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 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.
iMedUL-Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.
João
J
Lavrado
Anthony P
AP
Reszka
Rui
R
Moreira
Stephen
S
Neidle
Alexandra
A
Paulo
D000818:Animals; D000962:Antimalarials; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D054856:G-Quadruplexes / Q000187:drug effects*; D026121:Indole Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects; D014709:Vero Cells
D000962:Antimalarials; D000970:Antineoplastic Agents; D026121:Indole Alkaloids; D008024:Ligands; D011804:Quinolines; C024015:cryptolepine