Expedient synthesis and anticancer evaluation of dual-action 9-anilinoacridine methyl triazene chimeras

Dipak Walunj; Katarina Egarmina; Helena Tuchinsky; Ofer Shpilberg; Oshrat Hershkovitz-Rokah; Flavio Grynszpan; Gary Gellerman

doi:10.1111/cbdd.13776

Expedient synthesis and anticancer evaluation of dual-action 9-anilinoacridine methyl triazene chimeras

Dipak Walunj, Katarina Egarmina, Helena Tuchinsky, Ofer Shpilberg, Oshrat Hershkovitz-Rokah, Flavio Grynszpan, Gary Gellerman

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (S_NAr) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC₅₀ values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action: methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.

Original language	English
Pages (from-to)	237-252
Number of pages	16
Journal	Chemical Biology and Drug Design
Volume	97
Issue number	2
DOIs	https://doi.org/10.1111/cbdd.13776
State	Published - Feb 2021

Keywords

Anilinoacridine
Anticancer
EAS
Molecular chimera
SAr
Triazene

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10.1111/cbdd.13776

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title = "Expedient synthesis and anticancer evaluation of dual-action 9-anilinoacridine methyl triazene chimeras",

abstract = "The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (SNAr) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC50 values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action: methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.",

keywords = "Anilinoacridine, Anticancer, EAS, Molecular chimera, SAr, Triazene",

author = "Dipak Walunj and Katarina Egarmina and Helena Tuchinsky and Ofer Shpilberg and Oshrat Hershkovitz-Rokah and Flavio Grynszpan and Gary Gellerman",

note = "Publisher Copyright: {\textcopyright} 2020 John Wiley & Sons A/S.",

year = "2021",

month = feb,

doi = "10.1111/cbdd.13776",

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AU - Walunj, Dipak

AU - Egarmina, Katarina

AU - Tuchinsky, Helena

AU - Shpilberg, Ofer

AU - Hershkovitz-Rokah, Oshrat

AU - Grynszpan, Flavio

AU - Gellerman, Gary

PY - 2021/2

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N2 - The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (SNAr) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC50 values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action: methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.

AB - The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (SNAr) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC50 values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action: methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.

KW - Anilinoacridine

KW - Anticancer

KW - EAS

KW - Molecular chimera

KW - SAr

KW - Triazene

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IS - 2

ER -

Expedient synthesis and anticancer evaluation of dual-action 9-anilinoacridine methyl triazene chimeras

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