title: Bis(dipyridophenazine)(2-(2'-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) hexafluorophosphate: a lesson in stubbornness.
abstract: Ruthenium complexes are currently considered to be among the most promising alternatives to platinum anticancer drugs. In this work, thirteen structural analogues and organelle/receptor-targeting peptide bioconjugates of a cytotoxic bis(dppz)-Ru(II) complex [Ru(dppz)2 (CppH)](PF6 )2 (1) were prepared, characterized, and assessed for their cytotoxicity and cellular localization (CppH=2-(2'-pyridyl)pyrimidine-4-carboxylic acid; dppz=dipyrido[3,2-a:2',3'-c]phenazine). It was observed that structural modifications (lipophilicity, charge, and size-based) result in the cytotoxic potency of 1 being compromised. Confocal microscopy studies revealed that unlike 1, the screened complexes/bioconjugates do not have a preferential accumulation in mitochondria. The results of this important structure-activity relationship strongly support our initial hypothesis that accumulation in mitochondria is crucial for 1 to exert its cytotoxic action.
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland) http://www.gassergroup.com. tanmaya.joshi3@uzh.ch.
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Joshi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pierroz
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005459:Fluorides / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D010710:Phosphates / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D056831:Coordination Complexes; D010710:Phosphates; D011743:Pyrimidines; C000601187:bis(dipyridophenazine)(2-(2'-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II); C012980:fluorophosphate; D012428:Ruthenium; C030986:pyrimidine; D005459:Fluorides
keywords: anticancer agents; bioinorganic chemistry; cytotoxicity; ruthenium polypyridyl complexes; structure-activity relationships