title: Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes.
abstract: Iron(III) complexes [FeL(B)] (1-4) of a tetradentate phenolate-based ligand (H3L) and biotin-conjugated dipyridophenazine bases (B), viz. 7-aminodipyrido [3,2-a:2',3'-c]-phenazine (dppza in 1), (N-dipyrido[3,2-a:2',3'-c]-phenazino)amidobiotin (dppzNB in 2), dipyrido [3,2-a:2',3'-c]-phenazine-11-carboxylic acid (dppzc in 3) and 2-((2-biotinamido)ethyl) amido-dipyrido[3,2-a:2',3'-c]-phenazine (dppzCB in 4) are prepared, characterized and their interaction with streptavidin and DNA and their photocytotoxicity and cellular uptake in various cells studied. The high-spin iron(III) complexes display Fe(III)/Fe(II) redox couple near -0.7 V versus saturated calomel electrode in dimethyl sulfoxide-0.1 M tetrabutylammonium perchlorate. The complexes show non-specific interaction with DNA as determined from the binding studies. Complexes with appended biotin moiety show similar binding to streptavidin as that of free biotin, suggesting biotin conjugation to dppz does not cause any loss in its binding affinity to streptavidin. The photocytotoxicity of the complexes is tested in HepG2, HeLa and HEK293 cell lines. Complex 2 shows higher photocytotoxicity in HepG2 cells than in HeLa or HEK293, forming reactive oxygen species. This effect is attributed to the presence of overexpressed sodium-dependent multi-vitamin transporters in HepG2 cells. Microscopic studies in HepG2 cells show internalization of the biotin complexes 2 and 4 essentially occurring by receptor-mediated endocytosis, which is similar to that of native biotin and biotin fluorescein isothiocyanate conjugate.
authors.affiliation: Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Sounik
authors.initials: S
authors.lastname: Saha
authors.forename: Ritankar
authors.initials: R
authors.lastname: Majumdar
authors.forename: Akhtar
authors.initials: A
authors.lastname: Hussain
authors.forename: Rajan R
authors.initials: RR
authors.lastname: Dighe
authors.forename: Akhil R
authors.initials: AR
authors.lastname: Chakravarty
mesh_terms: D001710:Biotin / Q000493:pharmacokinetics*; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000627:therapeutic use*; D008027:Light; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D017319:Photosensitizing Agents; D001710:Biotin; D007501:Iron
keywords: cellular uptake; dipyridophenazine biotin conjugates; iron; photocytotoxicity; reactive oxygen species; streptavidin binding