C-11 diamino cryptolepine derivatives NSC748392, NSC748393, and NSC748394: Anticancer profile and G-quadruplex stabilization

G-Quadruplex DNA ligands are promising novel anticancer agents with potentially fewer side effects and greater selectivity than standard anticancer drugs. However, the design of G-quadruplex ligands remains challenging since known chemical features increasing selectivity have often compromised drugability. Three C-11 diamino cryptolepine derivatives, with significant chemical differences between the side chains, low cytotoxicity to mammalian non-tumor cells (Vero cells) and drug-like properties, were selected for anticancer drug screening in the NCI Developmental Therapeutics Program. The three compounds showed good in vitro anticancer profiles with GI50 averages at sub-micromolar concentrations (0.32–0.78 μM), cytostatic effects (TGI) at micromolar concentrations (1.3–6.9 μM) and moderate cytotoxic effects to cancer cells (LC50) also at micromolar concentrations (4.7–33 μM), but only the compound with a linear alkylamine side chain (NSC748393) showed a good score in the in vivo anticancer Hollow Fiber assay. compare analysis of growth inhibition profile of NSC748393 suggested a multi-target mechanism. G-Quadruplex DNA binding affinity and selectivity studies by FRET-melting assays showed that NSC748392 and NSC478393, with aliphatic amine side chains, are good G-quadruplex ligands but not selective, whereas a C-11 aromatic side chain, as in NSC748394, increases selectivity although with decreasing binding affinity. Overall, NSC748393 can be considered a lead molecule for the design of effective but more selective anticancer drugs targeting telomeric G-quadruplexes.

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