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O
NH
2
DMF/POCl
3
Cl
N
+
R
Cl
N
H
N
N
N
R
R
Nu
Cl
Nu
X
+ Nu
N
N
N
N
R
R
R
R
Cl-cyclo-Cy
OR
1
Nu =
X
B(OH)
2
SR
1
Pd(PPh
3
)
4
H
2
O
NR
1
R
2
X
N
N
R
R
X = -NH
2
, -OH, -CONH(CH
2
)
2
OH
Figure 3.2 Synthesis and derivatization of cycloheptamethine cyanines (see text for
references).
bond).
65
Alternatively, palladium-catalyzed cross-coupling reaction has been
employed to form the more robust C
Cbond.
66,68
Both approaches have
been used for preparing a broad range of derivatives, including those
equipped with bioconjugatable groups.
36,47,65-70
Nucleophilic substitution
of chlorine atom in cycloheptamethine and benzocycloheptamethine
cyanines
with oxygen, nitrogen, or sulfur nucleophiles has
also been widely used for the attachment of groups to improve water
solubility,
71-73
prevent aggregation,
74
and alter the cyanine affinity to
albumin,
75
as well as to target or recognize motifs such as peptides,
69,75
glucosamine,
76
photosensitizers,
77
and zinc dipicolylamine group.
78,79
Cl-cyclo-Cy
2.3. Improvement of water solubility and chemical stability
One of the main problems with cyanine fluorophores is their chemical and
photochemical instability, especially under physiological conditions. Cya-
nines undergo many complex physicochemical transformations in solution,
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