Molecular Modeling Studies on G-Quadruplex Complexes of Telomerase Inhibitors:  Structure−Activity Relationships

Abstract

Inhibition of the ability of the enzyme telomerase to add telomeric repeats to the end of chromosomes is a novel target for potential anticancer therapy. This paper examines the hypothesis that compounds possessing a planar aromatic chromophore inhibit telomerase via stabilization of, and binding to, a folded guanine quadruplex structure. Two series of telomerase inhibitors have been designed based on the 2,6-disubstituted amidoanthracene-9,10-dione and 3,6-disubstituted acridine chromophores in order to investigate structure-activity relationships between biological activity and substituent group size. The relative binding energies between these compounds and the folded human telomere DNA quadruplex were determined using molecular simulation methods, involving explicitly solvated structures. The results obtained are in excellent agreement with the biological activity as measured in vitro using a modified TRAP assay and in general agreement with the ranking order of binding enthalpies found in isothermal titration calorimetry studies. This broad agreement provides strong support for the hypothesis that guanine quadruplexes are the primary target for telomerase inhibitors with extended planar chromophores.

Evaluation of binding of perylene diimide and benzannulated perylene diimide ligands to dna by electrospray ionization mass spectrometry

“…One promising class of quadruplex selective ligands are perylene diimides (PDIs) [35][36][37][38][39][40][41][42][43]. Recent solution studies of N,N=-bis [2-(1-piperidino)-ethyl]-3,4,9,10-perylenetetracarboxylic acid diimide (PIPER) [35] and N, N=-bis(4-morpholinylpropyl)-3,4,9,10-perylenetetracarboxylic acid diimide (Tel01) [38] indicate that these molecules exhibit G-quadruplex affinity by stacking on the faces of the terminal G-tetrads, thereby stabilizing the G-quadruplex structure.…”

G-Quadruplex Ligands as Stabilizer Targeting Telomerase Enzyme as Anti Cancer Agents

“…The protonated heterocyclic nitrogen atom (Compound 5) at physiological pH interacts G-quadruplex by increasing electron deficiency (IC 50 1.35 µM) [13]. In the acridine chromophore aniline substituent at 9 th position shows significant inhibitor activity for the Compound 6 (BRACO19) (IC 50 0.095 µM) and Compound 7 (IC 50 0.060 µM) [14].…”

“…Wheelhouse et al [24] reported cationic porphyrins, and among them, they found one of the Compound 23 (TMPyP4- [5,[10][11][12][13][14][15]20-tetra-(-N-Methyl-4-pyridyl)] porphine) as it stabilizes and stacked with G-Quadruplex DNA and inhibits telomerase enzyme with an IC 50 value of 6.5±1.4 µM. Analogs of TMPyP4 (e.g., Compound 24 -IC 50 5 µM) have been reported and found as the positively charged substituent's on meso positions, and the size of substitution are important, and the face of porphyrins should be available for stacking [25].…”

Telomere maintenance in childhood primitive neuroectodermal brain tumors

“…This makes telomerase in PNET, as in other cancers, a potentially useful diagnostic marker as well as a therapeutic target (White et al, 2001). Reported telomerase inhibitors include antisense oligodeoxynucleotides (Feng et al, 1995), ribozymes (Folini et al, 2000; Yokoyama et al, 1998), RT inhibitors (Strahl andBlackburn, 1996), G-quadruplex interacting compounds Read et al, 1999), small molecule inhibitors (Naasani et al, 1999), isothiazolone derivatives (Hayakawa et al, 1999), rhodacyanine derivatives (Wadhwa et al, 2002), and natural compounds including EGCG, the major polyphenol in green tea (Fujiki et al, 2001;Kinjo et al, 2002;Lyu et al, 2002;Naasani et al, 1998Naasani et al, , 2003. EGCG has been identified as a telomerase inhibitor with anticarcinogenic effects in various animal organs such as the esophagus, stomach, duodenum, colon, liver, pancreas, lung, breast, and skin (Naasani et al, 1998(Naasani et al, , 2003Suganuma et al, 1999).…”