Bioorganic & medicinal chemistry letters

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

PMID 20952194


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 GI(50) 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 (LC(50)) 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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Cryptolepine hydrate, ≥98% (HPLC)
C16H12N2 · xH2O