Modification of Cellular DNA by Synthetic Aziridinomitosenes

Chris M. Mallory; Ryan P. Carfi; SangPhil Moon; Kenneth A. Cornell; Don L. Warner

doi:10.1016/j.bmc.2015.10.028

Modification of Cellular DNA by Synthetic Aziridinomitosenes

Chris M. Mallory, Ryan P. Carfi, SangPhil Moon, Kenneth A. Cornell, Don L. Warner

Chemistry Department

Boise State University

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Abstract

Two synthetic aziridinomitosenes (AZMs), Me-AZM and H-AZM, structurally related to mitomycin C (MC) were evaluated for their anticancer activity against six cancer cell lines (HeLa, Jurkat, T47D, HepG2, HL-60, and HuT-78) and tested for their DNA-modifying abilities in Jurkat cells. Cytotoxicity assays showed that Me-AZM is up to 72-fold and 520-fold more potent than MC and H-AZM, respectively. Me-AZM also demonstrated increased DNA modification over MC and H-AZM in alkaline COMET and Hoechst fluorescence assays that measured crosslinks in cellular DNA. Me-AZM and H-AZM treatment of Jurkat cells was found to sponsor significant DNA-protein crosslinks using a K-SDS assay. The results clearly indicate that the AZM C6/C7 substitution pattern plays an important role in drug activity and supports both DNA-DNA and DNA-protein adduct formation as mechanisms for inducing cytotoxic effects.

Original language	American English
Pages (from-to)	7378-85
Number of pages	8
Journal	Bioorganic & Medicinal Chemistry
Volume	23
Issue number	23
DOIs	https://doi.org/10.1016/j.bmc.2015.10.028
State	Published - 1 Dec 2015

Keywords

mitomycin c
aziridinomitosene
DNA adducts
alkylating agents

EGS Disciplines

Chemistry

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@article{2f9b43f327b24839936713978210a41b,

title = "Modification of Cellular DNA by Synthetic Aziridinomitosenes",

abstract = "Two synthetic aziridinomitosenes (AZMs), Me-AZM and H-AZM, structurally related to mitomycin C (MC) were evaluated for their anticancer activity against six cancer cell lines (HeLa, Jurkat, T47D, HepG2, HL-60, and HuT-78) and tested for their DNA-modifying abilities in Jurkat cells. Cytotoxicity assays showed that Me-AZM is up to 72-fold and 520-fold more potent than MC and H-AZM, respectively. Me-AZM also demonstrated increased DNA modification over MC and H-AZM in alkaline COMET and Hoechst fluorescence assays that measured crosslinks in cellular DNA. Me-AZM and H-AZM treatment of Jurkat cells was found to sponsor significant DNA-protein crosslinks using a K-SDS assay. The results clearly indicate that the AZM C6/C7 substitution pattern plays an important role in drug activity and supports both DNA-DNA and DNA-protein adduct formation as mechanisms for inducing cytotoxic effects.",

keywords = "mitomycin c, aziridinomitosene, DNA adducts, alkylating agents",

author = "Mallory, \{Chris M.\} and Carfi, \{Ryan P.\} and SangPhil Moon and Cornell, \{Kenneth A.\} and Warner, \{Don L.\}",

year = "2015",

month = dec,

day = "1",

doi = "10.1016/j.bmc.2015.10.028",

language = "American English",

volume = "23",

pages = "7378--85",

number = "23",

}

TY - JOUR

T1 - Modification of Cellular DNA by Synthetic Aziridinomitosenes

AU - Mallory, Chris M.

AU - Carfi, Ryan P.

AU - Moon, SangPhil

AU - Cornell, Kenneth A.

AU - Warner, Don L.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Two synthetic aziridinomitosenes (AZMs), Me-AZM and H-AZM, structurally related to mitomycin C (MC) were evaluated for their anticancer activity against six cancer cell lines (HeLa, Jurkat, T47D, HepG2, HL-60, and HuT-78) and tested for their DNA-modifying abilities in Jurkat cells. Cytotoxicity assays showed that Me-AZM is up to 72-fold and 520-fold more potent than MC and H-AZM, respectively. Me-AZM also demonstrated increased DNA modification over MC and H-AZM in alkaline COMET and Hoechst fluorescence assays that measured crosslinks in cellular DNA. Me-AZM and H-AZM treatment of Jurkat cells was found to sponsor significant DNA-protein crosslinks using a K-SDS assay. The results clearly indicate that the AZM C6/C7 substitution pattern plays an important role in drug activity and supports both DNA-DNA and DNA-protein adduct formation as mechanisms for inducing cytotoxic effects.

AB - Two synthetic aziridinomitosenes (AZMs), Me-AZM and H-AZM, structurally related to mitomycin C (MC) were evaluated for their anticancer activity against six cancer cell lines (HeLa, Jurkat, T47D, HepG2, HL-60, and HuT-78) and tested for their DNA-modifying abilities in Jurkat cells. Cytotoxicity assays showed that Me-AZM is up to 72-fold and 520-fold more potent than MC and H-AZM, respectively. Me-AZM also demonstrated increased DNA modification over MC and H-AZM in alkaline COMET and Hoechst fluorescence assays that measured crosslinks in cellular DNA. Me-AZM and H-AZM treatment of Jurkat cells was found to sponsor significant DNA-protein crosslinks using a K-SDS assay. The results clearly indicate that the AZM C6/C7 substitution pattern plays an important role in drug activity and supports both DNA-DNA and DNA-protein adduct formation as mechanisms for inducing cytotoxic effects.

KW - mitomycin c

KW - aziridinomitosene

KW - DNA adducts

KW - alkylating agents

UR - https://scholarworks.boisestate.edu/chem_facpubs/101

U2 - 10.1016/j.bmc.2015.10.028

DO - 10.1016/j.bmc.2015.10.028

M3 - Article

C2 - 26541587

VL - 23

SP - 7378

EP - 7385

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 23

ER -

Modification of Cellular DNA by Synthetic Aziridinomitosenes

Abstract

Keywords

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