title: Drug self-association modulates the cellular bioavailability of DNA minor groove-directed terbenzimidazoles.
abstract: The terbenzimidazoles are a class of anticancer agents that bind in the DNA minor groove. These compounds also exhibit a propensity for self-association, which can potentially impact their cellular bioavailabilities and activities. We have explored this possibility by using a broad range of biophysical and cytological techniques to characterize the self-association and cellular uptake properties of two terbenzimidazole analogues, 5-phenylterbenzimidazole (5PTB) and 5-phenyl-2'-(indolo-6-yl)bibenzimidazole (5P2'IBB). Concentration- and temperature-dependent fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy studies reveal that 5PTB and 5P2'IBB exhibit differing self-association properties. In this connection, 5PTB exhibits an enhanced propensity for self-association and forms larger and more stable aggregates than 5P2'IBB. In addition, the net uptake of 5PTB into human lymphoblast cells is diminished relative to that of 5P2'IBB. These observations suggest that the self-association properties of terbenzimidazoles modulate the cellular bioavailabilities of the compounds, with enhanced self-association propensity and aggregate size leading to reduced cellular bioavailability.
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854-5635, USA.
authors.forename: Qasim A
authors.initials: QA
authors.lastname: Khan
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Barbieri
authors.forename: Annankoil R
authors.initials: AR
authors.lastname: Srinivasan
authors.forename: Yuh-Hwa
authors.initials: YH
authors.lastname: Wang
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: LaVoie
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pilch
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013696:Temperature; D013997:Time Factors
chemical_list: C513856:5-phenyl-2'-(indolo-6-yl)bibenzimidazole; C103388:5-phenyl-2-(2'-(benzimidazol-5''-yl)benzimidazol-5'-yl)benzimidazole; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007211:Indoles; D004247:DNA