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Journal of Biomolecular Structure and Dynamics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tbsd20
Determination of DNA Cleavage Specificity by Esperamicins a
a
b
b
Min Lu , Qiu Guo , Bala Krishnan , Jerzy Golik , b
b
Ira E. Rosenberg , Terrence W. Doyle & Neville R. Kallenbach
a
a
Department of Chemistry , New York University , New York , New York , 10003 b
Bristol-Myers Squibb Company Pharmaceutical Research Institute , 5 Research Parkway P.O. Box 5100, Wallingford , Connecticut , 06492 Published online: 21 May 2012.
To cite this article: Min Lu , Qiu Guo , Bala Krishnan , Jerzy Golik , Ira E. Rosenberg , Terrence W. Doyle & Neville R. Kallenbach (1991) Determination of DNA Cleavage Specificity by Esperamicins, Journal of Biomolecular Structure and Dynamics, 9:2, 285-298, DOI: 10.1080/07391102.1991.10507913 To link to this article: http://dx.doi.org/10.1080/07391102.1991.10507913
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the Content.
Downloaded by [Purdue University] at 11:43 12 April 2015
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Journal of Biomolecular Structure & Dynamics, JSSN 0739-1102 Volume 9. Issue Number 2 (1991}, ©Adenine Press (1991).
Determination of DNA Cleavage Specificity by Esperamicins Min Lu 1, Qiu Guo 1, Bala Krishnan2 , J erzy Golik2 , Ira E. Rosenberg2 , Terrence W. Doyle 2 and Neville R. Kallenbach 1 Downloaded by [Purdue University] at 11:43 12 April 2015
1
Department of Chemistry New York University New York, New York 10003 2
Bristol-Myers Squibb Company Pharmaceutical Research Institute 5 Research Parkway P.O. Box 5100 Wallingford, Connecticut 06492 Abstract The esperamicins are members of a class of potent antitumor antibiotics that contain strained diacetylenic ring sytems capable of forming DNA -cleaving diradicals upon reaction with thiols. Here we show that the diacetylenic ring core itself determines the sequence specificity for scission of duplex DNA): esperamicinA 1, and three products of hydrolysis of the glycon, esperamicins C. D. and E, are found to retain a common sequence preference. The sugar residues exert a strong influence on the cleavage efficiency, presumably by interacting nonspecifically with DNA The presence of a branch in the DNA is found locally to inhibit scission by esperamicins, and this effect is shown to be due to the core also.
Introduction
The esperamicins (Figure 1) are natural products of the fungus Actinomadura verrucosospora (1) and are among the most potent antibiotic agents known (2). The structure of esperamicin A 1 ( esp A 1) has been determined (3,4) and consists of a diacetylenic ring system attached to four sugar residues and an aromatic ring. The proposed mechanism of action of esp A 1 involves binding of the strained conjugated enediyne ring in the minor groove of DNA, leading to cleavage of the duplex when this ring undergoes an intramolecular rearrangement to form a phenylene diradical triggered by a reduction of the trisulfide group (4). In vivo, esp A 1 shows activity in a prophage induction assay at exceptionally low concentrations-picograms per mi.and is biologically active at concentrations far below the adriamycins (2,5). In vitro, esp A 1 exhibits a sequence dependent cleavage pattern in duplex DNA (5,6). Esp A 1 and the related compounds esp C (lacking 2-deoxy-L-fucose and the anthranilate ring) and esp D (lacking the thiomethyl hexopyranose in addition), have a preference for
285
Lu eta/.
286
CH 3 ~0CH3 I
~ :-...
OCH, NHcoLcH 2
0
:,t!-7 Ll.o . ~ HO. , -
SSSCH
Downloaded by [Purdue University] at 11:43 12 April 2015
~
, CHl
O
OH
NH
Hl
OCH 3
SSSCH 3 HO
0
CH10CONH
~
H3 NH..
-~
OH
H 3
~CH3
Journal of Biomolecular Structure and Dynamics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tbsd20
Determination of DNA Cleavage Specificity by Esperamicins a
a
b
b
Min Lu , Qiu Guo , Bala Krishnan , Jerzy Golik , b
b
Ira E. Rosenberg , Terrence W. Doyle & Neville R. Kallenbach
a
a
Department of Chemistry , New York University , New York , New York , 10003 b
Bristol-Myers Squibb Company Pharmaceutical Research Institute , 5 Research Parkway P.O. Box 5100, Wallingford , Connecticut , 06492 Published online: 21 May 2012.
To cite this article: Min Lu , Qiu Guo , Bala Krishnan , Jerzy Golik , Ira E. Rosenberg , Terrence W. Doyle & Neville R. Kallenbach (1991) Determination of DNA Cleavage Specificity by Esperamicins, Journal of Biomolecular Structure and Dynamics, 9:2, 285-298, DOI: 10.1080/07391102.1991.10507913 To link to this article: http://dx.doi.org/10.1080/07391102.1991.10507913
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the Content.
Downloaded by [Purdue University] at 11:43 12 April 2015
This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions
Journal of Biomolecular Structure & Dynamics, JSSN 0739-1102 Volume 9. Issue Number 2 (1991}, ©Adenine Press (1991).
Determination of DNA Cleavage Specificity by Esperamicins Min Lu 1, Qiu Guo 1, Bala Krishnan2 , J erzy Golik2 , Ira E. Rosenberg2 , Terrence W. Doyle 2 and Neville R. Kallenbach 1 Downloaded by [Purdue University] at 11:43 12 April 2015
1
Department of Chemistry New York University New York, New York 10003 2
Bristol-Myers Squibb Company Pharmaceutical Research Institute 5 Research Parkway P.O. Box 5100 Wallingford, Connecticut 06492 Abstract The esperamicins are members of a class of potent antitumor antibiotics that contain strained diacetylenic ring sytems capable of forming DNA -cleaving diradicals upon reaction with thiols. Here we show that the diacetylenic ring core itself determines the sequence specificity for scission of duplex DNA): esperamicinA 1, and three products of hydrolysis of the glycon, esperamicins C. D. and E, are found to retain a common sequence preference. The sugar residues exert a strong influence on the cleavage efficiency, presumably by interacting nonspecifically with DNA The presence of a branch in the DNA is found locally to inhibit scission by esperamicins, and this effect is shown to be due to the core also.
Introduction
The esperamicins (Figure 1) are natural products of the fungus Actinomadura verrucosospora (1) and are among the most potent antibiotic agents known (2). The structure of esperamicin A 1 ( esp A 1) has been determined (3,4) and consists of a diacetylenic ring system attached to four sugar residues and an aromatic ring. The proposed mechanism of action of esp A 1 involves binding of the strained conjugated enediyne ring in the minor groove of DNA, leading to cleavage of the duplex when this ring undergoes an intramolecular rearrangement to form a phenylene diradical triggered by a reduction of the trisulfide group (4). In vivo, esp A 1 shows activity in a prophage induction assay at exceptionally low concentrations-picograms per mi.and is biologically active at concentrations far below the adriamycins (2,5). In vitro, esp A 1 exhibits a sequence dependent cleavage pattern in duplex DNA (5,6). Esp A 1 and the related compounds esp C (lacking 2-deoxy-L-fucose and the anthranilate ring) and esp D (lacking the thiomethyl hexopyranose in addition), have a preference for
285
Lu eta/.
286
CH 3 ~0CH3 I
~ :-...
OCH, NHcoLcH 2
0
:,t!-7 Ll.o . ~ HO. , -
SSSCH
Downloaded by [Purdue University] at 11:43 12 April 2015
~
, CHl
O
OH
NH
Hl
OCH 3
SSSCH 3 HO
0
CH10CONH
~
H3 NH..
-~
OH
H 3
~CH3
