Abstract
The antibiotics known as bleomycins constitute a family of natural products clinically employed for the treatment of a wide spectrum of cancers. The drug acts as an antitumor agent by virtue of the ability of a metal complex of the antibiotic to cleave DNA. Bleomycins are differentiated by their C-terminal regions. Previous structural studies involving metal–bleomycin–DNA triads have allowed the identification of the bithiazole-(C-terminus substituent) segment in this molecule as the one that most closely interacts with DNA. Three different modes of binding of metallo-bleomycins to DNA (partial or total intercalation of the bithiazole unit between DNA bases, or binding to the minor groove) have been proposed in the literature. The therapeutic use of bleomycin is frequently associated with the development of pulmonary fibrosis. The severity of this side effect has been attributed to the C-terminus of the antibiotic by some researchers. The degree of pulmonary toxicity of bleomycin-A2 and -A5, were found to be higher than those of bleomycin-B2 and peplomycin. Since the introduction of Blenoxane to clinical medicine in 1972, attempts have been made at modifying the basic bleomycin structure at the C-terminus to improve its therapeutic index. However, the pharmacological and toxicological importance of particular C-termini on bleomycin remains unclear. The present study was designed to determine the effect of Zn(II)bleomycin-A2, -A5, -B2, and Zn(II)peplomycin on the structure of a DNA hairpin containing the 5′-GC-3′ binding site. We provide evidence that different Zn(II)bleomycins affect the structure of the tested DNA segment in different fashions.
Similar content being viewed by others
Abbreviations
- A:
-
Adenine
- Ala:
-
β-Aminoalanine
- b-b:
-
Base–base
- Bit:
-
Bithiazole
- BLMs:
-
Bleomycins
- b-s:
-
Base–sugar
- C:
-
Cytosine
- 1D:
-
One-dimensional
- Δδs:
-
Differences in chemical shifts
- FID:
-
Free induction decay
- G:
-
Guanine
- Gul:
-
α-l-Gulose
- Hist:
-
β-Hydoxyhistidine
- Mann:
-
α-d-Mannose
- MBLMs:
-
Metallo-bleomycins
- NMR:
-
Nuclear magnetic resonance
- NOE:
-
Nuclear Overhauser effect cross-signals
- NOESY:
-
Nuclear Overhauser effect spectroscopy
- OL:
-
Oligonucleotide
- PEP:
-
Peplomycin
- ppm:
-
Parts per million
- Pyr:
-
Pyrimidinylpropionamide
- s-s:
-
Sugar–sugar
- T:
-
Thymine
- Tails:
-
C-terminus substituents
- Thre:
-
Threonine
- TOCSY:
-
Totally correlated spectroscopy
- Val:
-
Methylvalerate
References
Umezawa H, Maeda K, Takeuchi T, Okami J (1966) J Antibiot 19:200–209
Bennett JM, Reich SD (1979) Ann Intern Med 90:945–948
Carlson RW, Sikic BI, Turbow MM, Ballon SC (1983) J Clin Oncol 1:645–651
Hecht SM (1995) In: Foye WO (ed) Cancer chemotherapeutic agents. ACS Professional Reference Book, Washington, D. C, pp 369–388
Einhorn LH, Donohue J (1977) Ann Intern Med 87:293–298
Umezawa H (1997) In: Hecht SM (ed) Bleomycin: chemical, biochemical and biological aspects. Springer, New York, pp 24–36
Schroeder BR, Ghare MI, Bhattacharya C, Paul R, Yu ZQ, Zaleski PA, Bozeman TC, Rishel MJ, Hecht SM (2014) J Am Chem Soc 136:13641–13656
Caceres-Cortes J, Sugiyama H, Ikudome K, Saito I, Wang AHJ (1997) Biochemistry 36:9995–10005
Hoehn ST, Junker HD, Bunt RC, Turner CJ, Stubbe J (2001) Biochemistry 40:5894–5905
Lui SM, Vanderwall DE, Wu W, Tang X-J, Turner CJ, Kozarich JW, Stubbe J (1997) J Am Chem Soc 119:9603–9613
Manderville RA, Ellena JF, Hecht SM (1995) J Am Chem Soc 117:7891–7903
Vanderwall DE, Lui SM, Turner CJ, Kozarich JW, Stubbe J (1997) Chem Biol 4:373–387
Wu W, Vaderwall DE, Stubbe J, Kozarich JW, Turner CJ (1994) J Am Chem Soc 116:10843–10844
Wu W, Vanderwall DE, Lui SM, Tang X-J, Turner CJ, Kozarich JW, Stubbe J (1996) J Am Chem Soc 118:1268–1280
Wu W, Vanderwall DE, Turner CJ, Kozarich JW, Stubbe J (1996) J Am Chem Soc 118:1281–1294
Wu W, Vanderwall DE, Teramoto S, Lui SM, Hoehn ST, Tang X-J, Turner CJ, Boger DL, Kozarich JW, Stubbe J (1998) J Am Chem Soc 120:2239–2250
Wu W, Vanderwall DE, Turner CJ, Hoehn S, Chen JY, Kozarich JW, Stubbe J (2002) Nucleic Acids Res 30:4881–4891
Zhao CQ, Xia CW, Mao QK, Forsterling H, DeRose E, Antholine WE, Subczynski WK, Petering DH (2002) J Inorg Biochem 91:259–268
Goodwin KD, Lewis MA, Long EC, Georgiadis MM (2008) Proc Natl Acad Sci USA 105:5052–5056
Raisfeld IH, Chovan JP, Frost S (1982) Life Sci 30:1391–1398
Raisfeld IH, Chu P, Hart NK, Lane A (1982) Toxicol Appl Pharm 63:351–362
Raisfeld IH (1980) Toxicol Appl Pharm 56:326–336
Tanaka W, Takita T (1979) Heterocyles 13:469–476
Oka S (1980) Recent Results Cancer Res 74:163–171
Raisfeld IH, Kundahl ER, Sawey MJ, Chovan JP, Depasquale J (1982) Clin Res 30:A437
Raisfeld IH (1981) Clin Pharmacol Ther 29:274
Raisfeld IH (1980) Clin Res 28:A530
Raisfeld IH (1979) Clin Res 27:A445
Takahashi K, Aoyagi HS, Koyu A, Kuramochi H, Yoshioka O, Matsuda A, Fujii A, Umezawa H (1979) J Antibiot 32:36–42
Ito K, Handa J, Irie Y, Ezura H, Kumagai M, Irie Y, Suzuki A, Hagiwara T, Yamane H, Miyamoto K, Yamashita T, Tsubosaki M, Matsuda AN, Konoha N (1979) J Antibiot 32:387–450
Ishizuka M, Takayama H, Takeuchi T, Umezawa H (1967) J Antibiot 10:15–24
Ishizuka M, Takayama H, Takeuchi T, Umezawa H (1966) J Antibiot 19:260–271
Gobbi PG, Federico M (2012) CRC Cr Rev Oncol-Hem 82:18–24
Lehmann TE, Ming L-J, Rosen ME, Que L Jr (1997) Biochemistry 36:2807–2816
Lehmann TE, Serrano ML, Que L Jr (2000) Biochemistry 39:3886–3898
Lehmann TE (2002) J Biol Inorg Chem 7:305–312
Lehmann TE, Li Y (2012) J Antibiot 65:25–33
Lehmann TE, Li Y (2012) J Biol Inorg Chem 17:761–771
Li Y, Lehmann TE (2012) J Inorg Biochem 111:50–58
Feigon J, Denny WA, Leupin W, Kearns R (1984) J Med Chem 27:450–465
Batist G, Andrews JL Jr (1981) JAMA J Am Med Assoc 246:1449–1453
Cooper JAD Jr, White DA, Matthay RA (1986) Am Rev Respir Dis 133:321–340
Ginsberg SJ, Comis RL (1982) Semin Oncol 9:34–51
Muggia FM, Louie AC, Sikic BI (1983) Cancer Treat Rev 10:221–243
Acknowledgements
This work was supported in whole by the National Institute of Health [Grant 1R15GM106285-01A1]. Our gratitude also goes to Nippon Kayaku Co., Ltd. (Tokyo, Japan) for the generous gift of peplomycin. We also acknowledge Dr. Alexander Goroncy for help collecting the NMR data presented in this work.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lehmann, T.E., Murray, S.A., Ingersoll, A.D. et al. NMR study of the effects of some bleomycin C-termini on the structure of a DNA hairpin with the 5′-GC-3′ binding site. J Biol Inorg Chem 22, 121–136 (2017). https://doi.org/10.1007/s00775-016-1413-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-016-1413-4