Biochemistry
ARTICLE
’ AUTHOR INFORMATION
(8) Hurley, L. H., and Thurston, D. E. (1984) Pyrrolo-
(1,4)Benzodiazepine Antitumor Antibiotics: Chemistry, Interaction
with DNA, and Biological Implications. Pharm. Res. 1, 52–59.
(9) Gause, G. F., and Dudnik, Y. V. (1971) Interaction of antitumor
antibiotics with DNA: Studies on sibiromycin. Prog. Mol. Subcell. Biol., 33–39.
(10) Cargill, C., Bachmann, E., and Zbinden, G. (1974) Effects of
daunomycin and anthramycin on electrocardiogram and mitochondrial
metabolism of the rat heart. J. Natl. Cancer Inst. 53, 481–486.
(11) Lubawy, W. C., Dallam, R. A., and Hurley, L. H. (1980)
Protection against anthramycin-induced toxicity in mice by coenzyme
Q10. J. Natl. Cancer Inst. 64, 105–109.
(12) Kamal, A., Rao, M. V., Laxman, N., Ramesh, G., and Reddy,
G. S. (2002) Recent developments in the design, synthesis and structure-
activity relationship studies of pyrrolo[2,1-c][1,4]benzodiazepines as
DNA-interactive antitumour antibiotics. Curr. Med. Chem.: Anti-Cancer
Agents 2, 215–254.
Corresponding Author
*Department of Chemistry, Philipps-University Marburg,
D-35043 Marburg, Germany. Telephone: þ49 (0) 6421 28
25722. Fax: þ49 (0) 6421 28 22191. E-mail: marahiel@staff.
uni-marburg.de.
Funding Sources
This work has been supported by the Deutsche Forschungsge-
meinschaft and the LOEWE Center for Synthetic Microbiology
(SYNMIKRO).
’ ACKNOWLEDGMENT
(13) Itoh, J., Watabe, H., Ishii, S., Gomi, S., Nagasawa, M., Yamamoto,
H., Shomura, T., Sezaki, M., and Kondo, S. (1988) Sibanomicin, a new
pyrrolo[1,4]benzodiazepine antitumor antibiotic produced by a Micro-
monospora sp. J. Antibiot. 41, 1281–1284.
We thank Dr. Uwe Linne (Philipps-University Marburg, Mass
Spectrometry Facility) for support during mass spectrometric
analyses.
(14) Antonow, D., Cooper, N., Howard, P. W., and Thurston, D. E.
(2007) Parallel synthesis of
a novel C2-aryl pyrrolo[2,1-c]-
[1,4]benzodiazepine (PBD) library. J. Comb. Chem. 9, 437–445.
(15) Tiberghien, A. C., Hagan, D., Howard, P. W., and Thurston,
D. E. (2004) Application of the Stille coupling reaction to the synthesis
of C2-substituted endo-exo unsaturatedpyrrolo[2,1-c][1,4]benzodiazepines
(PBDs). Bioorg. Med. Chem. Lett. 14, 5041–5044.
(16) Gregson, S. J., Howard, P. W., Hartley, J. A., Brooks, N. A.,
Adams, L. J., Jenkins, T. C., Kelland, L. R., and Thurston, D. E. (2001)
Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine
DNA-interactive agent with highly efficient cross-linking ability and
potent cytotoxicity. J. Med. Chem. 44, 737–748.
(17) Parker, K. A., and Fedynyshyn, T. H. (1979) Synthesis of
Anhydrosibiromycinone: New Method for the Direct Synthesis of Pyrrolo-
1,4-Benzodiazepin-5-Ones. Tetrahedron Lett., 1657–1660.
(18) Hurley, L. H., and Speedie, M. K., Eds. (1981) Pyrrolo-
(1,4)benzodiazepines antibiotics: Anthramycin, tomaymycin and sibiromy-
cin, Vol. 4, Springer, Berlin.
’ ABBREVIATIONS
3HAA, 3-hydroxyanthranilic acid; 3HK, 3-hydroxykynurenine; 3
H4MAA, 3-hydroxy-4-methylanthranilic acid; 3H4MK, 3-hydro-
xy-4-methylkynurenine; 3,5DH4MAA, 3,5-dihydroxy-4-methylan-
thranilic acid; 5HAA, 5-hydroxyanthranilic acid; AA, anthranilic
acid; DOPA, 3,4-dihydroxyphenylalanine; FAD, flavin adenine
dinucleotide; NADþ and NADH, nicotinamide adenine dinu-
cleotide; NADPþ and NADPH, nicotinamide adenine dinucleo-
tide phosphate; NRPS, nonribosomal peptide synthetase; PBD,
pyrrolo[1,4]benzodiazepine; PLP, pyridoxyl 50-phosphate; PCP,
peptidyl carrier protein; SAM, S-adenosylmethionine.
’ REFERENCES
(19) Hurley, L. H. (1980) Elucidation and Formulation of Novel
Biosynthetic Pathways Leading to the Pyrrolo[1,4]Benzodiazepine
Antibiotics Anthramycin, Tomaymycin, and Sibiromycin. Acc. Chem.
Res. 13, 263–269.
(20) Rokem, J. S., and Hurley, L. H. (1981) Sensitivity and Perme-
ability of the Anthramycin Producing Organism Streptomyces-Refui-
neus to Anthramycin and Structurally Related Antibiotics. J. Antibiot.
34, 1171–1174.
(21) Hu, Y., Phelan, V., Ntai, I., Farnet, C. M., Zazopoulos, E., and
Bachmann, B. O. (2007) Benzodiazepine biosynthesis in Streptomyces
refuineus. Chem. Biol. 14, 691–701.
(22) Li, W., Chou, S., Khullar, A., and Gerratana, B. (2009) Cloning
and characterization of the biosynthetic gene cluster for tomaymycin, an
SJG-136 monomeric analog. Appl. Environ. Microbiol. 75, 2958–2963.
(23) Li, W., Khullar, A., Chou, S., Sacramo, A., and Gerratana, B.
(2009) Biosynthesis of sibiromycin, a potent antitumor antibiotic. Appl.
Environ. Microbiol. 75, 2869–2878.
(24) Brahme, N. M., Gonzalez, J. E., Mizsak, S., Rolls, J. R., Hessler,
E. J., and Hurley, L. H. (1984) Biosynthesis of the Lincomycins. 2.
Studies Using Stable Isotopes on the Biosynthesis of Methylthiolinco-
saminide Moiety of Lincomycin-A. J. Am. Chem. Soc. 106, 7878–7883.
(25) Brahme, N. M., Gonzalez, J. E., Rolls, J. P., Hessler, E. J., Mizsak,
S., and Hurley, L. H. (1984) Biosynthesis of the Lincomycins. 1. Studies
Using Stable Isotopes on the Biosynthesis of the Propyl-L-Hygric and
Ethyl-L-Hygric Acid Moieties of Lincomycin-A and Lincomycin-B.
J. Am. Chem. Soc. 106, 7873–7878.
(1) Parker, K. A., and Babine, R. E. (1982) Revision of assignment of
structure to the pyrrolodiazepinone anti-tumor antibiotic sibiromycin.
J. Am. Chem. Soc. 104, 7330–7331.
(2) Antonow, D., and Thurston, D. E. (2011) Synthesis of DNA-
Interactive Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). Chem. Rev.
111, 2815–2864.
(3) Petrusek, R. L., Anderson, G. L., Garner, T. F., Fannin, Q. L.,
Kaplan, D. J., Zimmer, S. G., and Hurley, L. H. (1981) Pyrrol-
[1,4]benzodiazepine antibiotics. Proposed structures and characteristics
of the in vitro deoxyribonucleic acid adducts of anthramycin, tomaymy-
cin, sibiromycin, and neothramycins A and B. Biochemistry 20, 1111–
1119.
(4) Kumar, R., and Lown, J. W. (2003) Recent developments in
novel pyrrolo[2,1-c][1,4]benzodiazepine conjugates: Synthesis and
biological evaluation. Mini Rev. Med. Chem. 3, 323–339.
(5) Kopka, M. L., Goodsell, D. S., Baikalov, I., Grzeskowiak, K.,
Cascio, D., and Dickerson, R. E. (1994) Crystal structure of a covalent
DNA-drug adduct: Anthramycin bound to C-C-A-A-C-G-T-T-G-G and
a molecular explanation of specificity. Biochemistry 33, 13593–13610.
(6) Clingen, P. H., De Silva, I. U., McHugh, P. J., Ghadessy, F. J.,
Tilby, M. J., Thurston, D. E., and Hartley, J. A. (2005) The XPF-ERCC1
endonuclease and homologous recombination contribute to the repair
of minor groove DNA interstrand crosslinks in mammalian cells
produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136.
Nucleic Acids Res. 33, 3283–3291.
(7) Thurston, D. E., Bose, D. S., Howard, P. W., Jenkins, T. C., Leoni,
A., Baraldi, P. G., Guiotto, A., Cacciari, B., Kelland, L. R., Foloppe, M. P.,
and Rault, S. (1999) Effect of A-ring modifications on the DNA-binding
behavior and cytotoxicity of pyrrolo[2,1-c][1,4]benzodiazepines. J. Med.
Chem. 42, 1951–1964.
(26) Gerratana, B. (2010) Biosynthesis, synthesis, and biological
activities of pyrrolobenzodiazepines. Med. Res. Rev..
(27) Golub, E. E., Ward, M. A., and Nishimura, J. S. (1969)
Biosynthesis of the actinomycin chromophore: Incorporation of
5691
dx.doi.org/10.1021/bi2006114 |Biochemistry 2011, 50, 5680–5692