Phenanthroline derivatives with improved selectivity as DNA-targeting anticancer or antimicrobial drugs.
Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10-phenanthroline-5,6-dione (phendione or L(1)), dipyrido[3,2-a:2',3'-c]phenazine (dppz or L(2)), and their corresponding platinum complexes ([PtL(1)Cl2] and [PtL(2)Cl2]), and provide the solid-state 3D structure for [PtL(1)Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL(1)Cl2] and [PtL(2)Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L(1) and [PtL(1)Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin-resistant cell line). The absence of antibacterial activity of [PtL(1)Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.
Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Sudeshna
S
Roy
Katharine D
KD
Hagen
Palanisamy Uma
PU
Maheswari
Martin
M
Lutz
Anthony L
AL
Spek
Jan
J
Reedijk
Gilles P
GP
van Wezel
D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010619:Phenazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D010618:Phenanthrolines; D010619:Phenazines; C443808:dipyrido(3,2-a-2',3'-c)phenazine; C037153:1,10-phenanthroline-5,6-dione; D004247:DNA