Design, synthesis and bioactivity of novel naphthalimide-benzotriazole conjugates against A549 cells via targeting BCL2 G-quadruplex and inducing autophagy
Copyright © 2022 Elsevier Inc. All rights reserved..
AIMS: In this study, a series of novel naphthalimide-benzotriazole conjugates (1a-3c) based on 1, 8-naphthalimide as a core skeleton, aiming at G-quadruplexes, were designed and synthesized, and their anti-cancer activity and mechanism were studied.
MATERIALS AND METHODS: Using the CCK-8 assay, FRET melting, EMSA, CD, and molecular docking, intracellular assays, western blotting, immunofluorescence, and flow cytometry.
KEY FINDINGS: By the CCK-8 assay, it was found that the compound, 2-(3-(piperazin-1-yl)propyl)-6-(1H-benzo [d][1,2,3]triazol-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3a), has better activity against A549 cells. Through extracellular assays, including FRET melting, EMSA, CD, and molecular docking, results showed that 3a selectively interacted with BCL2 G-quadruplex(es). Further studies by intracellular assays, including western blotting, immunofluorescence, flow cytometry, etc., verified that 3a mediated the death of A549 cells by two pathways: inhibition of the expression of the BCL2 gene, causing tumor cell apoptosis, and promotion of genetic instability, causing autophagy. This study suggests that the type of compounds, in particular, 3a, may be a potential molecule to explore for BCL2 G-quadruplex-targeted drugs against lung cancer.
SIGNIFICANCE: Our findings demonstrate that compound 3a as a BCL2 G-quadruplex ligand induces DNA damage, autophagy, and apoptosis in A549 cells. This study provides us with a type of lead compound as an anti-tumor drug.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:302 |
|---|---|
| Enthalten in: |
Life sciences - 302(2022) vom: 01. Aug., Seite 120651 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Wang, Xiao [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
86110UXM5Y |
|---|
| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 23.10.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.lfs.2022.120651 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM34120126X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM34120126X | ||
| 003 | DE-627 | ||
| 005 | 20231226011233.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.lfs.2022.120651 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1137.xml |
| 035 | |a (DE-627)NLM34120126X | ||
| 035 | |a (NLM)35597548 | ||
| 035 | |a (PII)S0024-3205(22)00351-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Wang, Xiao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design, synthesis and bioactivity of novel naphthalimide-benzotriazole conjugates against A549 cells via targeting BCL2 G-quadruplex and inducing autophagy |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.10.2023 | ||
| 500 | |a Date Revised 23.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Inc. All rights reserved. | ||
| 520 | |a AIMS: In this study, a series of novel naphthalimide-benzotriazole conjugates (1a-3c) based on 1, 8-naphthalimide as a core skeleton, aiming at G-quadruplexes, were designed and synthesized, and their anti-cancer activity and mechanism were studied | ||
| 520 | |a MATERIALS AND METHODS: Using the CCK-8 assay, FRET melting, EMSA, CD, and molecular docking, intracellular assays, western blotting, immunofluorescence, and flow cytometry | ||
| 520 | |a KEY FINDINGS: By the CCK-8 assay, it was found that the compound, 2-(3-(piperazin-1-yl)propyl)-6-(1H-benzo [d][1,2,3]triazol-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3a), has better activity against A549 cells. Through extracellular assays, including FRET melting, EMSA, CD, and molecular docking, results showed that 3a selectively interacted with BCL2 G-quadruplex(es). Further studies by intracellular assays, including western blotting, immunofluorescence, flow cytometry, etc., verified that 3a mediated the death of A549 cells by two pathways: inhibition of the expression of the BCL2 gene, causing tumor cell apoptosis, and promotion of genetic instability, causing autophagy. This study suggests that the type of compounds, in particular, 3a, may be a potential molecule to explore for BCL2 G-quadruplex-targeted drugs against lung cancer | ||
| 520 | |a SIGNIFICANCE: Our findings demonstrate that compound 3a as a BCL2 G-quadruplex ligand induces DNA damage, autophagy, and apoptosis in A549 cells. This study provides us with a type of lead compound as an anti-tumor drug | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Autophagy | |
| 650 | 4 | |a BCL2 | |
| 650 | 4 | |a G-quadruplex | |
| 650 | 4 | |a Naphthalimide-benzotriazole | |
| 650 | 7 | |a Naphthalimides |2 NLM | |
| 650 | 7 | |a benzotriazole |2 NLM | |
| 650 | 7 | |a 86110UXM5Y |2 NLM | |
| 650 | 7 | |a Sincalide |2 NLM | |
| 650 | 7 | |a M03GIQ7Z6P |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-bcl-2 |2 NLM | |
| 700 | 1 | |a Zhang, Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Xu-Qiong |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Panpan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Koutian |e verfasserin |4 aut | |
| 700 | 1 | |a Awadasseid, Annoor |e verfasserin |4 aut | |
| 700 | 1 | |a Narva, Suresh |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yan-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wen |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Life sciences |d 1965 |g 302(2022) vom: 01. Aug., Seite 120651 |w (DE-627)NLM000007579 |x 1879-0631 |7 nnns |
| 773 | 1 | 8 | |g volume:302 |g year:2022 |g day:01 |g month:08 |g pages:120651 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.lfs.2022.120651 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 302 |j 2022 |b 01 |c 08 |h 120651 | ||