Limits...
Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity.

Zhang W, Chen M, Ling Wu Y, Tanaka Y, Juan Ji Y, Lin Zhang S, He Wei C, Xu Y - Sci Rep (2015)

Bottom Line: Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells.Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%.This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China.

ABSTRACT
G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1-S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1-S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

No MeSH data available.


Related in: MedlinePlus

Structure of six novel benzo[k,l]thioxanthene-3,4-dicarboximides (S1–S6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4557076&req=5

f1: Structure of six novel benzo[k,l]thioxanthene-3,4-dicarboximides (S1–S6).

Mentions: Our previous studies showed that benzoxanthene derivatives containing 1,8-naphthalimide ring can interact with G-rich telomere sequences and inhibit human telomerase activity (unpublished data), and also other groups have demonstrated that the 1,8-naphthalimides, as precursors of benzothioxanthenes, and their derivatives and analogues can interact with double-stranded DNA1920 and G-quadrplexes2122 with high affinity through π-π stacking mode, showing strong anticancer activities. However, benzoxanthenes with naphthalimido aromatic nucleus alone and 1,8-naphthalimides have poor water solubility and selectivity between G-quadruplex and double-strands DNA. In order to address these issues, we further optimized and modified the structure of this kind of compounds, and synthesized six novel benzo[k,l]thioxanthene-3,4-dicarboximides (benzothioxanthene derivatives) S1–S6 (Fig. 1) with six kinds of protonated side chains which are optimum three carbon atoms-containing lengths sufficient to bind to G-quadruplex grooves22 as G-quadruplex targeted ligands. Introduction of these side chains to the benzothioxanthene mother structure is expected not only to increase hydropholicity, but also to effectively stabilize the G-quadruplex structure through the cationic functional groups directing toward the G-quadruplex grooves and then interacting with negatively charged phosphate groups23. Consequently these benzothioxanthene derivatives should have huge potential to stabilize G-quadruplex with enhanced specificity and anti-cancer activity by indirect inhibition of telomerase activity. Herein, we studied the interaction of S1–S6 with 26 nt telomeric DNAs (Table 1), including guanine-rich DNA (G-rich DNA), cytosine-rich DNA (C-rich DNA), double-stranded DNA (ds-DNA) and Mutated DNA (Mut-DNA), by electrophoretic mobility shift assay (EMSA), UV thermal melting and circular dichroism (CD) techniques to monitor the ability of the six compounds to induce the formation of and to stabilize G-quadruplexes formed in the examined DNAs and assessed their biological activities through real-time cell analysis (RTCA), trap assay and wound healing to two kinds of cancer cells, A549 and SGC7901 which both express telomerase.


Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity.

Zhang W, Chen M, Ling Wu Y, Tanaka Y, Juan Ji Y, Lin Zhang S, He Wei C, Xu Y - Sci Rep (2015)

Structure of six novel benzo[k,l]thioxanthene-3,4-dicarboximides (S1–S6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557076&req=5

f1: Structure of six novel benzo[k,l]thioxanthene-3,4-dicarboximides (S1–S6).
Mentions: Our previous studies showed that benzoxanthene derivatives containing 1,8-naphthalimide ring can interact with G-rich telomere sequences and inhibit human telomerase activity (unpublished data), and also other groups have demonstrated that the 1,8-naphthalimides, as precursors of benzothioxanthenes, and their derivatives and analogues can interact with double-stranded DNA1920 and G-quadrplexes2122 with high affinity through π-π stacking mode, showing strong anticancer activities. However, benzoxanthenes with naphthalimido aromatic nucleus alone and 1,8-naphthalimides have poor water solubility and selectivity between G-quadruplex and double-strands DNA. In order to address these issues, we further optimized and modified the structure of this kind of compounds, and synthesized six novel benzo[k,l]thioxanthene-3,4-dicarboximides (benzothioxanthene derivatives) S1–S6 (Fig. 1) with six kinds of protonated side chains which are optimum three carbon atoms-containing lengths sufficient to bind to G-quadruplex grooves22 as G-quadruplex targeted ligands. Introduction of these side chains to the benzothioxanthene mother structure is expected not only to increase hydropholicity, but also to effectively stabilize the G-quadruplex structure through the cationic functional groups directing toward the G-quadruplex grooves and then interacting with negatively charged phosphate groups23. Consequently these benzothioxanthene derivatives should have huge potential to stabilize G-quadruplex with enhanced specificity and anti-cancer activity by indirect inhibition of telomerase activity. Herein, we studied the interaction of S1–S6 with 26 nt telomeric DNAs (Table 1), including guanine-rich DNA (G-rich DNA), cytosine-rich DNA (C-rich DNA), double-stranded DNA (ds-DNA) and Mutated DNA (Mut-DNA), by electrophoretic mobility shift assay (EMSA), UV thermal melting and circular dichroism (CD) techniques to monitor the ability of the six compounds to induce the formation of and to stabilize G-quadruplexes formed in the examined DNAs and assessed their biological activities through real-time cell analysis (RTCA), trap assay and wound healing to two kinds of cancer cells, A549 and SGC7901 which both express telomerase.

Bottom Line: Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells.Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%.This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China.

ABSTRACT
G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1-S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1-S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

No MeSH data available.


Related in: MedlinePlus