Amides of pyrrole- and thiophene-fused anthraquinone derivatives : A role of the heterocyclic core in antitumor properties
Copyright © 2020 Elsevier Masson SAS. All rights reserved..
Heteroarene-fused anthraquinone derivatives represent a class of perspective anticancer drug candidates capable of targeting multiple vital processes including drug resistance. Taking advantage of previously demonstrated potential of amide derivatives of heteroarene-fused anthraquinones, we herein dissected the role of the heterocyclic core in antitumor properties. A new series of naphtho[2,3-f]indole-3- and anthra[2,3-b]thiophene-3-carboxamides was synthesized via coupling the respective acids with cyclic diamines. New compounds demonstrated a submicromolar antiproliferative potency close to doxorubicin (Dox) against five tumor cell lines of various tissue origin. In contrast to Dox, the new compounds were similarly cytotoxic for HCT116 colon carcinoma cells (wild type p53) and their isogenic p53 knockout counterparts. Modification of the heterocyclic core changed the targeting properties: the best-in-series naphtho[2,3-f]indole-3-carboxamide 8 formed more affine complexes with DNA duplex than furan and thiophene analogs, a property that can be translated into a stronger inhibition of topoisomerase 1 mediated DNA unwinding. At tolerable doses the water soluble derivative 8 significantly inhibited tumor growth (up to 79%) and increased the lifespan (153%) of mice bearing P388 lymphoma transplants. Together with better solubility for parenteral administration and well tolerance by animals of the indole derivative 8 indicates prospects for further search of new antitumor drug candidates among the heteroarene-fused anthraquinones.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:199 |
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| Enthalten in: |
European journal of medicinal chemistry - 199(2020) vom: 01. Aug., Seite 112294 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tikhomirov, Alexander S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.02.2021 Date Revised 01.02.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2020.112294 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM310112303 |
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| 100 | 1 | |a Tikhomirov, Alexander S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Amides of pyrrole- and thiophene-fused anthraquinone derivatives |b A role of the heterocyclic core in antitumor properties |
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| 500 | |a Date Revised 01.02.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Heteroarene-fused anthraquinone derivatives represent a class of perspective anticancer drug candidates capable of targeting multiple vital processes including drug resistance. Taking advantage of previously demonstrated potential of amide derivatives of heteroarene-fused anthraquinones, we herein dissected the role of the heterocyclic core in antitumor properties. A new series of naphtho[2,3-f]indole-3- and anthra[2,3-b]thiophene-3-carboxamides was synthesized via coupling the respective acids with cyclic diamines. New compounds demonstrated a submicromolar antiproliferative potency close to doxorubicin (Dox) against five tumor cell lines of various tissue origin. In contrast to Dox, the new compounds were similarly cytotoxic for HCT116 colon carcinoma cells (wild type p53) and their isogenic p53 knockout counterparts. Modification of the heterocyclic core changed the targeting properties: the best-in-series naphtho[2,3-f]indole-3-carboxamide 8 formed more affine complexes with DNA duplex than furan and thiophene analogs, a property that can be translated into a stronger inhibition of topoisomerase 1 mediated DNA unwinding. At tolerable doses the water soluble derivative 8 significantly inhibited tumor growth (up to 79%) and increased the lifespan (153%) of mice bearing P388 lymphoma transplants. Together with better solubility for parenteral administration and well tolerance by animals of the indole derivative 8 indicates prospects for further search of new antitumor drug candidates among the heteroarene-fused anthraquinones | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anthraquinone | |
| 650 | 4 | |a Antitumor activity | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a DNA binding | |
| 650 | 4 | |a Indole | |
| 650 | 4 | |a Multidrug resistance | |
| 650 | 4 | |a Reactive oxygen species | |
| 650 | 4 | |a Structure-activity relationship | |
| 650 | 4 | |a Thiophene | |
| 650 | 4 | |a Topoisomerase 1 | |
| 650 | 7 | |a Amides |2 NLM | |
| 650 | 7 | |a Anthraquinones |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Heterocyclic Compounds |2 NLM | |
| 650 | 7 | |a Pyrroles |2 NLM | |
| 650 | 7 | |a Thiophenes |2 NLM | |
| 700 | 1 | |a Litvinova, Valeria A |e verfasserin |4 aut | |
| 700 | 1 | |a Andreeva, Daria V |e verfasserin |4 aut | |
| 700 | 1 | |a Tsvetkov, Vladimir B |e verfasserin |4 aut | |
| 700 | 1 | |a Dezhenkova, Lyubov G |e verfasserin |4 aut | |
| 700 | 1 | |a Volodina, Yulia L |e verfasserin |4 aut | |
| 700 | 1 | |a Kaluzhny, Dmitry N |e verfasserin |4 aut | |
| 700 | 1 | |a Treshalin, Ivan D |e verfasserin |4 aut | |
| 700 | 1 | |a Schols, Dominique |e verfasserin |4 aut | |
| 700 | 1 | |a Ramonova, Alla A |e verfasserin |4 aut | |
| 700 | 1 | |a Moisenovich, Mikhail M |e verfasserin |4 aut | |
| 700 | 1 | |a Shtil, Alexander A |e verfasserin |4 aut | |
| 700 | 1 | |a Shchekotikhin, Andrey E |e verfasserin |4 aut | |
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