binds effectively to the covalent Topo I/DNA complex ( Fig. 3b ) through the agency of six hydrogen bonds (see yellow dashed lines) with two adjacent bases of DNA ( viz.…”

“…In previous studies 6 we identified certain securinine derivatives that act as Topo I inhibitors. Since various linked/dimeric forms of other inhibitors, notably benzimidazoles, seem to exhibit better activity than the parent (monomeric) systems, 7 – 11 we were prompted to construct novel, dimeric securinine derivatives for the purpose of examining their Topo I-inhibitory activities.…”

Unique indolizidine alkaloid securinine is a promising scaffold for the development of neuroprotective and antitumor drugs

“…New securinine derivatives shown in Scheme 8 (ref. 51 ) were obtained using a non-stereoselective one-step Baylis–Hillman reaction 52–54 between securinine and aromatic aldehydes, which are more reactive and susceptible to further derivatization than the corresponding alkylaldehydes.…”

Biologically active indolizidine alkaloids

“…Virosecurinine ( 14 , Figure 4C), the (+)‐enantiomer of securinine, and viroallosecurinine ( 15 , Figure 4C), which differs from 14 in the orientation of the carbon at the indolizidine ring junction, were isolated from Securinega virosa leaves by Tatematsu et al 54 The two alkaloids exhibited significant in vitro cytotoxicity with ED 50 values of 2.9 and 0.9 μg/ml, respectively, in P388 cells. It is worth noting that Topoisomerase I inhibitory activity has been reported for novel securinine derivatives containing a β′‐hydroxy‐α,β‐unsaturated ketone system 152 . The compounds act by a different mechanism from that of camptothecin; they specifically inhibited the combination of DNA and Topoisomerase I rather than the formation of drug–enzyme–DNA covalent ternary complexes.…”