Macrocyclic pyridyl polyoxazoles: Selective RNA and DNA G-quadruplex ligands as antitumor agents

Suzanne G. Rzuczek; Daniel S. Pilch; Angela Liu; Leroy Liu; Edmond J. Lavoie; Joseph E. Rice

doi:10.1021/jm1000612

Macrocyclic pyridyl polyoxazoles: Selective RNA and DNA G-quadruplex ligands as antitumor agents

Suzanne G. Rzuczek, Daniel S. Pilch, Angela Liu, Leroy Liu, Edmond J. Lavoie, Joseph E. Rice

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

83 Citations (Scopus)

Abstract

The synthesis of a series of 24-membered pyridine-containing polyoxazole macrocycles is described. Seventeen new macrocycles were evaluated for cytotoxic activity against RPMI 8402, KB-3, and KB-3 cell lines that overexpress the efflux transporters MDR1 (KBV-1) and BCRP (KBH5.0). Macrocycles in which the pyridyl-polyoxazole moiety is linked by a 1,3-bis(aminomethyl)phenyl group with a 5-(2-aminoethyl)- (18) or a 5-(2-dimethylaminoethyl)- substituent (19) displayed the greatest cytotoxic potency. These compounds exhibit exquisite selectivity for stabilizing G-quadruplex DNA with no stabilization of duplex DNA or RNA. Compound 19 stabilizes quadruplex mRNA that encodes the cell-cycle checkpoint protein kinase Aurora A to a greater extent than the quadruplex DNA of a human telomeric sequence. These data may suggest a role for G-quadruplex ligands interacting with mRNA being associated with the biological activity of macrocyclic polyoxazoles. Compound 19 has significant in vivo anticancer activity against a human breast cancer xenograft (MDA-MB-435) in athymic nude mice.

Original language	English
Pages (from-to)	3632-3644
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	9
DOIs	https://doi.org/10.1021/jm1000612
Publication status	Published - May 13 2010
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/jm1000612

Cite this

@article{cb61f7e57e4e424c88946e5d535867ab,

title = "Macrocyclic pyridyl polyoxazoles: Selective RNA and DNA G-quadruplex ligands as antitumor agents",

abstract = "The synthesis of a series of 24-membered pyridine-containing polyoxazole macrocycles is described. Seventeen new macrocycles were evaluated for cytotoxic activity against RPMI 8402, KB-3, and KB-3 cell lines that overexpress the efflux transporters MDR1 (KBV-1) and BCRP (KBH5.0). Macrocycles in which the pyridyl-polyoxazole moiety is linked by a 1,3-bis(aminomethyl)phenyl group with a 5-(2-aminoethyl)- (18) or a 5-(2-dimethylaminoethyl)- substituent (19) displayed the greatest cytotoxic potency. These compounds exhibit exquisite selectivity for stabilizing G-quadruplex DNA with no stabilization of duplex DNA or RNA. Compound 19 stabilizes quadruplex mRNA that encodes the cell-cycle checkpoint protein kinase Aurora A to a greater extent than the quadruplex DNA of a human telomeric sequence. These data may suggest a role for G-quadruplex ligands interacting with mRNA being associated with the biological activity of macrocyclic polyoxazoles. Compound 19 has significant in vivo anticancer activity against a human breast cancer xenograft (MDA-MB-435) in athymic nude mice.",

author = "Rzuczek, {Suzanne G.} and Pilch, {Daniel S.} and Angela Liu and Leroy Liu and Lavoie, {Edmond J.} and Rice, {Joseph E.}",

year = "2010",

month = may,

day = "13",

doi = "10.1021/jm1000612",

language = "English",

volume = "53",

pages = "3632--3644",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "9",

}

TY - JOUR

T1 - Macrocyclic pyridyl polyoxazoles

T2 - Selective RNA and DNA G-quadruplex ligands as antitumor agents

AU - Rzuczek, Suzanne G.

AU - Pilch, Daniel S.

AU - Liu, Angela

AU - Liu, Leroy

AU - Lavoie, Edmond J.

AU - Rice, Joseph E.

PY - 2010/5/13

Y1 - 2010/5/13

N2 - The synthesis of a series of 24-membered pyridine-containing polyoxazole macrocycles is described. Seventeen new macrocycles were evaluated for cytotoxic activity against RPMI 8402, KB-3, and KB-3 cell lines that overexpress the efflux transporters MDR1 (KBV-1) and BCRP (KBH5.0). Macrocycles in which the pyridyl-polyoxazole moiety is linked by a 1,3-bis(aminomethyl)phenyl group with a 5-(2-aminoethyl)- (18) or a 5-(2-dimethylaminoethyl)- substituent (19) displayed the greatest cytotoxic potency. These compounds exhibit exquisite selectivity for stabilizing G-quadruplex DNA with no stabilization of duplex DNA or RNA. Compound 19 stabilizes quadruplex mRNA that encodes the cell-cycle checkpoint protein kinase Aurora A to a greater extent than the quadruplex DNA of a human telomeric sequence. These data may suggest a role for G-quadruplex ligands interacting with mRNA being associated with the biological activity of macrocyclic polyoxazoles. Compound 19 has significant in vivo anticancer activity against a human breast cancer xenograft (MDA-MB-435) in athymic nude mice.

AB - The synthesis of a series of 24-membered pyridine-containing polyoxazole macrocycles is described. Seventeen new macrocycles were evaluated for cytotoxic activity against RPMI 8402, KB-3, and KB-3 cell lines that overexpress the efflux transporters MDR1 (KBV-1) and BCRP (KBH5.0). Macrocycles in which the pyridyl-polyoxazole moiety is linked by a 1,3-bis(aminomethyl)phenyl group with a 5-(2-aminoethyl)- (18) or a 5-(2-dimethylaminoethyl)- substituent (19) displayed the greatest cytotoxic potency. These compounds exhibit exquisite selectivity for stabilizing G-quadruplex DNA with no stabilization of duplex DNA or RNA. Compound 19 stabilizes quadruplex mRNA that encodes the cell-cycle checkpoint protein kinase Aurora A to a greater extent than the quadruplex DNA of a human telomeric sequence. These data may suggest a role for G-quadruplex ligands interacting with mRNA being associated with the biological activity of macrocyclic polyoxazoles. Compound 19 has significant in vivo anticancer activity against a human breast cancer xenograft (MDA-MB-435) in athymic nude mice.

UR - http://www.scopus.com/inward/record.url?scp=77952045784&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952045784&partnerID=8YFLogxK

U2 - 10.1021/jm1000612

DO - 10.1021/jm1000612

M3 - Article

C2 - 20359224

AN - SCOPUS:77952045784

SN - 0022-2623

VL - 53

SP - 3632

EP - 3644

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -

Macrocyclic pyridyl polyoxazoles: Selective RNA and DNA G-quadruplex ligands as antitumor agents

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this