title: Transition-metal norharmane compounds as possible cytotoxic agents: New insights based on a coordination chemistry perspective.
abstract: New first-row transition-metal compounds with the ligand norharmane (9H-Pyrido[3,4-b]indole; Hnor) are reported. The compounds have the general formula [M(LL)(Hnor)(NO3)2](MeOH)0-1(M=Co, Ni, Cu, Zn; LL=2,2'-bipyridyl (bpy), 1,10-phenanthroline (phen)) and have been characterized by physical and analytical methods. X-ray structural analysis revealed that the compound of formula [Cu(phen)(Hnor)(NO3)2], (1) has a distorted 6-coordinated octahedrally-based geometry, with a planar-based [CuN3O] core, where Cu-L varies between 1.99 and 2.04Å and two weak axial CuO contacts (2.209 and 2.644Å) from two different nitrates. Based on spectroscopic similarities, the other compounds appear to have the same or very similar coordination geometries. The compounds showed clear cell growth inhibitory effects in two different cancer cell lines in vitro, with the copper and zinc complexes being the most toxic and in fact almost comparable to cisplatin. Flow-cytometry analysis confirmed induction of apoptosis in cancer cells treated with the compounds. Interestingly, co-incubation of the cells with metal complexes and CuCl2induced an increase in the cytotoxic effects, most likely due to the conversion of the metal compounds in the corresponding, and most active, copper analogues.
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Rais Ahmad
authors.initials: RA
authors.lastname: Khan
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Andreia
authors.initials: A
authors.lastname: de Almeida
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Farhan
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Alsalme
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; Cardiff School of Chemistry, Cardiff University, Main Building, Park place, Cardiff CF10 3A, United Kingdom. Electronic address: CasiniA@cardiff.ac.uk.
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ghazzali
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. Electronic address: Reedijk@chem.leidenuniv.nl.
authors.forename: Jan
authors.initials: J
authors.lastname: Reedijk
mesh_terms: D000072283:A549 Cells; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008670:Metals / Q000737:chemistry*
chemical_list: D002243:Carbolines; D003603:Cytotoxins; D008670:Metals; C010262:norharman; D002945:Cisplatin
keywords: 9H-Pyrido[3,4-b]indole; Antiproliferative properties; Cobalt; Copper; Nickel; Zinc