Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i] phenanthridine-12-carboxylic acid: Potent cytotoxic and topoisomerase I-targeting agents

Shejin Zhu; Alexander L. Ruchelman; Nai Zhou; Angela A. Liu; Leroy F. Liu; Edmond J. LaVoie

doi:10.1016/j.bmc.2005.07.033

Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i] phenanthridine-12-carboxylic acid: Potent cytotoxic and topoisomerase I-targeting agents

Shejin Zhu, Alexander L. Ruchelman, Nai Zhou, Angela A. Liu, Leroy F. Liu, Edmond J. LaVoie

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

55 Citations (Scopus)

Abstract

The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h] [1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC₅₀ values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells.

Original language	English
Pages (from-to)	6782-6794
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2005.07.033
Publication status	Published - Dec 15 2005
Externally published	Yes

Keywords

Antitumor
Benzo[i]phenanthridine
Cytotoxic
Topoisomerase I

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmaceutical Science
Organic Chemistry

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10.1016/j.bmc.2005.07.033

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title = "Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i] phenanthridine-12-carboxylic acid: Potent cytotoxic and topoisomerase I-targeting agents",

abstract = "The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h] [1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells.",

keywords = "Antitumor, Benzo[i]phenanthridine, Cytotoxic, Topoisomerase I",

author = "Shejin Zhu and Ruchelman, {Alexander L.} and Nai Zhou and Liu, {Angela A.} and Liu, {Leroy F.} and LaVoie, {Edmond J.}",

year = "2005",

month = dec,

day = "15",

doi = "10.1016/j.bmc.2005.07.033",

language = "English",

volume = "13",

pages = "6782--6794",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "24",

}

TY - JOUR

T1 - Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i] phenanthridine-12-carboxylic acid

T2 - Potent cytotoxic and topoisomerase I-targeting agents

AU - Zhu, Shejin

AU - Ruchelman, Alexander L.

AU - Zhou, Nai

AU - Liu, Angela A.

AU - Liu, Leroy F.

AU - LaVoie, Edmond J.

PY - 2005/12/15

Y1 - 2005/12/15

N2 - The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h] [1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells.

AB - The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h] [1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells.

KW - Antitumor

KW - Benzo[i]phenanthridine

KW - Cytotoxic

KW - Topoisomerase I

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DO - 10.1016/j.bmc.2005.07.033

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VL - 13

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JO - Bioorganic and Medicinal Chemistry

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ER -

Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i] phenanthridine-12-carboxylic acid: Potent cytotoxic and topoisomerase I-targeting agents

Abstract

Keywords

ASJC Scopus subject areas

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