Toward G-Quadruplex-Based Anticancer Agents: Biophysical and Biological Studies of Novel AS1411 Derivatives

Abstract

Certain G-quadruplex forming guanine-rich oligonucleotides (GROs), including AS1411, are endowed with cancer-selective antiproliferative activity. They are known to bind to nucleolin protein, resulting in the inhibition of nucleolin-mediated phenomena. However, multiple nucleolin-independent biological effects of GROs have also been reported, allowing them to be considered promising candidates for multi-targeted cancer therapy. Herein, with the aim of optimizing AS1411 structural features to find GROs with improved anticancer properties, we have studied a small library of AS1411 derivatives differing in the sequence length and base composition. The AS1411 derivatives were characterized by using circular dichroism and nuclear magnetic resonance spectroscopies and then investigated for their enzymatic resistance in serum and nuclear extract, as well as for their ability to bind nucleolin, inhibit topoisomerase I, and affect the viability of MCF-7 human breast adenocarcinoma cells. All derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411. In addition, most of them showed an improved antiproliferative activity on MCF-7 cells compared to AS1411 despite a weaker binding to nucleolin. Our results support the hypothesis that the antiproliferative properties of GROs are due to multi-targeted effects.

G-Quadruplex-Based Drug Delivery Systems for Cancer Therapy

“…Other AS1411 derivatives, with greater resistance to nucleases can also be used as potential carriers of anticancer drugs. For instance, four new derivatives (AS1411-G, AS1411-GT, AS1411-GT-T8 and AS1411-GT-5′tr) were proposed in order to optimize AS1411 structural features and to find G-rich sequences to improve anticancer properties [ 46 ]. Three of them (AS1411-G, AS1411-GT and AS1411-GT-T8) have eight G-tracts, which in principle may allow the formation of two tandem G4s connected by a linker [ 46 ].…”

“…For instance, four new derivatives (AS1411-G, AS1411-GT, AS1411-GT-T8 and AS1411-GT-5′tr) were proposed in order to optimize AS1411 structural features and to find G-rich sequences to improve anticancer properties [ 46 ]. Three of them (AS1411-G, AS1411-GT and AS1411-GT-T8) have eight G-tracts, which in principle may allow the formation of two tandem G4s connected by a linker [ 46 ]. The four derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411 [ 46 ].…”

“…Three of them (AS1411-G, AS1411-GT and AS1411-GT-T8) have eight G-tracts, which in principle may allow the formation of two tandem G4s connected by a linker [ 46 ]. The four derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411 [ 46 ]. Moreover, most of them (except AS1411-GT-T8) showed an improved anti-proliferative effect on MCF-7 cells compared to AS1411 [ 46 ].…”

Covalent Bi-Modular Parallel and Antiparallel G-Quadruplex DNA Nanocostructs Reduce Viability of Patient Glioma Primary Cell Cultures

“…Recently, some more derivatives of AS1411 with anti-proliferative activity toward MCF-7 cells have been developed [ 12 ]. GQs with three-tetrad structures were 10 times more active than the initial AS1411 with two-tetrad GQ.…”

Exploring New Potential Anticancer Activities of the G-Quadruplexes Formed by [(GTG2T(G3T)3] and Its Derivatives with an Abasic Site Replacing Single Thymidine

“…Recently, a covalent bi-modular version of the sequence [G 3 (TG 3 ) 3 ] has proven to possess anti-proliferative activity for the neural cancer cell line U87 [25]. Contrary to the significant number of studies concerning the antiproliferative aptamers AS1411 [26,27] (and its analogues [28,29]) and TBA [20] (and its derivatives [30][31][32][33][34][35][36][37][38]), only limited comparable investigations have regarded other aptamers. For example, in the case of the aptamer T30175, no research concerning potential antiproliferative properties has been reported to date, although its sequence partially overlaps those of EAD and S13 and its structure is strictly correlated to that of T30923, as demonstrated by CD (Circular Dichroism), NMR (Nuclear Magnetic Resonance), gel electrophoresis, and molecular dynamics simulations [9,10,39].…”