Chemical Research in Toxicology
ARTICLE
’ ACKNOWLEDGMENT
(15) Kelner, M. J., McMorris, T. C., Montoya, M. A., Estes, L., Uglik,
S. F., Rutherford, M., Samson, K. M., Bagnell, R. D., and Taetle, R.
(1998) Characterization of acylfulvene histiospecific toxicity in human
tumor cell lines. Cancer Chemother. Pharmacol. 41, 237–242.
(16) Kelner, M. J., McMorris, T. C., Montoya, M. A., Estes, L., Uglik,
S. F., Rutherford, M., Samson, K. M., Bagnell, R. D., and Taetle, R.
(1999) Characterization of MGI 114 (HMAF) histiospecific toxicity in
human tumor cell lines. Cancer Chemother. Pharmacol. 44, 235–240.
(17) Herzig, M. C. S., Arnett, B., MacDonald, J. R., and Woynar-
owski, J. M. (1999) Drug uptake and cellular targets of hydroxymethy-
lacylfulvene (HMAF). Biochem. Pharmacol. 58, 217–225.
(18) Woynarowski, J. M., Napier, C., Koester, S. K., Chen, S.-F.,
Troyer, D., Chapman, W., and MacDonald, J. R. (1997) Effects on DNA
integrity and apoptosis induction by a novel antitumor sesquiterpene
drug, 6-hydroxymethylacylfulvene (HMAF, MGI 114). Biochem. Phar-
macol. 54, 1181–1193.
We thank Dr. Beverly Ostrowski for assistance with NMR
experiments and Dr. Sarah Kliegman for assistance with data
analysis and helpful discussion. We also thank Professor Court-
ney Aldrich for helpful comments regarding the manuscript.
’ ABBREVIATIONS
AFs, acylfulvenes; PTGR1, prostaglandin reductase 1; AOR, alkenal/
one oxidoreductase; HMAF, hydroxymethylacylfulvene; ctDNA,
calf thymus DNA; rPTGR1, rat PTGR1; NaOD, sodium deuter-
oxide; D2O, deuterium oxide; NaBD4, sodium borodeuteride;
dAdo, deoxyadenosine; dGuo, deoxyguanosine; NOESY, nuclear
Overhauser effect spectroscopy; HRMS, high-resolution mass
spectroscopy; PPG, polypropethylene glycol; H2SO4, sulfuric
acid; NaBH4, sodium borohydride; MeOH, methanol; hPTGR1,
human PTGR1; DMEM, Dulbecco's modified Eagle's medium;
NADPD, 4,40-d2-NADPH; NTH, neutral thermal hydrolysis.
(19) McMorris, T. C., Elayadi, A. N., Yu, J., Hu, Y., and Kelner, M. J.
(1999) Metabolism of antitumor hydroxymethylacylfulvene by rat liver
cytosol. Drug Metab. Dispos. 27, 983–985.
(20) McMorris, T. C., Elayadi, A. N., Yu, J., and Kelner, M. J. (1999)
Metabolism of antitumor acylfulvene by rat liver cytosol. Biochem.
Pharmacol. 57, 83–88.
’ REFERENCES
(21) Dick, R. A., Kwak, M. K., Sutter, T. R., and Kensler, T. W.
(2001) Antioxidative function and substrate specificity of NAD(P)H-
dependent alkenal/one oxidoreductase. A new role for leukotriene B4
12-hydroxydehydrogenase/15-oxoprostaglandin 13-reductase. J. Biol.
Chem. 276, 40803–40810.
(22) Neels, J. F., Gong, J., Yu, X., and Sturla, S. J. (2007) Quantitative
correlation of drug bioactivation and deoxyadenosine alkylation by
acylfulvene. Chem. Res. Toxicol. 20, 1513–1519.
(23) Gong, J., Vaidyanathan, V. G., Yu, X., Kensler, T. W., Peterson,
L. A., and Sturla, S. J. (2007) Depurinating acylfulvene-DNA adducts:
Characterizing cellular chemical reactions of a selective antitumor agent.
J. Am. Chem. Soc. 129, 2101–2111.
(1) Boger, D. L., and Garbaccio, R. M. (1999) Shape-dependent
catalysis: Insights into the source of catalysis for the CC-1065 and
duocarmycin DNA alkylation reaction. Acc. Chem. Res. 32, 1043–1052.
(2) Lin, A. J., Cosby, L. A., Shansky, C. W., and Sartorelli, A. C.
(1972) Potential bioreductive alkylating agents. 1. Benzoquinone deri-
vatives. J. Med. Chem. 15, 1247–1252.
(3) Anchel, M., Hervey, A., and Robbins, W. J. (1952) Production of
illudin M and of a fourth crystalline compound by Clitocybe Illudens.
Proc. Natl. Acad. Sci. U.S.A. 38, 927–928.
(4) McMorris, T. C., and Anchel, M. (1965) Fungal metabolites.
The structures of the novel sesquiterpenoids illudin-S and -M. J. Am.
Chem. Soc. 87, 1594–1600.
(24) Ichinose, K., Kodera, M., Leeper, F. J., and Battersby, A. R.
(1999) Biosynthesis of porphyrins and related macrocycles. Part 51.
Proof that a reductive step occurs during the biosynthesis of vitamin B12
by the microaerophilic organism, Propionibacterium shermanii. J. Chem.
Soc. Perkin Trans. 1 8, 879–887.
(25) Evans, D. A., and Fu, G. C. (1990) Conjugate reduction of α,β-
unsaturated carbonyl compounds by catecholborane. J. Org. Chem.
55, 5678–5680.
(26) Mahoney, W. S., Brestensky, D. M., and Stryker, J. M. (1988)
Selective hydride-mediated conjugate reduction of α,β-unsaturated car-
bonyl compounds using [(Ph3P)CuH]6. J. Am. Chem. Soc. 110, 291–293.
(27) Jackson, W. R., and Zurqiyah, A. (1965) The occurrence of 1,2-
or 1,4-addition in the reduction of some α,β-unsaturated ketones with
metal hydrides. J. Chem. Soc. 5280–5287.
(28) Hays, P. A. (2005) Proton Nuclear Magnetic Resonance
Spectroscopy (NMR) Methods for determining the purity of reference
drug standards and illicit forensic drug seizures. J. Forensic Sci. 50, 1342.
(29) Anthoney, D. A., and Twelves, C. J. (2001) DNA: still a target
worth aiming at? A review of new DNA-interactive agents. Am.
J. PharmacoGenomics 1, 67–81.
(30) Lin, A. J., and Sartorelli, A. C. (1973) 2,3-Dimethyl-5,6-bis-
(methylene)-1,4-benzoquinone. The active intermediate of bioreductive
alkylating agents. J. Org. Chem. 38, 813–815.
(31) Zein, N., and Kohn, H. (1987) Covalent binding of mitomycin
C to nucleosides under reductive conditions. J. Am. Chem. Soc.
109, 1576–1577.
(32) Tomasz, M., Chowdary, D., Lipman, R., Shimotakahara, S.,
Veiro, D., Walker, V., and Verdine, G. L. (1986) Reaction of DNA with
chemically or enzymatically activated mitomycin C: isolation and
structure of the major covalent adduct. Proc. Natl. Acad. Sci. U.S.A.
83, 6702–6706.
(33) Iyer, V. N., and Szybalski, W. (1964) Mitomycins and porfir-
omycin: Chemical mechanism of activation and cross-linking of DNA.
Science 145, 55–58.
(5) McMorris, T. C., Kelner, M. J., Wang, W., Diaz, M. A., Estes,
L. A., and Taetle, R. (1996) Acylfulvenes, a new class of potent antitumor
agents. Experientia 52, 75–80.
(6) McMorris, T. C., Kelner, M. J., Wang, W., Yu, J., Estes, L. A., and
Taetle, R. (1996) (Hydroxymethyl)acylfulvene: An illudin derivative
with superior antitumor properties. J. Nat. Prod. 59, 896–899.
(7) McMorris, T. C. (1999) Discovery and development of sesqui-
terpenoid derived hydroxymethylacylfulvene: A new anticancer drug.
Bioorg. Med. Chem. 7, 881–886.
(8) Schobert, R., Knauer, S., Seibt, S., and Biersack, B. (2011)
Anticancer active illudins: Recent developments of a potent alkylating
compound class. Curr. Med. Chem. 18, 790–807.
(9) Kelner, M. J., McMorris, T. C., and Taetle, R. (1990) Preclinical
evaluation of illudins as anticancer agents: Basis for selective cytotoxicity.
J. Natl. Cancer Inst. 82, 1562–1565.
(10) Kelner, M. J., McMorris, T. C., Beck, W. T., Zamora, J. M., and
Taetle, R. (1987) Preclinical evaluation of illudins as anticancer agents.
Cancer Res. 47, 3186–3189.
(11) Woynarowska, B. A., Woynarowski, J. M., Herzig, M. C., Roberts,
K., Higdon, A. L., and MacDonald, J. R. (2000) Differential cytotoxicity
and induction of apoptosis in tumor and normal cells by hydroxymethy-
lacylfulvene (HMAF). Biochem. Pharmacol. 59, 1217–1226.
(12) MacDonald, J. R., Muscoplat, C. C., Dexter, D. L., Mangold, G. L.,
Chen, S. F., Kelner, M. J., McMorris, T. C., and Von Hoff, D. D. (1997)
Preclinical antitumor activity of 6-hydroxymethylacylfulvene, a semisyn-
thetic derivative of the mushroom toxin illudin S. Cancer Res. 57, 279–283.
(13) Gong, J., Neels, J. F., Yu, X., Kensler, T. W., Peterson, L. A., and
Sturla, S. J. (2006) Investigating the role of stereochemistry in the
activity of anticancer acylfulvenes: Synthesis, reductase-mediated bioac-
tivation, and cellular toxicity. J. Med. Chem. 49, 2593–2599.
(14) Dick, R. A., Yu, X., and Kensler, T. W. (2004) NADPH alkenal/
one oxidoreductase activity determines sensitivity of cancer cells to the
chemotherapeutic alkylating agent irofulven. Clin. Cancer Res. 10,
1492–1499.
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dx.doi.org/10.1021/tx200401u |Chem. Res. Toxicol. 2011, 24, 2044–2054