Design, synthesis, and evaluation of psorospermin/quinobenzoxazine hybrids as structurally novel antitumor agents

Mu Yong Kim, Younghwa Na, Hariprasad Vankayalapati, Mary Gleason-Guzman, Laurence Hurley

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Topoisomerase II, an enzyme that catalyzes changes in the topology of DNA, plays several key roles in DNA metabolism and chromosome structure, and it is the primary cytotoxic target for a number of clinically important DNA intercalating agents such as doxorubicin. It seems likely that if these intercalating topoisomerase II poisons are structurally modified to also be DNA alkylating agents, they will have increased dwell time on the topoisomerase II-DNA complex and increased potency and selectivity for cancer cells, On the basis of insights into the mechanisms of action of psorospermin and the quinobenzoxazine A-62176 and molecular modeling studies of these compounds with duplex DNA, we have designed and synthesized a series of novel hybrid DNA-interactive compounds that alkylate DNA most efficiently at sequences directed by topoisomerase II. The epoxydihydrofuran ring of psorospermin was used as a DNA alkylating moiety, and this was fused to the pyridobenzophenoxazine ring of A-62176. The chlorohydrin ring opened form of the epoxide was also prepared and tested. These hybrid compounds showed enhanced DNA alkylating activity in the presence of topoisomerase II, exhibited significant activity against all the cancer cells tested at submicromolar concentrations, and were more potent than both parent compounds. However, the biochemical assays indicated that they lost some of the topoisomerase II and Mg2+ dependency for reaction with DNA that is associated with psorospermin and A-62176, respectively.

Original languageEnglish (US)
Pages (from-to)2958-2972
Number of pages15
JournalJournal of Medicinal Chemistry
Volume46
Issue number14
DOIs
StatePublished - Jul 3 2003

Fingerprint

Antineoplastic Agents
Type II DNA Topoisomerase
A 62176
DNA
Chlorohydrins
Cells
psorospermin
Intercalating Agents
Chromosome Structures
Molecular modeling
Poisons
Alkylating Agents
Epoxy Compounds
Chromosomes
Metabolism
Doxorubicin
Assays
Neoplasms
Topology
Enzymes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, synthesis, and evaluation of psorospermin/quinobenzoxazine hybrids as structurally novel antitumor agents. / Kim, Mu Yong; Na, Younghwa; Vankayalapati, Hariprasad; Gleason-Guzman, Mary; Hurley, Laurence.

In: Journal of Medicinal Chemistry, Vol. 46, No. 14, 03.07.2003, p. 2958-2972.

Research output: Contribution to journalArticle

Kim, Mu Yong ; Na, Younghwa ; Vankayalapati, Hariprasad ; Gleason-Guzman, Mary ; Hurley, Laurence. / Design, synthesis, and evaluation of psorospermin/quinobenzoxazine hybrids as structurally novel antitumor agents. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 14. pp. 2958-2972.
@article{9cbe0aa7af9845339e19a83dcac00bbd,
title = "Design, synthesis, and evaluation of psorospermin/quinobenzoxazine hybrids as structurally novel antitumor agents",
abstract = "Topoisomerase II, an enzyme that catalyzes changes in the topology of DNA, plays several key roles in DNA metabolism and chromosome structure, and it is the primary cytotoxic target for a number of clinically important DNA intercalating agents such as doxorubicin. It seems likely that if these intercalating topoisomerase II poisons are structurally modified to also be DNA alkylating agents, they will have increased dwell time on the topoisomerase II-DNA complex and increased potency and selectivity for cancer cells, On the basis of insights into the mechanisms of action of psorospermin and the quinobenzoxazine A-62176 and molecular modeling studies of these compounds with duplex DNA, we have designed and synthesized a series of novel hybrid DNA-interactive compounds that alkylate DNA most efficiently at sequences directed by topoisomerase II. The epoxydihydrofuran ring of psorospermin was used as a DNA alkylating moiety, and this was fused to the pyridobenzophenoxazine ring of A-62176. The chlorohydrin ring opened form of the epoxide was also prepared and tested. These hybrid compounds showed enhanced DNA alkylating activity in the presence of topoisomerase II, exhibited significant activity against all the cancer cells tested at submicromolar concentrations, and were more potent than both parent compounds. However, the biochemical assays indicated that they lost some of the topoisomerase II and Mg2+ dependency for reaction with DNA that is associated with psorospermin and A-62176, respectively.",
author = "Kim, {Mu Yong} and Younghwa Na and Hariprasad Vankayalapati and Mary Gleason-Guzman and Laurence Hurley",
year = "2003",
month = "7",
day = "3",
doi = "10.1021/jm030096i",
language = "English (US)",
volume = "46",
pages = "2958--2972",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "14",

}

TY - JOUR

T1 - Design, synthesis, and evaluation of psorospermin/quinobenzoxazine hybrids as structurally novel antitumor agents

AU - Kim, Mu Yong

AU - Na, Younghwa

AU - Vankayalapati, Hariprasad

AU - Gleason-Guzman, Mary

AU - Hurley, Laurence

PY - 2003/7/3

Y1 - 2003/7/3

N2 - Topoisomerase II, an enzyme that catalyzes changes in the topology of DNA, plays several key roles in DNA metabolism and chromosome structure, and it is the primary cytotoxic target for a number of clinically important DNA intercalating agents such as doxorubicin. It seems likely that if these intercalating topoisomerase II poisons are structurally modified to also be DNA alkylating agents, they will have increased dwell time on the topoisomerase II-DNA complex and increased potency and selectivity for cancer cells, On the basis of insights into the mechanisms of action of psorospermin and the quinobenzoxazine A-62176 and molecular modeling studies of these compounds with duplex DNA, we have designed and synthesized a series of novel hybrid DNA-interactive compounds that alkylate DNA most efficiently at sequences directed by topoisomerase II. The epoxydihydrofuran ring of psorospermin was used as a DNA alkylating moiety, and this was fused to the pyridobenzophenoxazine ring of A-62176. The chlorohydrin ring opened form of the epoxide was also prepared and tested. These hybrid compounds showed enhanced DNA alkylating activity in the presence of topoisomerase II, exhibited significant activity against all the cancer cells tested at submicromolar concentrations, and were more potent than both parent compounds. However, the biochemical assays indicated that they lost some of the topoisomerase II and Mg2+ dependency for reaction with DNA that is associated with psorospermin and A-62176, respectively.

AB - Topoisomerase II, an enzyme that catalyzes changes in the topology of DNA, plays several key roles in DNA metabolism and chromosome structure, and it is the primary cytotoxic target for a number of clinically important DNA intercalating agents such as doxorubicin. It seems likely that if these intercalating topoisomerase II poisons are structurally modified to also be DNA alkylating agents, they will have increased dwell time on the topoisomerase II-DNA complex and increased potency and selectivity for cancer cells, On the basis of insights into the mechanisms of action of psorospermin and the quinobenzoxazine A-62176 and molecular modeling studies of these compounds with duplex DNA, we have designed and synthesized a series of novel hybrid DNA-interactive compounds that alkylate DNA most efficiently at sequences directed by topoisomerase II. The epoxydihydrofuran ring of psorospermin was used as a DNA alkylating moiety, and this was fused to the pyridobenzophenoxazine ring of A-62176. The chlorohydrin ring opened form of the epoxide was also prepared and tested. These hybrid compounds showed enhanced DNA alkylating activity in the presence of topoisomerase II, exhibited significant activity against all the cancer cells tested at submicromolar concentrations, and were more potent than both parent compounds. However, the biochemical assays indicated that they lost some of the topoisomerase II and Mg2+ dependency for reaction with DNA that is associated with psorospermin and A-62176, respectively.

UR - http://www.scopus.com/inward/record.url?scp=0038460855&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038460855&partnerID=8YFLogxK

U2 - 10.1021/jm030096i

DO - 10.1021/jm030096i

M3 - Article

VL - 46

SP - 2958

EP - 2972

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 14

ER -