title: Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds: comparison with TPEN and PAC-1.
abstract: The lipophilic, cell-penetrating zinc chelator N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, 1) and the zinc chelating procaspase-activating compound PAC-1 (2) both have been reported to induce apoptosis in various cell types. The relationship between apoptosis-inducing ability and zinc affinity (Kd), have been investigated with two new model compounds, ZnA-DPA (3) and ZnA-Pyr (4), and compared to that of TPEN and PAC-1. The zinc-chelating o-hydroxybenzylidene moiety in PAC-1 was replaced with a 2,2'-dipicoylamine (DPA) unit (ZnA-DPA, 3) and a 4-pyridoxyl unit (ZnA-Pyr, 4), rendering an order of zinc affinity TPEN>ZnA-Pyr>ZnA-DPA>PAC-1. The compounds were incubated with the rat pheochromocytoma cell line PC12 and cell death was measured in combination with ZnSO4, a caspase-3 inhibitor, or a ROS scavenger. The model compounds ZnA-DPA (3) and ZnA-Pyr (4) induced cell death at higher concentrations as compared to PAC-1 and TPEN, reflecting differences in lipophilicity and thereby cell-penetrating ability. Addition of ZnSO4 reduced cell death induced by ZnA-Pyr (4) more than for ZnA-DPA (3). The ability to induce cell death could be reversed for all compounds using a caspase-3-inhibitor, and most so for TPEN (1) and ZnA-Pyr (4). Reactive oxygen species (ROS), as monitored using dihydro-rhodamine (DHR), were involved in cell death induced by all compounds. These results indicate that the Zn-chelators ZnA-DPA (3) and ZnA-Pyr (4) exercise their apoptosis-inducing effect by mechanisms similar to TPEN (1) and PAC-1 (2), by chelation of zinc, caspase-3 activation, and ROS production.
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway.
authors.forename: O Alexander H
authors.initials: OA
authors.lastname: Strand
authors.forename: Gulzeb
authors.initials: G
authors.lastname: Aziz
authors.forename: Sidra Farzand
authors.initials: SF
authors.lastname: Ali
authors.forename: Ragnhild E
authors.initials: RE
authors.lastname: Paulsen
authors.forename: Trond Vidar
authors.initials: TV
authors.lastname: Hansen
authors.forename: Pål
authors.initials: P
authors.lastname: Rongved
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D005029:Ethylenediamines / Q000737:chemistry* / Q000633:toxicity; D006835:Hydrazones / Q000737:chemistry* / Q000633:toxicity; D016716:PC12 Cells; D010848:Picolinic Acids / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry* / Q000633:toxicity; D011736:Pyridoxine / Q000737:chemistry; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*; D019287:Zinc Sulfate / Q000737:chemistry / Q000633:toxicity
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; C501847:2,2'-dipicolylamine; D000588:Amines; D061945:Caspase Inhibitors; D002614:Chelating Agents; D005029:Ethylenediamines; D006835:Hydrazones; D010848:Picolinic Acids; D010879:Piperazines; D017382:Reactive Oxygen Species; D019287:Zinc Sulfate; D053148:Caspase 3; D015032:Zinc; D011736:Pyridoxine; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Apoptosis; CVRXLMUYFMERMJ-UHFFFAOYSA-N; Caspase-3 activation; PAC-1 analogues; QFPVDYVNRNGXRQ-FSJBWODESA-N; ROS production; UBFPFEYJQOUETN-UHFFFAOYSA-N; YQNRVGJCPCNMKT-LFVJCYFKSA-N; Zinc chelators