Synthesis and fluorescent properties of 6-(4-biphenylyl)-3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine analogues of acyclovir and ganciclovir

Article abstract of DOI:10.1081/NCN-120022684

Tricyclic (T) analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2) carrying the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system [i.e., 6-(4-BrPh)TACV, 5 and 6-(4-BrPh)TGCV, 6] were transformed into 6-[(4′-R²)-4-biphenylyl] derivatives of T

Full text of DOI:10.1081/NCN-120022684

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Synthesis and Fluorescent Properties of 6-(4-
Biphenylyl)-3,9-dihydro-9-oxo-5H-imidazo[1,2-
A]purine Analogues of Acyclovir and Ganciclovir
Tomasz Goslinski a , Grazyna Wenska b , Bozenna Golankiewicz a d , Jan Balzarini c & Erik De
Clercq c
a Institute of Bioorganic Chemistry, Polish Academy of Sciences , Poznań, Poland
b Department of Chemistry , Adam Mickiewicz University , Poznań, Poland
c Rega Institute for Medical Research, Katholieke Universiteit Leuven , Leuven, Belgium
d Polish Academy of Sciences, Institute of Bioorganic Chemistry , ul. Noskowskiego 12/14,
PL-61-704, Poznan, Poland
Published online: 31 Aug 2006.
To cite this article: Tomasz Goslinski , Grazyna Wenska , Bozenna Golankiewicz , Jan Balzarini & Erik De Clercq (2003)
Synthesis and Fluorescent Properties of 6-(4-Biphenylyl)-3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine Analogues of Acyclovir
and Ganciclovir, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 911-914, DOI: 10.1081/NCN-120022684
To link to this article: http://dx.doi.org/10.1081/NCN-120022684
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 911–914, 2003
Synthesis and Fluorescent Properties of 6-(4-Biphenylyl)-3,9-
dihydro-9-oxo-5H-imidazo[1,2-A]purine Analogues of
Acyclovir and Ganciclovir
Tomasz Goslinski,1 Grazyna Wenska,2 Bozenna Golankiewicz,1,
*
Jan Balzarini,3 and Erik De Clercq3
1
´
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
2
´
Department of Chemistry, Adam Mickiewicz University, Poznan, Poland
3Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Leuven, Belgium
ABSTRACT
Tricyclic (T) analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2) carrying
the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system [i.e., 6-(4-BrPh)TACV, 5
and 6-(4-BrPh)TGCV, 6] were transformed into 6-[(40-R2)-4-biphenylyl] deriva-
tives of TACV (7–9) and TGCV (10–12) by Suzuki cross coupling with 4-substi-
tuted phenylboronic acids. Compound 11 (R2 ¼ CH2OH) showed a high (ꢀ1000)
selectivity index against herpes simplex virus type 1 (HSV-1) together with advan-
tageous fluorescence properties (emission in visible region, little overlap with
absorption and moderate intensity).
Key Words: Acyclovir; Ganciclovir; Tricyclic analogues; Fluorescent
properties.
*Correspondence: Bozenna Golankiewicz, Polish Academy of Sciences, Institute of Bio-
organic Chemistry, ul. Noskowskiego 12=14, PL-61-704 Poznan, Poland; Fax: þ48 61 852
0532; E-mail: bogolan@ibch.poznan.pl.
911
DOI: 10.1081/NCN-120022684
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

912
Goslinski et al.
We have previously reported that two potent antivirals, acyclovir, ACV,
9-[(2-hydroxyethoxy) methyl]guanine, 1 and its (1,3-dihydroxy-2-propoxy) congener,
ganciclovir, GCV, 2 may be rendered intrinsically fluorescent by conversion of their
guanine moiety into the tricyclic 3,9-dihydro-9-oxo-6-phenyl-5H-imidazo[1,2-
a]purine system to form 6-PhTACV and 6-PhTGCV derivatives.[1] Appropriate
substitution in the 4 position of 6-phenyl group resulted in 6-(4-R1Ph) TACV and
–TGCV, with antiviral activity comparable to that of parent compounds 1 and
2.[2] The presence of an acyloxy group such as the 4-R1 substituent provided strong
fluorescence, as with derivatives 3, 4.[3]
In order to further improve the fluorescence characteristics of the TACV and
TGCV analogues, we synthesized a series of 6-[(40-R2)-4-biphenylyl] derivatives.
Parent compounds 1 and 2 were converted into 6-(4-BrPh) TACV 5, and 6-(4-BrPh)
TGCV 6, respectively, according to a previously described method for an alkylation-
condensation reaction using appropriate bromoketone[1] followed by Suzuki cross-
coupling[4] with 4-substituted phenylboronic acids (Sch. 1). The target biphenylyl
derivatives 7–12, obtained in approximately 50% yield after chromatographic purifi-
cation (silica gel, CH2Cl2=MeOH gradient) and recrystallization (i-PrOH=H2O)
1
were fully characterized by elemental analyses, H and 13C NMR spectra as well as
absorption and fluorescence spectra.
FLUORESCENCE
The absorption and emission spectra of selected acyclovir analogues are pre-
sented in Fig. 1. Identical spectral changes were observed for ganciclovir derivatives
10–12. Replacement of 6-phenyl with 6-biphenylyl substituent resulted in ca. 10 nm
batochromic shift of the lowest energy absorption band and a substantial increase in
its intensity. The value of emax determined for the compound 9 at lmax ¼ 320 nm
equals to 27,600 dm3 molꢁ1 cmꢁ1. The effect of 6-biphenylyl substituent on the
Scheme 1. Reagents and conditions: (a) NAH=DMF, 4-BrPhCOCH2Br, room temp, 4 h,
then NH4OHaq; (b) NAH=DMF, 4-[(CH3)2CHCOO]PhCOCH2Br, room temp, 4 h; (c) 5
or 6, DMF-H2O, Pd(Ph3P)4, 4-(HO)2BPhF or 4-(HO)2BPhCH2OH, K2CO3, 85–90ꢂC,
3–5 h; (d) 5 or 6, DMF-H2O, Pd(Ph3P)4, 4-[(CH3)4C2O2B]PhOH, K2CO3, 85ꢂC, 2–4 h.

Fluorescent Analogues of Acyclovir and Ganciclovir
913
Figure 1. Normalized absorption (A) and fluorescence (F) spectra of compounds 3,8,9 in
H2O-CH3OH (10:1; v:v) and compound 7 in CH3OH; (7,8,9: lexc ¼ 340 nm; 3: lexc ¼ 310 nm).
position and intensity of the fluorescence band was similar (Fig. 1). Among the com-
pounds studied the 40-hydroxymethylbiphenylyl derivatives 8 and 11 exhibited the
most advantageous fluorescence properties. The emission of 11 was moderately
intense (j ¼ 0.15), relatively long-lived (t ¼ 3.9 ns), extended into the visible region,
and the emission band was well separated from absorption band.
BIOLOGICAL ACTIVITY
The novel TACV and TGCV derivatives were evaluated against herpes simplex
virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV) and cytome-
galovirus (CMV) in human embryonic lung (HEL) cell cultures. The effects of the
compounds on cell morphology were evaluated in parallel with their antiviral activ-
ity according to procedures described previously.[5] The insertion of an additional
phenyl ring into the substituent at the 6 position generally reduced the antiviral
activity and selectivity. However, this reduction in activity was less pronounced
for HSV-1 and HSV-2 than for VZV and CMV. Compound 11, advantageous from
the fluorescence viewpoint was inhibitory to TKþ HSV-1 and TKþ HSV-2 within the
concentration range of 0.08–0.4 mg=mL, well below the cytotoxicity threshold
(80 mg=mL). It could be considered as an antiherpetic drug candidate worthy of
further evaluation from both a therapeutic as well as diagnostic viewpoint, for the
treatment and non-invasive diagnosis of HSV infections, the latter because of its
fluorescent properties.

914
Goslinski et al.
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