Orthogonally positioned diamino pyrrole- and imidazole-containing polyamides: Synthesis of 1-(3-substituted-propyl)-4-nitropyrrole-2-carboxylic acid and 1-(3-Chloropropyl)-4-nitroimidazole-2-carboxylic Acid

Article abstract of DOI:10.1080/00397911.2013.839795

Pyrrole- and imidazole-containing polyamides can be tailored to recognize the DNA 6-8 base pair sequence. We found that adding a second amino group via the N1-position of pyrrole or imidazole in polyamides could enhance their DNA binding affinity and wate

Full text of DOI:10.1080/00397911.2013.839795

This article was downloaded by: [University of Lethbridge]
On: 19 August 2014, At: 22:08
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Orthogonally Positioned Diamino Pyrrole-
and Imidazole-Containing Polyamides:
Synthesis of 1-(3-Substituted-propyl)-4-
nitropyrrole-2-carboxylic Acid and 1-
(3-Chloropropyl)-4-nitroimidazole-2-
carboxylic Acid
Vijay Satam a , Pravin Patil a , Balaji Babu b , Toni Rice a , Alexander
Porte a , Shannon Alger a , Matthias Zeller b & Moses Lee a
a Department of Chemistry , Hope College , Holland , Michigan , USA
b Department of Chemistry , Youngstown State University ,
Youngstown , Ohio , USA
Accepted author version posted online: 08 Nov 2013.Published
online: 24 Feb 2014.
To cite this article: Vijay Satam , Pravin Patil , Balaji Babu , Toni Rice , Alexander Porte ,
Shannon Alger , Matthias Zeller & Moses Lee (2014) Orthogonally Positioned Diamino Pyrrole- and
Imidazole-Containing Polyamides: Synthesis of 1-(3-Substituted-propyl)-4-nitropyrrole-2-carboxylic
Acid and 1-(3-Chloropropyl)-4-nitroimidazole-2-carboxylic Acid, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:7, 968-975, DOI:
10.1080/00397911.2013.839795
To link to this article: http://dx.doi.org/10.1080/00397911.2013.839795
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.
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

Synthetic Communications1, 44: 968–975, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.839795
ORTHOGONALLY POSITIONED DIAMINO PYRROLE-
AND IMIDAZOLE-CONTAINING POLYAMIDES:
SYNTHESIS OF 1-(3-SUBSTITUTED-PROPYL)-4-
NITROPYRROLE-2-CARBOXYLIC ACID AND
1-(3-CHLOROPROPYL)-4-NITROIMIDAZOLE-2-
CARBOXYLIC ACID
Vijay Satam,1 Pravin Patil,1 Balaji Babu,2 Toni Rice,1
Alexander Porte,1 Shannon Alger,1 Matthias Zeller,2 and
Moses Lee1
1Department of Chemistry, Hope College, Holland, Michigan, USA
2Department of Chemistry, Youngstown State University, Youngstown, Ohio,
USA
GRAPHICAL ABSTRACT
Abstract Pyrrole- and imidazole-containing polyamides can be tailored to recognize the
DNA 6–8 base pair sequence. We found that adding a second amino group via the
N1-position of pyrrole or imidazole in polyamides could enhance their DNA binding affinity
and water solubility while retaining sequence specificity. Synthesis of the key 1-substituted-
4-nitropyrrole (and imidazole)-2-carboxylic acid building blocks are described.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Diamino polyamides; DNA binding; imidazole; pyrrole; sequence specificity
Received August 7, 2013.
Address correspondence to Moses Lee, Department of Chemistry, Hope College, Holland,
MI 49423, USA. E-mail: lee@hope.edu
968

1-SUBSTITUTED PYRROLES AND IMIDAZOLES
969
INTRODUCTION
Many human diseases, including cancer, are caused by aberrant gene
expression.[1] The transcription factors responsible for the growth and metastatic
behavior of human cancers can be regulated by cell-permeable small molecules that
disrupt transcription factor–DNA interactions that could stop aberrant gene
expression pathways.[2] Pyrrole (P)-imidazole (I) polyamides (PAs) are analogs of
distamycin (1, Fig. 1) that bind in the minor groove of DNA and they are capable
of regulating the expression of specific genes.[3] PAs are also shown to control cancer
growth in vivo.[4] The established pairing rules (I=P binds G=C and P=I binds C=G,
P=P binds either to A=T or T=A,[5] and I=I binds T=G mismatched base pairs[6]) have
enabled researchers to design and synthesize the P- and I-PAs to target virtually any
DNA 6–8 base-pair sequence. Recently, our group has augmented the usefulness of
PAs by reporting a new class of compounds called Hx-amides.[7] These are modified
PAs that contain a fluorescent 4-methoxyphenylbenzimidazole or Hx moiety, and
they bind in the minor groove with a similar mechanism as PAs. A stacked Hx motif
behaves as two contiguous pyrrole units; thus, a stacked Hx=PP unit recognizes two
A=T base pairs, and a stacked Hx=II unit recognizes CC=GG.[7] In addition to the
ability to track Hx-amides in cells by fluorescence, Hx-amides have enhanced
binding affinity over their N-formamido PA counterparts.[7]
Despite these advances, major challenges still limit the PA field. These include
the need to increase the water solubility of PAs and their penetration into cells and
Figure 1. Structures of distamycin (1) as a hydrochloride salt, f-IPI (2), diamino f-IPI (3), diamino f-IPI
(4), diamino Ph-IPI (5) [f ¼ formamido, Ph ¼ benzamido, P or I ¼ site of 1-(3-aminoalkyl) moiety], f-IPP
(6), f-PIP (7), f-P(CN)IP (8), f-PPP (9), and f-PP(alkyne)P (10).

970
V. SATAM ET AL.
localization in the nucleus. Instead of focusing on larger, linked PAs, such as
hairpins,[8] H-pins,[9] and cyclic PAs,[10] our group has focused on simpler PAs, such
as tri- and tetraamides.[11] To overcome some of these challenges, our group has
reported novel N1-modified PAs that include a second amino functionality. The
basis for this design are as follows. First, N1-modified PAs are relatively underex-
plored.[12] Second, the second amino group can be protonated, thereby making the
diamino PAs more water soluble than their respective monoamino counterparts.
The second positively charged ammonium group could also enhance the electrostatic
attraction between the PAs and the negatively charged phosphodiester backbone on
DNA. This would enhance the binding affinity. Third, modification of N1 does not
increase the molar mass and size of the PAs in any significant way, thereby giving the
molecules a better chance of diffusing into cells and concentrating in the nucleus.
Accordingly, our group has reported the synthesis and DNA binding properties
of a group of diamino PAs as shown in Fig. 1. Analogs f-IPI (or PA 2),[13] diamino
PAs f-IPI (3), f-IPI (4), and Ph-IPI (5) bind strongly to their cognate sequence
50-ACGCGT-30, a biological relevant site.[14] The latter three compounds have com-
parable sequence specificity as PA 2 and they have improved solubility in water. PAs 3
and 5 have superior binding affinity to their cognate sequence than their respective
monoamino counterparts, with PA 4 showing comparable binding affinity to PA 2.
A similar water-solubility advantage was observed for PAs 6, 7, and 9 compared to
their respective monoamino counterparts[14] yet they gave similar sequence specificity
and either stronger or comparable binding affinity to their respective monoamino
PAs. As part of our studies, we have also synthesized PAs 8 and 10, which contained
a 3-cyanoalkyl- or 1-(4-pentynyl) pyrrole group,[15] respectively. Clearly, the
N1-position of pyrrole and imidazole offers an opportunity for designing newer
generations of PAs and Hx-amides. Even though several 1-alkylaminopyrrole PAs
have been reported,[12] and only two 1-alkylaminoimidazole PAs have been described
by us,[12,14] we felt the approach reported herein, which uses 1-substituted-4-nitropyr-
role-(and imidazole)-2-carboxylic acid building blocks, is more efficient than the
strategies previously reported. First, the number of reaction steps to synthesize the
PAs isminimal. Second, the nitro-carboxylic acid structures of 11a–c and 12 make
them highly amenable to the Schotten–Baumann reaction, amine–acid chloride
coupling approach, which offers advantages over other approaches in terms of
chemical yields, costs, and purity.[16]
Accordingly, we hereby report the synthesis of novel 1-(3-modifiedpropyl)-
4-nitro-pyrrole-2-carboxylic acids 11a–c and 1-(3-chloropropyl)-4-nitroimidazole-2-
carboxylic acid 12. Upon incorporation of the chloroalkyl moiety in the PAs, the
chlorine atom could be transformed into the amine either by direct displacement
with ammonia in methanol[14,17] or in a stepwise manner (sodium azide, DMF,
and heat; followed by catalytic hydrogenation).[14]
RESULTS AND DISCUSSION
The synthesis of 1-(3-substitutedpropyl)-4-nitropyrrole-2-carboxylic acids
11a–c is shown in Scheme 1. It involves an SN2 reaction of ethyl 4-nitro-1H-pyrrole-2-
carboxylate 13[18] with 1-bromo-3-chloropropane in the presence of anhydrous
potassium carbonate and potassium iodide and in dry acetone under reflux. The

1-SUBSTITUTED PYRROLES AND IMIDAZOLES
971
Scheme 1. (a) 1-Bromo-3-chloropropane, K2CO3, KI, dry acetone, reflux, 16 h for 14a. (b) 4-Bromobutyr-
onitrile, K2CO3, KI, dry acetone, reflux, overnight for 14b. (c) 5-iodo-1-pentyne, K2CO3, dry acetone,
reflux, overnight for 14c. (d) (i) 4.0 M NaOH, 15 min, reflux, (ii) 6.0 M HCl.
reaction yielded ethyl 1-(3-chloropropyl)-4-nitropyrrole-2-carboxylate 14a as a
yellow solid in 85% yield. Hydrolysis of the ester moiety in compound 14a in aqueous
sodium hydroxide solution under reflux conditions afforded the desired 1-(3-
chloropropyl)-4-nitropyrrole-2-carboxylic acid 11a in 86% yield. The conditions were
optimized to reduce the amount of dimer formation due to substitution of two
pyrrole-NH moieties of 13 at both ends of 1-bromo-3-chloropropane during the
SN2 reaction and over hydrolysis of the alkyl chloride moiety in the second
step. The preparation of acids 11b and c were achieved using the same process
except 4-bromobutyronitrile=potassium iodide and 5-iodo-1-pentyne were used,
respectively.
Our initial synthesis of 1-(3-chloropropyl)-4-nitroimidazole-2-carboxylic acid
12 utilized an approach we had reported earlier.[12a] That involved alkylation at
N1 of imidazole with 1-bromo-3-chloropropane, followed by installation of the
ethoxycarbonyl group at C2. These transformations were successful but subsequent
attempts to introduce a nitro group at the C4 position using a wide range of
methods[12,19] failed to give more than a tiny amount of the product 18. A fruitful
synthesis of acid 12 is given in Scheme 2. It required the synthesis of ethyl
4-nitro-1H-imidazole-2-carboxylate 17,[20] using a similar strategy for the synthesis
of acids 11a–c. Imidazole ester 16 was synthesized by reaction of 1-benzylimidazole
with ethyl chloroformate to give ester 15 in 50% yield.[20] Removal of the benzyl
group by catalytic hydrogenation afforded ester 16 in quantitative yield, which upon
nitration using fuming nitric acid and concentrated sulfuric acid gave the desired
ester 17 in 86% yield.[20] Ester 17 was reacted with 1-bromo-3-chloropropane in
the presence of anhydrous potassium carbonate and potassium iodide in dry
dimethylformamide at 60–65 ꢀC to yield the desired N1-(3-chloropropyl) product
18 in 74% yield, with minor admixture of the 3-bromopropyl derivative. Because
of the mesomeric nature of imidazole, we needed to ascertain the exact position of
the chloroalkyl group on the imidazole unit. That was unambiguously accomplished
through a single-crystal X-ray diffraction study on ester 18, and the structure is

972
V. SATAM ET AL.
Scheme 2. (a) Ethylchloroformate, dry Et3N, dry MeCN, ꢁ20 ꢀC for 15 min, rt for 16 h. (b) H2, 10% Pd-C,
cold ethanol, 16 h, rt. (c) Fuming HNO3, conc. H2SO4, 60–65 ꢀC for 3 h. (d) 1-Bromo-3-chloropropane,
K2CO3, KI, dry DMF, 60–65 ꢀC, 2.5 h. (e) (i) LiOH, THF:H2O (1:1), rt, overnight, (ii) 6.0 M HCl.
shown in Fig. 2. Selective hydrolysis of ester 18 was achieved using lithium hydroxide
in tetrahydrofuran (THF) and water at room temperature to furnish the desired
1-(3-chloropropyl)-4-nitroimidazole-2-carboxylic acid 12 in 88% yield.
In conclusion, modification of the N1-position of pyrrole and imidazole offers
an opportunity for the design and synthesis of newer generations of DNA sequence–
specific binding PAs. Reporting the synthesis of the key 1-substituted-4-nitropyrrole
(and imidazole)-2-carboxylic acidsynthonswill enable further developmentinthe field
of polyamide minor groove binding ligands.
Figure 2. X-ray crystal structure of ethyl 1-(3-chloropropyl)-4-nitro-1H-imidazole-2-carboxylate 18 (50%
thermal ellipsoid probability level). Minor disorder of Cl and Br omitted for clarity. The X-ray structural
information has been deposited in the Cambridge Crystallographic Data Centre (CCDC 922340) and can
be obtained via www.ccdc.cam.ac.uk/data_request/cif.

1-SUBSTITUTED PYRROLES AND IMIDAZOLES
973
EXPERIMENTAL
The general experimental information as well as the syntheses and characteriza-
tion of esters 14b, 14c, and 18 as well as acids 11b, 11c, and 12 are given in the
supplementary materials section. Representative syntheses of ester 14a and acid
11a are given here.
Ethyl 1-(3-Chloropropyl)-4-nitropyrrole-2-carboxylate 14a
A solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate 13[18] (2.0 g, 10.8 mmol),
anhydrous K2CO3 (4.5 g, 32.6 mmol), and KI (1.98 g, 11.95 mmol) in dry acetone
(25 mL) was refluxed for 30 min. 1-Bromo-3-chloropropane (1.0 mL, 11.95 mmol)
was added to the reaction mixture. The reaction mixture was refluxed for 16 h, cooled
to room temperature, and filtered. The filtrate was concentrated under reduced press-
ure. The residue obtained was dissolved in CHCl3 (20 mL) and washed with water
(10 mL ꢂ 2). The organic layer was dried over anhydrous Na2SO4 and concentrated
to obtain the crude compound, which was purified by column chromatography using
silica gel and CHCl3 as the eluent. Ester 14a was isolated as a yellow solid (2.41 g,
85%). Mp 74–76 ꢀC, Rf 0.71 (2% MeOH=CHCl3). IR (KBr): 3300–2500 br, 3113,
2960, 1676, 1541, 1511, 1480, 1414, 1368, 1308, 1282, 1254, 1216, 1191, 1155, 1106,
1089, 977, 914, 863, 818, 749, 721, 658.1H NMR (CDCl3): 7.70 (s, 1H); 7.46 (s,
1H); 4.55 (t, J ¼ 6.6, 2H); 4.32 (q, J ¼ 7.0, 2H); 3.51 (t, J ¼ 6.6, 2H); 2.29 (quint,
J ¼ 6.6, 2H); 1.37 (t, J ¼ 7.0, 3H). 13C NMR (CDCl3): 159.97; 135.56; 127.19;
122.40; 113.37; 61.09; 47.45; 41.16; 33.07; 14.24. MS (EI): 260 (35Mþ, 80%), 262
(37Mþ, 25%). HR-MS (EI): 260.0567 (35Mþ, C10H1335ClN2O4þ; calc. 260.0564).
1-(3-Chloropropyl)-4-nitropyrrole-2-carboxylic Acid 11a
Aqueous NaOH solution (4.0 M, 15mL) was added to a solution of ethyl
1-(3-chloropropyl)-4-nitropyrrole-2-carboxylate 14a (3.0 g, 11.5mmol) in MeOH
(10 mL). The reaction mixture was refluxed for 15min. The solvent was removed under
reduced pressure. Water (10mL) was added to the reaction mixture. The reaction
mixture was cooled to 0–5 ꢀC and acidified using 6.0 M HCl until pH was 1. The sepa-
rated white solid was filtered and dried to obtain acid 11a (2.29 g, 86%). Mp 190–194 ꢀC.
Rf 0.16 (5% MeOH=CHCl3). IR (KBr): 3139, 3114, 2970, 2845, 1675, 1560, 1541, 1480,
1
1447, 1414, 1368, 1308, 1282, 1254, 1191, 1154, 1106, 1089, 914, 773, 658. H NMR
(CDCl3): 7.77 (d, J ¼ 1.2, 1H); 7.61 (d, J ¼ 1.2, 1H); 4.57 (t, J ¼ 6.2, 2H); 3.52
(t, J ¼ 6.2, 2H); 2.31 (quint, J ¼ 6.2, 2H). 13C NMR (CDCl3): 163.63; 135.87; 128.32;
120.89; 115.47; 47.61; 40.98; 32.97. MS (EI): 232 (35Mþ, 50%), 234 (37Mþ, 18%).
HR-MS (EI): 232.0247 (35Mþ, C8H935ClN2O4þ; calc. 232.0251).
FUNDING
The authors thank the National Science Foundation (CHE 0809162, CHE0922623)
for their support. The x-ray diffractometer at Youngstown State University was
funded by NSF Grant 0087210, Ohio Board of Regents Grant CAP-491, and
Youngstown State University.

974
V. SATAM ET AL.
SUPPLEMENTARY INFORMATION
Full experimental detail for esters 14b, 14c, and 18 and acids 11b, 11c, and 12;
1
and H and 13C NMR spectra of esters 14a–c and 18 as well as acids 11a–c and 12
are provided. This material can be found via the ‘‘Supplementary Content’’ section
of this article’s Web page.
REFERENCES
1. (a) Maher, B. ENCODE: The human encyclopaedia. Nature 2012, 489, 46–48; (b) Collins,
F. S.; Green, E. D.; Guttmacher, A. E.; Guyer, M. S. A vision for the future of genomics
research: A blueprint for the genomic era. Nature 2003, 422, 835–847.
2. Cai, X.; Gray Jr., P. J.; Von Hoff, D. D. DNA minor groove binders: Back in the groove.
Cancer Treat. Rev. 2009, 35, 437–450.
3. (a) Gottesfeld, J. M. Small molecules affecting transcription in Friedreich ataxia. Pharma-
col. Ther. 2007, 116, 236–248; (b) Dervan, P. B.; Poulin-Kerstien, A. T.; Fechter, E. J.;
Edelson, B. S. Regulation of gene expression by synthetic DNA-binding ligands. Top.
Curr. Chem. 2005, 253, 1–31; (c) Hochhauser, D.; Kotecha, M.; O’Hare, C.; Morris,
P. J.; Hartley, J. M.; Taherbhai, Z.; Harris, D.; Forni, C.; Mantovani, R.; Lee, M.;
Hartley, J. A. Modulation of topoisomerase IIa expression by a DNA sequence-specific
polyamide. Mol. Cancer Ther. 2007, 6, 346–354.
4. (a) Chou, C. J.; Farkas, M. E.; Tsai, S. M.; Alvarez, D.; Dervan, P. B.; Gottesfeld, J. M.
Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous
leukemia. Mol. Cancer Ther. 2008, 7, 769–778; (b) Raskatov, J. A.; Nickols, N. G.;
Hargrove, A. E.; Marinov, G. K.; Wold, B.; Dervan, P. B. Gene expression changes in
a tumor xenograft by a pyrrole-imidazole polyamide. Proc. Natl. Acad. Sci. USA 2012,
109, 16041–16045; (c) Minoshima, M.; Chou, J. C.; Lefebvre, S.; Bando, T.; Shinohara,
K.; Gottesfeld, J. M.; Sugiyama, H. Potent activity against K562 cells by polyamide-
seco-CBI conjugates targeting histone H4 genes. Bioorg. Med. Chem. 2010, 18, 168–174.
5. Dervan, P. B.; Edeleson, B. S. Recognition of the DNA minor groove by pyrrole-
imidazole polyamides. Curr. Opin. Struc. Biol. 2003, 13, 284–299.
6. (a) Lacy, E. R.; Cox, K. K.; Wilson, W. D.; Lee, M. Recognition of TꢃG mismatched base
pairs in DNA by ed imidazole-containing polyamides: Surface plasmon resonance and
circular dichroism studies. Nucleic Acids Res. 2002, 30, 1834–1841; (b) Rucker, V. C.;
Foister, S.; Melander, C.; Dervan, P. B. Sequence-specific fluorescence detection of double
strand DNA. J. Am. Chem. Soc. 2003, 125, 1195–1198.
7. Satam, V.; Patil, P.; Babu, B.; Gregory, M.; Bowerman, M.; Savagian, M.; Lee, M.; Tzou,
S.; Olson, K.; Liu, Y.; Ramos, J.; Wilson, W. D.; Bingham, J. P.; Kiakos, K.; Hartley,
J. A.; Lee, M. Design, synthesis, and DNA binding characteristics of a group of orthogon-
ally positioned diamino, N-formamido, pyrrole-, and imidazole-containing polyamides.
Bioorg. Med. Chem. Lett. 2013, 23, 1699–1702.
8. (a) Dervan, P. B.; Edelson, B. S. Recognition of the DNA minor groove by pyrrole-
imidazole polyamides. Curr. Opin. Struc. Biol. 2003, 13, 284; (b) Murty, M. S. R. C.;
Sugiyama, H. Biology of N-methylpyrrole-N-methylimidazole hairpin polyamide. Biol.
Pharm. Bull. 2004, 27, 468–474.
9. (a) Chen, Y.-H.; Lown, J. W. A new DNA minor groove binding motif cross-linked
lexitropsins. J. Am. Chem. Soc. 1994, 116, 6995–7005; (b) Greenberg, W. A.; Baird, E.
E.; Dervan, P. B. A comparison of H-Pin and hairpin polyamide motifs for the recog-
nition of the minor groove of DNA. Chem. Eur. J. 1998, 4, 796–805; (c) Mackay, H.;
Brown, T.; Uthe, P. B.; Westrate, L.; Sielaff, A.; Jones, J.; Lajiness, J. P.; Kluza, J.;

1-SUBSTITUTED PYRROLES AND IMIDAZOLES
975
O’Hare, C.; Nguyen, B.; Davis, Z.; Bruce, C.; Wilson, W. D.; Hartley, J. A.; Lee, M.
Sequence-specific and high affinity recognition of 50-ACGCGT-30 by rationally designed
pyrrole-imidazole H-pin polyamides: Thermodynamic and structural studies. Bioorg.
Med. Chem. 2008, 16, 9145–9153.
10. Li, B. C.; Montgomery, D. C.; Puckett, J. W.; Dervan, P. B. Synthesis of cyclic Py-Im
polyamide libraries. J. Org. Chem. 2013, 78, 124–133.
11. Lacy, E. R.; Le, N. M.; Price, C. A.; Lee, M.; Wilson, D. W. Influence of a terminal
formamido group on the sequence recognition of DNA by polyamides. J. Am. Chem.
Soc. 2002, 124, 2153–2163.
12. (a) Lee, M.; Preti, C. S.; Vinson, E.; Wyatt, M. D.; Hartley, J. A. GC sequence-specific
recognition by an N-formamido, C-terminus-modified, and imidazole-containing
analogue of netropsin. J. Med. Chem. 1994, 37, 4073–4075; (b) Satz, A. L.; Bruice, T.
C. Recognition in the minor groove of double-stranded DNA by microgonotropens.
Acc. Chem. Res. 2002, 35, 86–95; (c) Moretti, R.; Donato, L. J.; Brezinski, M. L.; Stafford,
R. L.; Hoff, H.; Thorson, J. S.; Dervan, P. B.; Ansari, A. Z. Targeted chemical wedges
reveal the role of allosteric DNA modulation in protein–DNA assembly. ACS Chem. Biol.
2008, 3, 220–229; (d) Carlson, C. D.; Warren, C. L.; Hauschild, K. E.; Ozers, M. S.; Qadir,
N.; Bhimsaria, D.; Lee, Y.; Cerrina, F.; Ansari, A. Z. Specificity landscapes of DNA
binding molecules elucidate biological function. Proc. Natl. Acad. Sci. USA 2010, 107,
4544–4549; (e) Fujimoto, J.; Bando, T.; Minoshima, M.; Kashiwazaki, G.; Nishijima,
S.; Shinohara, K.; Sugiyama, H. Perylene-conjugated pyrrole polyamide as a sequence-
specific fluorescent probe. Bioorg. Med. Chem. 2008, 16, 9741–9744.
13. Buchmueller, K. L.; Bailey, S. L.; Matthews, D. A.; Taherbhai, Z. T.; Register, J. K.;
Davis, Z. S.; Bruce, C. D.; O’Hare, C.; Hartley, J. A.; Lee, M. Physical and structural
basis for the strong interactions of the–ImPy-central pairing motif in the polyamide
f-ImPyIm. Biochemisry 2006, 45, 13551–13565.
14. Chavda, S.; Babu, B.; Patil, P.; Plaunt, A.; Ferguson, A.; Lee, M.; Tzou, S.; Sjoholm, R.;
Rice, T.; Mackay, H.; Ramos, J.; Wang, S.; Lin, S.; Kiakos, K.; Wilson, W. D.; Hartley, J.
A.; Lee M. Design, synthesis, and DNA binding characteristics of a group of orthogonally
positioned diamino, N-formamido, pyrrole-, and imidazole-containing polyamides.
Bioorg. Med. Chem. 2013, 21, 3907–3918.
15. Babu, B.; Brien, K. A.; Satam, V.; Plaunt, A.; Pressler, M.; Shen, H.; Alger, S.; Ogilvie,
R.; Sjoholm, R.; Tzou, S.; Sweat, O.; Rice, T.; Mackay, H.; Seymour, M. D.; Lee, M.
Synthesis and DNA-binding properties of 1,2,3-triazole-linked H-pin pyrrole- and
imidazole-containing polyamides formed by the Huisgen reaction. Heterocycl. Commun.
2012, 18, 79–85.
16. Lown, J. W.; Krowicki, K. Efficient total syntheses of the oligopeptide antibiotics netrop-
sin and distamycin. J. Org. Chem. 1985, 50, 3774–3779.
17. Ramos, J. P.; Babu, B.; Chavda, S.; Liu, Y.; Plaunt, A.; Ferguson, A.; Savagian, M.; Lee,
M.; Tzou, S.; Lin, S.; Kiakos, K.; Wang, S.; Lee, M.; Hartley, J. A.; Wilson, W. D.
Affinity and kinetic modulation of polyamide-DNA interactions by N-modification of
the heterocycles. Biopolymers 2013, 99, 497–507.
18. (a) Hale, W. J.; Hoyt, W. H. The constitution of the nitro-a-carbopyrrolic acids. J. Am.
Chem. Soc. 1915, 37, 2538–2552; (b) Fanta, P. E. Sodium nitromalonaldehyde monohy-
drate. Org. Synth. Collect. Vol. 1963, 4, 844.
19. Krowicki, K.; Lown, J. W. Synthesis of novel imidazole-containing DNA minor groove
binding oligopeptides related to the antiviral antibiotic netropsin. J. Org. Chem. 1987,
52, 3493–3501.
20. Zimmerman, H.; Brueckener, D.; Henninger, K.; Rosentreter, U.; Hendrix, M.;
Keldenich, J.; Lang, D.; Radtke, M.; Paulsen, D.; Kern, A. Heterocyclyamide-substituted
imidazoles. US Patent 2008=0176859 A1, July 24, 2008.