Synthesis and release kinetics of polymerisable ester drug conjugates: Towards pH-responsive infection-resistant urinary biomaterials

Article abstract of DOI:10.1016/j.tetlet.2013.03.020

Herein we report the synthesis, characterisation and hydrolytic release kinetics of a suite of novel, polymerisable ester quinolone conjugates with varying alkenyl chain lengths. Hydrolysis was shown to proceed up to 17-fold faster upon elevation of pH from neutral to pH 9.29, making these conjugates attractive for the development of 'designer' infection-resistant urinary biomaterials exploiting the increase in urine pH reported at the onset of catheter-associated infection to trigger drug release.

Full text of DOI:10.1016/j.tetlet.2013.03.020

Tetrahedron Letters 54 (2013) 2511–2514
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and release kinetics of polymerisable ester drug conjugates:
towards pH-responsive infection-resistant urinary biomaterials
⇑
Colin P. McCoy , Nicola J. Irwin, Christopher Brady, David S. Jones, Gavin P. Andrews, Sean P. Gorman
School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the synthesis, characterisation and hydrolytic release kinetics of a suite of novel, poly-
merisable ester quinolone conjugates with varying alkenyl chain lengths. Hydrolysis was shown to pro-
ceed up to 17-fold faster upon elevation of pH from neutral to pH 9.29, making these conjugates
attractive for the development of ‘designer’ infection-resistant urinary biomaterials exploiting the
increase in urine pH reported at the onset of catheter-associated infection to trigger drug release.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 2 January 2013
Revised 14 February 2013
Accepted 6 March 2013
Available online 13 March 2013
Keywords:
Chain length
pH elevation
Ester hydrolysis
Drug-polymer conjugates
Implantation of medical devices, with their inherent suscepti-
bility to bacterial colonisation, has been implicated in over half
of all hospital-acquired infections,1 hence there is currently a sig-
nificant interest in the development of antimicrobial biomaterials.
Currently marketed drug-eluting medical devices rely on diffusive
release of therapeutic agents from the device surface,2 however,
clinical performance is limited by suboptimal release kinetics: an
initial burst of surface-localised agent restricting long-term effec-
tiveness, followed by continuous antimicrobial elution in subther-
apeutic levels potentially augmenting bacterial resistance
problems.3 Furthermore, voids left by release of drug from within
the polymer matrix may compromise mechanical performance.4
The ideal drug-eluting polymer system would be engineered to
display tunable release properties and, in the context of infec-
tion-resistant devices, be capable of achieving a precise ‘on–off’ re-
sponse.5 Recently, much interest has been generated in the
application of labile-drug polymer conjugates to three-dimen-
sional drug delivery systems.6 This strategy provides an additional
level of control over drug release, mediated by cleavage of the ther-
apeutic from pendant groups attached to the polymer main chain,
while simultaneously preserving structural integrity.2
upon the availability of two key components: firstly, an appropri-
ate hydrolysable linkage to allow release of the incorporated drug
and, secondly, a functional group amenable to free radical co-poly-
merisation with vinyl monomers to allow permanent incorpora-
tion within biomaterials. Characterisation of hydrolysis kinetics
across a full pH range (pH 2–pH 12) informs the use of these novel
ester drug conjugates in the development of a chemically-triggered
release system exploiting the elevation in urine pH caused by ure-
ase-producing urinary pathogens, such as Proteus mirabilis,8 to trig-
ger antimicrobial cleavage, specifically through controlled
hydrolysis of an ester bond.
Nalidixic acid adopts a very stable pseudo six-membered ring
structure, resulting either from strong intramolecular hydrogen
bonding between the carbonyl oxygen of the naphthyridine ring
carbonyl group with the hydrogen of the carboxylic acid group,
effectively rendering the carboxylic acid group chemically inert,9
or from conjugation of the carboxylic acid carbonyl group with
the ring nitrogen. Direct esterification is therefore difficult and,
in addition, synthesis of a reactive acyl chloride derivative is hin-
dered by the concomitant chlorination of the aromatic methyl
group by thionyl chloride or oxalyl chloride.9 Amides of nalidixic
acid have, however, been successfully synthesised using mixed
carboxylic–carbonic anhydrides as intermediates.10,11 This strategy
has been adapted to the esterification of nalidixic acid during
examination of the effect of neighbouring group participation on
ester hydrolysis rates,12 and is extended herein to demonstrate
the effects of spacer chain length on the release of nalidixic acid
from polymerisable ester drug conjugates.
Herein we describe the synthesis of a series of polymerisable,
vinyl-functionalised derivatives of nalidixic acid (1), a naphthyrid-
inone antibiotic with a wide spectrum of activity against common
Gram-negative urinary pathogens,7 via a two-step procedure
involving the preparation of a reactive nalidixic anhydride inter-
mediate 2 and subsequent esterification with a range of deproto-
nated alkenols 3–8. The design of the conjugates was predicated
The mixed anhydride {[(1-ethyl-7-methyl-4-oxo-1,4-dihydro-
1,8-naphthyridine-3-carbonyl) amino] acetic acid ethyl ester} (2)
formed from the reaction of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-
⇑
Corresponding author. Tel.: +44 28 9097 2081; fax: +44 28 9024 7794.
E-mail address: c.mccoy@qub.ac.uk (C.P. McCoy).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.020

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C. P. McCoy et al. / Tetrahedron Letters 54 (2013) 2511–2514
Table 1
1,8-naphthyridine-3-carboxylic acid (nalidixic acid) (1) with ethyl
chloroformate in the presence of triethylamine at ambient temper-
ature, as shown in Scheme 1, was isolated in 85% yield.13 Subse-
quent coupling with the appropriate deprotonated alkenol 3–8,
as summarised in Scheme 1, yielded conjugates 9–14 in yields of
32–62%, following work-up and purification by column
chromatography.14
To determine the effects of pH and spacer length on the hydro-
lysis behaviour of the ester drug conjugates, solutions of each
derivative 9–14 were prepared in aqueous buffers with pH values
ranging from pH 2 to pH 12 and a constant ionic strength of
154 mmol, prepared according to Table 1, and analysed by UV–vis-
ible spectroscopy. Verification of the pH was performed through-
out the study. Prior to hydrolysis, conjugates 9–14 show an
absorbance maximum at 258 nm due to the n–p⁄ transition of
the carbonyl group and a less intense band at 330 nm with a shoul-
Formulation of universal buffer
pH
Stocka
(
lL)
2 M NaOH (
lL)
KCl (mg)
H2O (mL)
2.3
2.8
1111
1000
1000
833
833
833
714
714
714
625
625
67
71.0
61.8
55.6
42.2
35.3
25.8
8.6
1.8
0
10.60
10.62
11.20
10.12
10.65
11.43
10.29
10.80
11.44
10.31
10.95
180
245
292
350
437
429
486
557
530
601
4.01
5.03
6.01
7.04
7.98
9.05
9.98
11.3
11.96
0
0
a
Stock solution (100 mL) contains 2.7 mL of H3PO4, 2.29 mL of AcOH and 2.48 g
of H3BO3 dissolved in deionised H2O.19
der at 320 nm corresponding to the extended p-system of the nal-
The progress of the hydrolytic reactions for 9–14 in aqueous
buffer solutions of the appropriate pH was monitored by quantifi-
cation of the first-order rate constant using spectral data at
320 nm. Conjugates 9–14 demonstrate a similar hydrolytic behav-
iour with negligible hydrolysis below pH 7 during the study period
of 144 h. Of particular significance to the development of pH-trig-
gered drug-eluting urinary biomaterials is the approximate order
of magnitude logarithmic increase in hydrolytic rate between pH
7 and pH 9, and 1.5–2.5 orders of magnitude logarithmic increase
between pH 7 and pH 12, as shown in Table 2. The regression coef-
ficients describing the linear relationship between rates of hydro-
lysis and pH for each conjugate confirm the mechanism of
reaction as general base-catalysed hydrolysis. Steric and electronic
effects are both acknowledged to contribute to variation in hydro-
lytic rates.16–18 The major variant between the studied compounds
in this study is the length of the alkenyl spacer, which is electron-
ically insulated from the nalidixyl chromophore. The monomeric
materials presented are likely to be less influenced by steric factors
than their polymeric or co-polymeric counterparts; indeed the ob-
served hydrolysis rate constants in Table 2 show no significant cor-
relation with chain length in solution. Following co-polymerisation
with an appropriate hydrogel backbone, variation in steric hin-
drance and subsequent accessibility to attacking nucleophiles is
expected to modulate the rate of the ester hydrolysis according
to the length of the spacer chain, making it possible to both prede-
termine and sustain subsequent release kinetics of the selected
idixate chromophore, as previously reported for derivatives of
nalidixic acid.15 Hydrolysis proceeds in an analogous manner to lit-
erature reports,12 with a bathochromic shift of 4 nm of the longest-
wavelength band with a shoulder to a single band of lower inten-
sity. Figure 1 shows overlaid UV–visible spectra of conjugate 10
after various times during the course of hydrolysis as a representa-
tive example of the behaviour of 9–14. The similar spectral changes
observed for all conjugates at pH values greater than pH 9 together
with the isosbestic point at 334 nm indicate that 9–14 hydrolyse
by a similar process involving a single reaction: cleavage of the es-
ter bond between the nalidixic moiety and the alkenyl spacer, with
no side reactions. Furthermore, nalidixic acid (1) possesses the
same aromatic p-system as the ester drug conjugates 9–14, there-
fore no significant spectral changes were expected during hydroly-
sis; the 4 nm bathochromic shift observed upon liberation of
nalidixic acid (1) may be attributed to the loss of a minor stabilis-
ing interaction resulting from the small degree of overlap between
the vinyl moiety and this
p
-system.12 Liberation of free nalidixic
acid (1) was confirmed by identification of the reaction products
following chromatographic separation. Conversely, UV–visible
spectra of the conjugates in universal buffers below pH 9 exhibit
no appreciable evolution of nalidixic acid after a similar time
(30 h). The slight decrease in intensity of the longest-wavelength
band over time, shown by the overlaid spectra of 10 at pH 6.15, Fig-
ure 2, suggests that ester hydrolysis does occur at neutral and
acidic pH, albeit at a very slow rate.
Scheme 1. Synthesis of 2, a mixed anhydride of nalidixic acid (1) and vinyl drug conjugates 9–14.

C. P. McCoy et al. / Tetrahedron Letters 54 (2013) 2511–2514
2513
Figure 1. Overlaid UV–Visible spectra of conjugate 10 at various times during the course of hydrolysis in pH 9.79 buffer at 37 °C. Arrows indicate trends in spectral change
with time. The spectral changes are representative of conjugates 9–14. Inset shows the first order rate plot using concentration data calculated from absorbance at 320 nm as
a function of time for conjugate 10.
Figure 2. Overlaid UV-Visible spectra of conjugate 10 at various times during the course of hydrolysis in pH 6.15 buffer at 37 °C. Arrows indicate trends in spectral change
with time. The spectral changes are representative of conjugates 9–14. Spectra shown were recorded at times of 0, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24 and 30 h.
drug by judicious incorporation of vinyl conjugates in a polymeric
biomaterial.
In summary, we have successfully synthesised and character-
ised the solution hydrolysis of a suite of novel polymerisable ester
naphthyridinone conjugates with varying vinyl chain lengths. The
accelerated rate of hydrolytic cleavage of the ester bond linking
nalidixic acid to the vinyl spacer as the pH is increased from neu-
tral presents these novel conjugates as promising candidates to-
wards the development of pH-responsive infection-resistant
biomaterials, specifically in the field of urinary catheterisation
where infection and encrustation complicate the care of almost
all long-term catheterised patients.

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C. P. McCoy et al. / Tetrahedron Letters 54 (2013) 2511–2514
vacuum left an oily residue, to which EtOAc (70 mL) was added to precipitate
Table 2
any nalidixic acid present in the reaction mixture, which was then removed by
filtration. The product was purified by flash chromatography over silica gel
(eluent/EtOAc to give conjugates 9–13 from alcohols 3–7, respectively, and
eluent/hexane/EtOAc to give conjugate 14 from alcohol 8).
Hydrolysis rate constants for conjugates 9–14 at pH 7.09, pH 9.29 and pH 11.96
Conjugate
Hydrolysis rate constant
k (Â10À3) (hÀ1
)
Conjugate
carboxylic acid 2-propen-1-ol ester (44%): molar extinction coefficient
) = 10,300 molÀ1 d m3 cmÀ1 (H2O, pH 7, k = 320 nm); mp 97–99 °C; 1H NMR
9:
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
pH
(
e
7.09
9.29
11.30
(CDCl3, 400 MHz) dH: 1.5 (t, J = 8 Hz, 3H, NCH2CH3); 2.66 (s, 3H, Ar-CH3); 4.5 (q,
J = 8 Hz, 2H, NCH2CH3); 4.85 (d, J = 9 Hz, 2H, OCH2CH@CH2); 5.23 (dd, J = 13,
5 Hz, 1H, CH@CH cis); 5.43 (dd, J = 19, 6 Hz, 1H, CH@CH trans); 6.01 (m, 1H,
CH@CH2); 7.18 (d, J = 6 Hz, 1H, Ar-H); 8.57 (s, 1H, Ar-H); 8.59 (d, J = 6 Hz, 1H,
Ar-H). IR (KBr, cmÀ1): 1676 (OC@O); 1644 (Ar C@O); 1625 (C@C); 1612, 1585
(Ar C@C); 1212, 1013 (C–O). CI-MS m/z (%): 273.12 [M+H]+ (100), 274.13 (18),
275.14 (10), 276.14 (2).
9
10
11
12
13
14
19.73
1.39
6.89
4.17
5.79
8.47
81.85
23.55
30.70
34.75
25.73
67.13
568.02
767.01
526.37
575.38
677.18
713.92
Conjugate
10:
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid 3-buten-1-ol ester (62%):
e
= 10,900 molÀ1 d m3 cmÀ1 (H2O,
pH 7, k = 320 nm); mp 86–88 °C; 1H NMR (CDCl3, 400 MHz) dH: 1.42 (t, J = 8 Hz,
3H, NCH2CH3); 2.49 (m, 2H, OCH2CH2CH@CH2); 2.59 (s, 3H, Ar-CH3); 4.3 (t,
J = 8 Hz, 2H, OCH2CH2CH@CH2); 4.4 (q, J = 8 Hz, 2H, NCH2CH3); 5.06 (dd, J = 12,
4 Hz, 1H, CH@CH cis); 5.13 (dd, J = 19, 6 Hz, 1H, CH@CH trans); 5.85 (m, 1H,
CH@CH2); 7.18 (d, J = 6 Hz, 1H, Ar-H); 8.57 (s, 1H, Ar-H); 8.59 (d, J = 6 Hz, 1H,
Ar-H). IR (KBr, cmÀ1): 1676 (OC@O); 1640 (Ar C@O); 1628 (C@C); 1613, 1586
(Ar C@C); 1220, 1015 (C–O). CI-MS m/z (%): 287.14 [M+H]+ (100), 288.14 (18).
Acknowledgements
This work was funded by the Department for Employment and
Learning, Northern Ireland. The use of the EPSRC National Mass
Spectrometry Service Centre, Swansea is gratefully acknowledged.
Conjugate
11:
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid 4-penten-1-ol ester (57%):
e
= 11,200 molÀ1 d m3 cmÀ1 (H2O,
pH 7, k = 320 nm); mp 81–82 °C; 1H NMR (CDCl3, 400 MHz) dH: 1.5 (t, J = 8 Hz,
3H, NCH2CH3); 1.9 (m, 2H, OCH2CH2CH2); 2.24 (m, 2H, CH2CH2CH@CH2); 2.66
(s, 3H, Ar-CH3); 4.36 (t, J = 8 Hz, 2H, OCH2CH2CH2); 4.48 (q, J = 8 Hz, 2H,
NCH2CH3); 5.02 (dd, J = 12, 4 Hz, 1H, CH@CH cis); 5.10 (dd, J = 19, 6 Hz, 1H,
CH@CH trans); 5.87 (m, 1H, CH@CH2); 7.24 (d, J = 6 Hz, 1H, Ar-H); 8.61 (s, 1H,
Ar-H); 8.65 (d, J = 6 Hz, 1H, Ar-H). IR (KBr, cmÀ1): 1674 (OC@O); 1637 (Ar
C@O); 1628 (C@C); 1607, 1589 (Ar C@C); 1221, 1015 (C–O). CI-MS m/z (%):
301.15 [M+H]+ (100), 302.16 (18).
References and notes
1. Darouiche, R. O. N. Eng. J. Med. 2004, 350, 1422–1429.
2. Nowatzki, P. J.; Koepsel, R. R.; Stoodley, P.; Min, K.; Harper, A.; Murata, H. Acta
Biomater. 2012, 8, 1869–1880.
3. Campoccia, D.; Montanaro, L.; Speziale, P.; Arciola, C. Biomaterials 2010, 31,
6363–6377.
4. Huynh, T.; Padois, K.; Sonvico, F.; Rossi, A.; Zani, F.; Pirot, F. Eur. J. Pharmacol.
Biopharm. 2010, 74, 255–264.
5. McCoy, C.; Brady, C.; Cowley, J.; McGlinchey, S.; McGoldrick, N.; Kinnear, D.
Expert Opin. Drug Del. 2010, 7, 605–616.
6. Schoenmakers, R.; van de Wetering, P.; Elbert, D.; Hubbell, J. J. Controlled
Release 2004, 95, 291–300.
7. Jacoby, G. A. In Antibiotic Discovery and Development; Dougherty, T. J., Pucci, M.
J., Eds.; Springer: US, 2012; Vol. 1, pp 119–146.
8. Stickler, D. J. J. Med. Microbiol. 2006, 55, 489–494.
9. Ghosh, M. In Progress in Biomedical Polymers; Gebelein, C. G., Dunn, R. L., Eds.;
Plenum Press: New York, 1990; Vol. 1, pp 335–345.
10. AboulFadl, T.; Fouad, E. Pharmazie 1996, 51, 30–33.
11. Kim, S.; Lee, J.; Kim, Y. J. Org. Chem. 1985, 50, 560–565.
12. McCoy, C.; Morrow, R.; Edwards, C.; Jones, D.; Gorman, S. Bioconjugate Chem.
2007, 18, 209–215.
13. General procedure for the synthesis of [(1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carbonyl) amino] acetic acid ethyl ester (a nalidixic anhydride)
(2): Et3N (22.3 mmol) and ethyl chloroformate (21.2 mmol) were added to a
Conjugate
12:
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid 5-hexen-1-ol ester (32%):
e
= 11,800 molÀ1 d m3 cmÀ1 (H2O,
pH 7, k = 320 nm); mp 54–55 °C; 1H NMR (CDCl3, 400 MHz) dH: 1.5 (t, J = 6 Hz,
3H, NCH2CH3); 1.58 (m, 2H, OCH2CH2CH2CH2); 1.82 (m, 2H, OCH2CH2CH2CH2);
2.11 (m, 2H, CH2CH2CH@CH2); 2.66 (s, 3H, Ar-CH3); 4.34 (t, J = 8 Hz, 2H,
OCH2CH2CH2); 4.48 (q, J = 6 Hz, 2H, NCH2CH3); 4.75 (dd, J = 11, 4 Hz, 1H,
CH@CH cis); 4.90 (dd, J = 17, 5 Hz, 1H, CH@CH trans); 5.82 (m, 1H, CH@CH2);
7.24 (d, J = 6 Hz, 1H, Ar-H); 8.61 (s, 1H, Ar-H); 8.65 (d, J = 6 Hz, 1H, Ar-H). IR
(KBr, cmÀ1): 1695 (OC@O); 1631 (Ar C@O); 1629 (C@C); 1613, 1592 (Ar C@C);
1213, 1011 (C–O). CI-MS m/z (%): 315.17 [M+H]+ (100), 316.17 (18), 317.18 (2).
Conjugate
13:
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid 2-buten-1-ol ester (39%):
e
= 10,700 molÀ1 d m3 cmÀ1 (H2O,
pH 7, k = 320 nm); mp 91–92 °C; 1H NMR (CDCl3, 400 MHz) dH: 1.49 (t, J = 8 Hz,
3H, NCH2CH3); 1.75 (d, J = 8 Hz, 3H, CH@CHCH3); 2.66 (s, 3H, Ar-CH3); 4.48 (q,
J = 8 Hz, 2H, NCH2CH3); 4.78 (d, J = 7 Hz, 2H, OCH2CH@CH); 5.75 (m, 1H,
CH@CHCH3); 5.91 (m, 1H, CH@CHCH3); 7.24 (d, J = 6 Hz, 1H, Ar-H); 8.61 (s, 1H,
Ar-H); 8.65 (d, J = 6 Hz, 1H, Ar-H). IR (KBr, cmÀ1): 1681 (OC@O); 1647 (Ar
C@O); 1631 (C@C); 1609, 1595 (Ar C@C); 1220, 1125 (C–O). CI-MS m/z (%):
287.14 [M+H]+ (100), 288.14 (18).
solution
of
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid (1) (15.7 mmol) in anhydrous CH2Cl2 (100 mL). The solution
was stirred for 30 min at ambient temperature, before washing with 0.2 M HCl
(2 Â 20 mL) and H2O (1 Â 40 mL). The organic phase was dried over anhydrous
MgSO4, filtered, and evaporated to dryness under vacuum.12 Recrystallisation
from MeCN gave a white solid (85%) with a melting point between 122–124 °C.
H NMR (CDCl3, 400 MHz) dH: 1.41 (t, J = 8 Hz, 3H, NCH2CH3); 1.54 (t, J = 8 Hz,
3H, OCH2CH3); 2.65 (s, 3H, Ar-CH3); 4.37 (q, J = 8 Hz, 2H, NCH2CH3); 4.51 (q,
J = 8 Hz, 2H, OCH2CH3); 7.29 (d, J = 6 Hz, 1H, Ar-H); 8.63 (d, J = 6 Hz, 1H, Ar-H);
8.69 (s, 1H, Ar-H). IR (KBr, cmÀ1): 1771 (O@C–O–C); 1737 (OC@O); 1646 (Ar
C@O); 1609, 1585 (Ar C@C); 1174, 1014 (C–O).
Conjugate
14:
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid 9-decen-1-ol ester (47%):
e
= 12,900 molÀ1 d m3 cmÀ1 (H2O,
pH 7, k = 320 nm); 1H NMR (CDCl3, 400 MHz) dH: 1.41 (t, J = 8 Hz, 3H,
NCH2CH3); 1.20–2.02 (m, 14H, OCH2C7H14CH@CH2); 2.59 (s, 3H, Ar-CH3);
4.25 (t, J = 7 Hz, 2H, OCH2C7H14); 4.4 (q, J = 8 Hz, 2H, NCH2CH3); 4.84 (dd, J = 11,
4 Hz, 1H, CH@CH cis); 4.9 (dd, J = 19, 6 Hz, 1H, CH@CH trans); 5.71 (m, 1H,
CH@CH2); 7.18 (d, J = 6 Hz, 1H, Ar-H); 8.55 (s, 1H, Ar-H); 8.69 (d, J = 6 Hz, 1H,
Ar-H). IR (KBr, cmÀ1): 1676 (OC@O); 1646 (Ar C@O); 1625 (C@C); 1612, 1590
(Ar C@C); 1205, 1150 (C–O). CI-MS m/z (%): 371.23 [M+H]+ (100), 372.24 (24),
273.24 (4).
14. General procedure for the synthesis of polymerisable ester drug conjugates 9–14: A
solution of the appropriate alkenol 3–8 (8.0 mmol) and NaH (8.8 mmol) in
anhydrous THF (100 mL) was refluxed for 1 h then cooled to ambient
15. Vargas, F.; Zoltan, T.; Rivas, C.; Ramirez, A.; Cordero, T.; Diaz, Y. J. Photochem.
Photobiol., B Biol. 2008, 92, 83–90.
16. Charton, M. J. Am. Chem. Soc. 1974, 97, 3691–3693.
17. DeTar, D. F.; Binzet, S.; Darba, P. J. Org. Chem. 1985, 50, 5304–5308.
18. Taft, R. W. J. Am. Chem. Soc. 1952, 74, 3120–3128.
19. Koller, C. N. Biochem. Biophys. Res. Commun. 1992, 184, 692–699.
temperature.
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carbonyl) amino acetic acid ethyl ester (2) (8.0 mmol) was added over
15 min and the mixture stirred for a further 10 min before the addition of
EtOH (5 mL) to deactivate any residual NaH. Evaporation to dryness under