A two-step synthesis of medicinally-important 1,8-naphthalimide peptidyls by solid phase organic synthesis

Article abstract of DOI:10.1016/j.tetlet.2012.08.007

A new approach for a short synthesis of novel medicinally-important mono-, bis- and tris-1,8-naphthalimide peptidyl derivatives is described. The method generates efficiently 1,8-naphthalimides with variable spacer lengths and charged, polar or hydrophobi

Full text of DOI:10.1016/j.tetlet.2012.08.007

Tetrahedron Letters 53 (2012) 5611–5615
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A two-step synthesis of medicinally-important 1,8-naphthalimide peptidyls
by solid phase organic synthesis
⇑
Tamara Brider, Gary Gellerman
Department of Biological Chemistry, Ariel University Center of Samaria, PO Box 3, Ariel 40700, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach for a short synthesis of novel medicinally-important mono-, bis- and tris-1,8-naphthal-
imide peptidyl derivatives is described. The method generates efficiently 1,8-naphthalimides with vari-
able spacer lengths and charged, polar or hydrophobic residues at desired positions, which can
increase binding affinity, conformational stability, intracellular transport and/or biological activity. The
synthetic routes reported in this work are both general and applicable, and significantly expand the scope
of potential 1,8-naphthalimide anticancer candidates.
Received 27 April 2012
Revised 18 July 2012
Accepted 2 August 2012
Available online 19 August 2012
Keywords:
Solid-phase organic synthesis (SPOS)
Ó 2012 Elsevier Ltd. All rights reserved.
1
,8-Naphthalimide peptidyls
Bi- and tri-nuclei intercalators
Fmoc chemistry
Valuable anticancer 1,8-naphthalimide derivatives are an
important class of drug candidates characterized by high cytotoxic
activity towards a variety of murine and human tumour cells. 1,8-
have reported the synthesis of mono- and bis-1,8-naphthalimide
DNA binding molecules. The bisintercalators, based on 1,8-naph-
thalimide moieties, exhibited both higher affinity and selectivity
1
8
9
Naphthalimides are DNA-intercalating agents with high antitu-
mour activity, which bind to DNA by insertion between the base
in binding compared to their mono counterparts. The improved
bioactivity of the covalent dimers of 1,8-naphthalimides can be
attributed to the increased local concentration of the active moiety.
The traditional solution syntheses of 1,8-naphthalimide ana-
logues involve several steps and harsh reaction conditions, requir-
ing laborious purification of intermediates and final compounds.10
Solid phase organic synthesis (SPOS) is a fast and efficient tech-
nique that has become a productive approach in the discovery of
bioactive hits.
2
pairs of the double helix. The main driving forces for their DNA
binding ability are charge transfer interactions and stacking be-
tween the base pairs. Nowadays, it is accepted that their antitu-
mour activity is closely related to their ability to inhibit human
DNA topo II. Moreover, bis-1,8-naphthalimide analogues kill
eukaryotic cells by stabilizing the cleavage complex of topo II with
3
DNA. The development of naphthalimide class of compounds as
anticancer agents has resulted in a series of drug candidates
including mitonafide and amonafide as shown in Figure 1, which
have been tested in clinical trials. Mitonafide has been studied in
phase I and phase II clinical trials in which it exhibited good activ-
Therefore, we decided to develop a short and efficient SPOS
method for the rapid generation of new 1,8-naphthalimide core
based compounds. In the context of exploring the rapid derivatiza-
tion of 1,8-naphthalimide scaffold we found that assembly of a 1,8-
naphthalimide core on a solid support was a useful methodology,
generating relatively diverse and pure products without any puri-
fication step, and, therefore, enhancing greatly their availability for
examination in biological systems.
4
ity against solid tumours. Unfortunately, mitonafide was found to
possess central nervous system toxicity. Two other compounds of
the bis-naphthalimide series, elinafide5 and bisnafide6 are under-
going clinical trials.
Evidence has been presented showing that intercalating re-
agents are capable of targeting DNA without inducing DNA damage
and additional mutations in cellular genes. This phenomenon re-
duces side effects and the risk of developing secondary cancers,
thereby supporting the discovery of nongenotoxic DNA-binding
small molecules as anticancer therapies.7 Several research groups
This Letter describes the two-step solid phase synthesis of novel
mono- and bis-1,8-naphthalimide peptidyl derivatives using the
Fmoc chemistry compatible protocol developed by us. The syn-
thetic strategy generates rapidly 1,8-naphthalimides with variable
spacer lengths and charged, polar or hydrophobic residues at de-
sired positions, which can lead to increased binding affinity, con-
formational stability, intracellular transport and biological
activity. The results described here should permit advanced conju-
gation of 1,8-naphthalimides with biomolecules, such as peptides,
antibodies, and proteins, modulating their activity, bioavailability
and applicability.
⇑
Corresponding author. Tel.: +972 3 937 1442.
E-mail addresses: btamara81@yahoo.com (T. Brider),
G. Gellerman).
garyg@ariel.ac.il
(
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.007

5
612
T. Brider, G. Gellerman / Tetrahedron Letters 53 (2012) 5611–5615
N
O
N
O
O
O
N
N
N
H
N
H
O
O
O
NH2
amonafide
elinafide
N
O
O
N
O
H
N
N
NO2
O
2
N
N
H
N
O
O
NO
2
mitonafide
bisnafide
Figure 1. Examples of known potent 1,8-naphthalimide drug candidates.
Amino acid prodrugs usually impart improved pharmacological
Scheme 2). These building blocks are able to generate bis-naph-
thalimides with a variety of longer dicationic linker chains (more
than 8 atoms) where the length, rigidity and charge density on
the chain are varied. Building blocks 3a, 3d and 3e were previ-
ously used for the synthesis of 1,8-naphthalimides in solution
characteristics such as enhanced transport and higher resistance to
metabolism, exhibiting slower rates of enzymatic activation for sus-
1
2
14
15
pended release of a drug. Based on these facts we first attempted
the assembly of a 1,8-naphthalimide peptidyl derivative with sev-
eral representative amino acids as possible minor and major groove
chemistry, while mesylates 3b,c were prepared by us from their
1
3
11,16
contact spacers. Initially, we attempted the imidation of 1,8-naph-
thalic anhydride 2b with preloaded Fmoc-( )Gln(Trt)-OH, Fmoc-
)Ser(t-Bu)-OH, Fmoc-( )Lys(Boc)-OH and Fmoc-( )Arg(Pbf)-OH on
Rink Amide MBHA. Double imidation of 1,8-naphthalic anhydride
b to bifunctional Fmoc-( )Lys(Fmoc)-OH on Cl-Trt polystyrene
parent 1,8-naphthalimide alcohols.
In addition, we aimed to
L
compare the efficiency of 1,8-naphthalimide alkyl mesylates 3b,c
versus alkyl bromides 3d,e in nucleophilic substitution of poly-
mer-supported diamino spacers to determine the optimized linker
construction method.
(
L
L
L
2
L
resin after Fmoc deprotection was also performed as shown in
Scheme 1. The purpose of this experiment was to examine the com-
patibility of both resins to the SPOS of 1,8-naphthalimide peptidyls.
Thus, after applying the standard Fmoc chemistry protocol for load-
ing amino acids (PyBoP, NMM in DMF for Rink amide) and subse-
quent Fmoc removal, 2b was successfully reacted (DMF, 70 °C)
As a feasibility experiment, we decided to prepare bis-1,8-naph-
thalimide 5a, which has a very similar structure to the drug candi-
dates bisnafide and elinafide (see Scheme 3). Notably, the
carboxylic acid group on 5a and other bis-1,8-naphthalimides
(see Scheme 4), released after cleavage from the Cl-Trt polystyrene
acid-sensitive resin, can act as an anchor point for conjugation
chemistry, which can improve the delivery and the pharmacoki-
netic properties of the developed bioactive candidates.
with the
after cleavage the corresponding AA-1,8-naphthalic peptidyls,
a–d in good yields and purities. When preloaded bifunctional
Fmoc-( )Lys(Fmoc)-OH on Cl-Trt polystyrene resin was used (load-
ing with NMM in CH Cl ) in the double imidation with five equiva-
lents of 2b, the corresponding bis-Lys-(1,8-naphthalic) 1e was
a-amino group of the preloaded amino acids, affording,
1
Thus, representative diFmoc protected acid L-DAB was loaded
on the resin using the standard method. After Fmoc release [(20%
L
2
2
piperidine/DMF (2 Â 20 min)], the mesylate 3b was reacted with
2
the preloaded and deprotected L-DAB in DMF in the presence of
1
9
successfully obtained, confirming the compatibility of both resins
in SPOS assembly of 1,8-naphthalimide peptidyls. Analogously, a
N-methylmorpholine (NMM) at 70 °C for 18 h. After acidic cleav-
age (5% TFA/CH Cl , 30 min, rt) the desired bis-1,8-naphthalimide
2
2
large variety of commercially available
L
and
D
diamino aliphatic
5a was obtained in good yield and purity.
acids can be used to synthesize rapidly bis-1,8-naphthalimides with
Encouraged by this result, we moved forward to explore linker
construction by varying the length and NH position. For this pur-
pose diFmoc protected L-Lys was chosen as a model, and after load-
ing on the Cl-Trt polystyrene resin and subsequent Fmoc release
using standard methods, it was submitted to the study (see
Scheme 4). First, bis-1,8-naphthalimide 4, which possesses a linker
with two amides along the chain, was successfully synthesized
using peptide coupling in DMF with PyBOP as the coupling reagent
1
7
variable distances between the two 1,8-naphthalimide nuclei for
structure–activity relationship (SAR). All the final compounds were
prepared in good yields and high purity regardless of the nature of
the amino acid linkers.
Published docking calculations revealed that the linker between
two naphthalimides plays a crucial role in affinity to nucleic acids,
contributing to the stability of the complex interacting with the
1
8,10b
minor groove of DNA.
Therefore, at this stage, we decided to
and a five-fold excess of building block 3a. When resin-bound L-Lys
extend our research on a solid phase assembly towards bis-1,8-
naphthalimides by applying linkage derivatization on solid support
between two 1,8-naphthalimide nuclei. In order to develop more
active DNA-binding antitumour agents, and to clarify the influence
of the aminoalkyl linker chain on their intricate modes of action, a
series of 1,8-naphthalimide building blocks were applied (see
was reacted with 2.2 equivalents of 3b,c,d,e differences in the
yields and purities of the products were observed. Apparently,
mesylates 3b and 3c upon heating at 70 °C in DMF in the presence
of NMM for 18 h gave the products in better yield and purity than
their alkyl bromide counterparts under the same conditions. When
a large excess of building blocks 3c,d,e were used, the interesting

T. Brider, G. Gellerman / Tetrahedron Letters 53 (2012) 5611–5615
5613
O2N
Fmoc(l)Gln(Trt)-OHor
Fmoc(l)Ser(tBu)-OHor
O
R
O
O
O
Fmoc(l)Lys(Boc)-OHor
Fmoc(l)Arg(Pbf)-OH,
O
2b (2.2 eq)
N
H
O N
NH2
H2N
2
H
AA(PG)
N
d then e
b then c
O
(Rink amide)
1
a R = -(CH2)4-NH2
b R = -(CH2)2-CONH2
c R = -CH2-OH
(94%, 97% purity)
(85%, 91% purity)
(93%, 94% purity)
d R = -(CH ) -NH-C(=NH)NH (87%, 88% purity)
2
3
2
O
O
O
O
O
O
N
O2N
OH
NO2
H2N
H2N
O
O
N
1. Fmoc-(l)Lys(Fmoc)-OH
a then c
2b (5 eq)
Cl
O
d then e
(
Cl-Trt)
O
O2N
1e (83%, 91% purity)
Scheme 1. Synthesis of mono and bis-(
2 2
L)AA-1,8-naphthalimide derivatives 1a–e from 2b. Reaction conditions: (a) NMM, CH Cl , 40 min, rt; (b) PyBOP, NMM, DMF, 40 min, rt;
(
2
c) 20% piperidine/DMF (2 x 20 min); (d) DMF, 70 °C; (e) TFA/H O/EDT (95:2.5:2.5).
OSO CH
2
3
(
CH )n
2
O
N
O
NH
2
-(CH
2
)n-OH
a then c
R
CO H
2
3b R = NO , n = 2
2
3
c R = NO , n = 3
2
H-β-Ala-OtBu
a then b
O
O
O
O
N
O
Br
R
NO2
2
a R = H
3
a
2
b R = NO2
O
N
O
H N
Br
2
a
R
3
3
d R = H
e R = NO
2
2 2 2 2 2
Scheme 2. Synthesis of 1,8-naphthalimide building blocks 3a–e. Reaction conditions: (a) DMF, 70 °C, 4 h; (b) TFA/CH Cl , 1:1, 4 h; (c) MeSO Cl, NMM, CH Cl , rt.
tris-1,8-naphthalimides 6a,b were obtained, after cleavage, in rea-
sonable yield and purity. Again, mesylated 3c gave better results
than analogous alkyl bromides 3d and 3e. The structure of 6b
characterized by MS and NMR spectrometry (see Supplementary
data). The purity of the synthesized compounds was determined
by HPLC (MeCN/0.1% TFA in H O).
2
(
the product of double alkylation on the less hindered side chain
In summary, we have developed a new method for the two-step
synthesis of mono-, bis- and tris-1,8-naphthalimide peptidyl deriv-
atives on solid phase. The resulting 1,8-naphthalimide peptidyls
were obtained in good yields rapidly affording novel potential
DNA intercalators with variable spacer lengths and charged, polar
amine) was confirmed by HMBC and HMQC experiments. Rapid
purification by solid phase extraction (RP-18, first washed with
water and then extracted with acetonitrile) of the cleaved crude
products was employed throughout this work. The products were

5
614
T. Brider, G. Gellerman / Tetrahedron Letters 53 (2012) 5611–5615
NO2
O
N
O
Conjugation
site
O
bisnafide
and
9
atoms,
HN
OH
two NH
3b
Fmoc-(l)DAB(Fmoc)-OH
a then b
H
2
N
O
O
elinafide
c then d
Cl
NH
O
H N
Cl-Trt
resin
O N
2
2
N
O
5a (89%, 94% purity)
Scheme 3. Synthesis of (
L
)DAB bis1,8-naphthalimide derivative 5a. Reaction conditions: (a) NMM, CH
Cl , 30 min, rt.
2
2
Cl
2
, 40 min, rt; (b) 20% piperidine/DMF (2 Â 20 min); (c) DMF, NMM,
7
0 °C,18 h; (d) 5%TFA/ CH
2
O
H
N
H
R
H
O
H
N
C-H
correlation
in 6b
O
R
CO H
2
N
O
H
H
HN
6
a R = H, from 3d (57%, 70% purity)
O
N
6
b R = NO , from 3c (84%, 91% purity)
2
from 3e (61%, 72% purity)
R
O
R
O
3
c,d,e (5 eq)
O
H
N
O
(CH )n
N
d then e
2
OH
3
b,c,d,e
Fmoc-(L)Lys(Fmoc)-OH
a then b
H N
O
d then e
2
NH
CH )n
O
Cl
(
2
Cl-Trt
resin
O
N
O
H N
2
3
c
a
R
NO2
5
5
5
b R = H, n = 3 (71%, 82% purity)
c R = NO , n = 2 (88%, 93% purity)
2
d R = NO , n = 3
2
from 3c (90%, 92% purity)
from 3e (73%, 81% purity)
O
O
H
N
H
N
N
N
NO2
O
O
O
O
O
OH
4
(85%, 96% purity)
Scheme 4. Synthesis of (
PyBOP, NMM, DMF, 40 min, rt; (d) DMF, NMM, 70 °C, 18 h; (e) 5%TFA/CH
L
)Lys bis- and tris-1,8-naphthalimide derivatives 4–6. Reaction conditions: (a) NMM, CH
Cl , 30 min, rt.
2
2
Cl , 40 min, rt; (b) 20% piperidine/DMF (2 Â 20 min); (c)
2
2

T. Brider, G. Gellerman / Tetrahedron Letters 53 (2012) 5611–5615
5615
or hydrophobic residues at desired positions. The in vitro antican-
cer activity of the synthesized compounds is under evaluation. At-
tempts to extend the building block repertoire in SPOS of 1,8-
naphthalimides and to optimize the reaction conditions in micro-
wave-assisted chemistry are in progress.
atmosphere for 20 min. MsCl (3.7 mL, 41 mmol) was added dropwise over
0 min. The mixture was stirred for 1 h at 0 °C and then at rt overnight. The
solution was cooled and cold 4 N NaOH (32 mL) was added. The organic phase
was washed with SO and
evaporated to give building blocks 3b and 3c as a yellow oils (4.73 g, 84%
yield for 3b and 4.96 g, 87% for 3c), which were used in the next steps without
1
H
2
O
(2 Â 50 mL), dried over anhydrous Na
2
4
further purification. Data for 3c: yellow oil, IR (KBr): 1710, 1695, 1520, 1450,
À1
1
270 cm , HRMS (CI, m/z) calcd for C16
H
15
N
2
O
7
S (MH+) 379.052, found
): 9.12 (s, 1H), 8.98 (s, 1H),
.64 (d, J = 7.8 Hz, 1H), 8.51 (d, J = 7.8 Hz, 1H), 8.07 (t, J = 7.8 Hz, 1H), 4.32 (t,
379.175; R
f 3
= 0.75 (EtOAc/PE, 1:1); 1H NMR (CDCl
Acknowledgements
8
J = 5.0 Hz, 2H), 4.06 (t, J = 5.0 Hz, 2H), 2.73 (s, 3H), 1.86–1.81 (m, 2H).
2. (a) Deshmukh, M.; Chao, P.; Kutscher, H. L.; Sinko, P. J. J. Med. Chem. 2010, 53,
1038–1047; (b) Landowski, C. P.; Song, X.; Amidon, G. L. Pharm. Res. 2005, 22,
The authors thank Dr. Alexandra Massarwa from the Ben-Gurion
University for the HRMS measurements of all new compounds and
Dr. Hugo Gotlib from the Bar Ilan University for 2D NMR experi-
ments and helpful advice.
1
1
1510–1518.
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Carlson, C.; Beal, P. A. Org. Lett. 2002, 2, 1465–1468; (c) Sebestik, J.; Matejka, P.;
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Supplementary data
14. David-Cordonnier, M. H.; Hildebrand, M. P.; Baldeyrou, Pindur U. Eur. J. Med.
Chem. 2007, 42, 752–771.
Supplementary data associated with this article can be found, in
the onlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.08.007.
15. (a) Tian, Z.-Y.; Xie, S.-G.; Wang, C.-J. Eur. J. Med. Chem. 2009, 44, 393–399; (b)
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2
References and notes
1
1
8. González-Bulnes, L.; Gallego, J. J. Am. Chem. Soc. 2009, 131, 7781–7791.
9. General procedure for the solid phase synthesis on Cl-Trt resin: To 2-
chlorotrityl resin (0.2 g, 0.28 mmol loading) in a jacketed fritted peptide
vessel was added a solution of protected amino acid (0.26 mmol) in dry DMF
1
.
(a) Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.; Reddy, G. S. K. Curr. Med.
Chem. Anti-Cancer Agents 2002, 2, 215–225; (b) Houghton, P. J.; Cheshire, P. J.;
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Zhang, Y.-H.; Li, Q.; Xu, F.-H.; Miao, J.-W. Apoptosis 2012, 17, 725–734.
Brana, M. F.; Ramos, A. Curr. Med. Chem. Anticancer Agents 2001, 1, 237–245.
Nitiss, J. L.; Zhou, J.; Rose, A.; Hsiung, Y.; Gale, K. C.; Osheroff, N. Biochemistry
(
1
3.5 mL), and after addition of diisopropylethylamine (DIEA, 185 mL,
.04 mmol) the mixture was shaken for 1.5 h. After completion of the
2
.
.
loading, dry MeOH (1.5 mL) was poured into the vessel and shaking was
continued for an additional 20 min. The solvent was removed by filtration and
3
1
998, 37, 3078–3089.
the following washings were performed sequentially: 2 Â CH
17:2:1), 2 Â CH Cl , 2 Â DMF, 2 Â CH Cl , 2 Â CH Cl /DMF (1:1) (3 mL each).
The Fmoc protecting group was removed by treatment with 20% piperidine in
NMP (2 Â 15 min, 5 mL each) and subsequent washing (2 Â CH Cl , 2 Â DMF,
mL each). Next, 3b–e (0.58 mmol of anhydride for 5b–d, or 1.3 mmol of 3c,d
for 6a,b), NMM (2.34 mmol) in DMF (4.5 mL) were added to the resin and
2 2
Cl /MeOH/DIEA
4
.
Malviya, V. K.; Liu, P. Y.; Alberts, D. S.; Surwit, E. A.; Craig, J. B.; Hanningan, E. V.
Am. J. Clin. Oncol. 1992, 15, 41–48.
(
2
2
2
2
2
2
5
6
.
.
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(a) LoRusso, P.; Demchik, L.; Corbett, T. H. Invest. New Drugs 1995, 13, 195–198;
2
2
5
(
b) Robinson, C. P.; Robinson, K. A.; Castaner, J. Drugs Future 1996, 21, 239–241.
7
8
.
.
Gurova, K. Future Oncol. 2009, 5, 1685–1713.
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Oncol. 1992, 15, 41–44.
o
shaken for 18 h at 70 C. The resin was washed with 2 Â DMF and 2 Â CH
3 mL each), dried in air and transferred to a vial for cleavage. Cleavage: a cold
solution of 5% TFA/2% triisopropylsilane in CH Cl (3 mL) was added. After
2 2
Cl
(
9
.
Bailly, C.; Brana, M. F.; Waring, J. Eur. J. Biochem. 1996, 240, 195–203.
2
2
shaking for 0.5 h, the solution was collected and the resin washed with cold
1
0. (a) Kamal, A.; Ramu, R.; Zingde, S. M. Bioorg. Med. Chem. 2008, 16, 7218–7224;
b) Filosa, R.; Peduto, A.; Bifulco, G. Bioorg. Med. Chem. 2009, 17, 13–24; (c)
Brana, M. F.; Cacho, M.; García, M. A.; Lacal, J. C. J. Med. Chem. 2004, 47, 1391–
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, 648–654; (e) Brana, M. F.; Castellano, J. M.; Perron, D.; Robinson, S. P. J. Med.
TFA (2 Â 1 mL each). After combining the TFA solutions, the solvent was
(
2
evaporated first under an N stream and then in vacuo to give after the usual
work-up (fast purification using solid-phase extraction pack an RP-18, first
washed with H O and then extracted with MeCN, 5 mL each). Data for 6a:
yellowish powder, (0.132 g, 57% yield). IR (KBr): 3600–3090 (br, s), 1705–1680
1
1
2
Chem. 1997, 40, 449–454; (f) Brana, M. F.; Cacho, M.; García, M. A.; Yuste, M. J.
Med. Chem. 2002, 45, 5813–5816; (g) Ikeda, H.; Nakamura, Y.; Saito, I.
Tetrahedron Lett. 2002, 43, 5525–5528.
À1
+
(
br, s), 1230 cm , HRMS (CI, m/z) calcd for C51
H
48
N
5
O
8
(MH ) 858.342, found
): 8.69–8.51 (m,12H), 7.88–7.82 (m, 6H),
.10–3.96 (m, 7H), 3.25–3.20 (m, 3H), 3.01–2.99 (m, 4H), 2.03–1.08 (m, 13H).
8
4
58.387; 1H NMR (300 MHz, DMSO-d
6
1
1. General procedure for the synthesis of mesylates 3b and 3c. A solution 3-nitro-
1
3
3
C NMR (75 MHz, CDCl ): 183.0, 160.3, 160.1, 152.2, 151.9, 146.4, 146.3,
1
,8-naphthalimide alcohol (obtained from 3-nitro-1,8-naphthalic anhydride
1
2
43.2, 140.1, 137.1, 123.3, 122.0, 71.9, 42.0, 40.5, 37.6, 36.3, 35.4, 34.1, 30.6,
6.5, 23.6, 22.1.
and the corresponding aminoalcohol) (18.4 mmol) and Et (25.6 mL,
3
N
1
84 mmol) in CH Cl (50 mL) was stirred at 0 °C under a nitrogen
2
2