Pyrimidoquinazoline-based antitumor agents. Design of topoisomerase II to DNA cross-linkers with activity against protein kinases

Edward B. Skibo; Xiaofen Huang; Rogelio Martinez; Robert H. Lemus; William A. Craigo; Robert T. Dorr

doi:10.1021/jm020285l

Pyrimidoquinazoline-based antitumor agents. Design of topoisomerase II to DNA cross-linkers with activity against protein kinases

Edward B. Skibo, Xiaofen Huang, Rogelio Martinez, Robert H. Lemus, William A. Craigo, Robert T. Dorr

Cancer Center

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

43 Scopus citations

Abstract

A series of pyrimidoquinazoline analogues, possessing either 4,5-g or 5,4-g fusion, were studied with respect to cytotoxicity, topoisomerase II inhibitory activity, in vivo activity, and DNA cleavage and DNA-protein cross-linking properties. These analogues were designed as electron-deficient anthraquinones with dual alkylating centers to cross-link DNA with topoisomerase II. Our studies verified the presence of DNA-protein cross-linking in vitro as well as topoisomerase II poisoning by pyrimidoquinazoline analogues. In addition, COMPARE analysis revealed that the pyrimidoquinazolines possess inhibitory activity against both topoisomerase II and protein kinases, such as the paullones, a dual property observed in other antineoplastic agents influencing phosphoester transfer.

Original language	English (US)
Pages (from-to)	5543-5555
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	45
Issue number	25
DOIs	https://doi.org/10.1021/jm020285l
State	Published - Dec 5 2002

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/jm020285l

Cite this

@article{7d989b0f4c04472abe5e7e57559cad6c,

title = "Pyrimidoquinazoline-based antitumor agents. Design of topoisomerase II to DNA cross-linkers with activity against protein kinases",

abstract = "A series of pyrimidoquinazoline analogues, possessing either 4,5-g or 5,4-g fusion, were studied with respect to cytotoxicity, topoisomerase II inhibitory activity, in vivo activity, and DNA cleavage and DNA-protein cross-linking properties. These analogues were designed as electron-deficient anthraquinones with dual alkylating centers to cross-link DNA with topoisomerase II. Our studies verified the presence of DNA-protein cross-linking in vitro as well as topoisomerase II poisoning by pyrimidoquinazoline analogues. In addition, COMPARE analysis revealed that the pyrimidoquinazolines possess inhibitory activity against both topoisomerase II and protein kinases, such as the paullones, a dual property observed in other antineoplastic agents influencing phosphoester transfer.",

author = "Skibo, {Edward B.} and Xiaofen Huang and Rogelio Martinez and Lemus, {Robert H.} and Craigo, {William A.} and Dorr, {Robert T.}",

year = "2002",

month = dec,

day = "5",

doi = "10.1021/jm020285l",

language = "English (US)",

volume = "45",

pages = "5543--5555",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "25",

}

TY - JOUR

T1 - Pyrimidoquinazoline-based antitumor agents. Design of topoisomerase II to DNA cross-linkers with activity against protein kinases

AU - Skibo, Edward B.

AU - Huang, Xiaofen

AU - Martinez, Rogelio

AU - Lemus, Robert H.

AU - Craigo, William A.

AU - Dorr, Robert T.

PY - 2002/12/5

Y1 - 2002/12/5

N2 - A series of pyrimidoquinazoline analogues, possessing either 4,5-g or 5,4-g fusion, were studied with respect to cytotoxicity, topoisomerase II inhibitory activity, in vivo activity, and DNA cleavage and DNA-protein cross-linking properties. These analogues were designed as electron-deficient anthraquinones with dual alkylating centers to cross-link DNA with topoisomerase II. Our studies verified the presence of DNA-protein cross-linking in vitro as well as topoisomerase II poisoning by pyrimidoquinazoline analogues. In addition, COMPARE analysis revealed that the pyrimidoquinazolines possess inhibitory activity against both topoisomerase II and protein kinases, such as the paullones, a dual property observed in other antineoplastic agents influencing phosphoester transfer.

AB - A series of pyrimidoquinazoline analogues, possessing either 4,5-g or 5,4-g fusion, were studied with respect to cytotoxicity, topoisomerase II inhibitory activity, in vivo activity, and DNA cleavage and DNA-protein cross-linking properties. These analogues were designed as electron-deficient anthraquinones with dual alkylating centers to cross-link DNA with topoisomerase II. Our studies verified the presence of DNA-protein cross-linking in vitro as well as topoisomerase II poisoning by pyrimidoquinazoline analogues. In addition, COMPARE analysis revealed that the pyrimidoquinazolines possess inhibitory activity against both topoisomerase II and protein kinases, such as the paullones, a dual property observed in other antineoplastic agents influencing phosphoester transfer.

UR - http://www.scopus.com/inward/record.url?scp=0037028067&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037028067&partnerID=8YFLogxK

U2 - 10.1021/jm020285l

DO - 10.1021/jm020285l

M3 - Article

C2 - 12459022

AN - SCOPUS:0037028067

SN - 0022-2623

VL - 45

SP - 5543

EP - 5555

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 25

ER -

Pyrimidoquinazoline-based antitumor agents. Design of topoisomerase II to DNA cross-linkers with activity against protein kinases

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this