3744
N. Aberle et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3741–3744
group rather than the p-methoxy. This molecule has
been reported to possess only weak cytotoxicity toward
a variety of cell lines,8 indicating the importance of the
C-5 substituent, and thus the exact C-5 deletion ana-
logue was not prepared here.
The results presented above demonstrate that replacing
the 2-aminoimidazole core of naamidine A with a
2-aminothiazole does not have a major influence on
the potency of the molecule: the direct thiazole
analogue of 1, 12a, was found to have an IC50 of
10 lM, which is very similar to the natural product
(3 lM), indicating that the N–CH3 component of the
heterocycle is not engaged in any interaction with the
target. Consistent with the results obtained for 1 and
2, the dehydrohydantoin moiety was also found to be
essential for activity in the thiazole series, compared
to the derivatives with unsubstituted amines at C-2.
The alanine-derived 17 suggests, however, that a small
cluster of heteroatoms at this position may be suffi-
cient, but this effect is lost upon introduction of a
larger substituent, such as 16.
No natural equivalent to the C-4 deletion analogue is
known. Its synthesis was achieved from an intermediate
in the synthesis of 1,7 as shown in Scheme 1. Reduction
of Weinreb amide 4 with LiAlH4 provided the aminoal-
dehyde 5. Following deprotection of the amine, expo-
sure of the resulting hydrochloride salt to a large
excess of cyanamide resulted in formation of the 2-
aminoimidazole 6. Hydrogenolysis of the benzyl ether
and installation of the dehydrohydantoin unit through
condensation with 1-methyl-3-trimethylsilylparabanic
acid9 provided the C-4 deletion analogue of naamidine
A, 7. Interestingly, the IC50 for this structure was found
to be 4 lM, indicating that the p-methoxybenzyl group
at C-4 of the imidazole ring does not contribute to the
activity of 1 (Table 1).
In summary, we have demonstrated that the ability of 1
to inhibit EGF- and IL3-dependent DNA synthesis is
not impaired by replacement of the imidazole core by
a thiazole. While none of the analogues demonstrated
greater potency than the natural product, there is scope
for optimization of the side chains based on the initial
observations made here. Also, the discovery that the
C-4 chain does not contribute to the activity of 1
provides the option of using an affinity reagent in
further mechanism of action studies.
To investigate the importance of the 2-aminoimidazole
core, as well as to obtain structure–activity relationship
data on other elements of the molecule, a small series of
2-aminothiazole derivatives was synthesized. The direct
thiazole analogue of 1, along with a number of other
derivatives, was prepared according the sequence shown
in Scheme 2, where the choice of Grignard reagent
defines the C-4 position of the final heterocycle. The
phenol of 4-hydroxyphenethyl alcohol was first
protected as the benzyl ether, then the primary alcohol
was oxidized to the aldehyde 8 using Dess-Martin
periodinane. Treatment with potassium cyanide in the
presence of sodium hydrogen sulfite resulted in the cya-
nohydrin 9. Conversion of 9 to the a-hydroxyketones
10a–c was achieved through in situ silylation of the
hydroxyl group using TMSOTf, followed by addition
of the appropriate Grignard reagent.10,11 After bromin-
ation with SOBr2, the a-bromoketones were condensed
with thiourea to afford the 2-aminothiazoles, which were
deprotected using BCl3 to give 11a–c. Installation of the
dehydrohydantoin unit was performed as above to give
the naamidine analogues 12a–c.
Supplementary data
Supplementary data associated with this article can be
References and notes
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A range of symmetrical 2-aminothiazoles was also syn-
thesized using similar methodology, starting from the
commercially available a-hydroxyketones benzoin
(13a) and anisoin (13 b, Scheme 3) and proceeding via
the a-chloroketones rather than the a-bromoketones.
The final analogues that were prepared in this series are
shown in Scheme 4. From the anisoin-derived 2-amino-
thiazole 14b, two different side chains were incorporated
into the 2-amino position to examine the effect of replac-
ing the dehydrohydantoin.
Each of the 2-aminothiazole derivatives prepared above
was subjected to the [3H]thymidine incorporation assay
to determine its effect on both EGF- and IL3-dependent
mitogenesis. In all cases, except for 15b, the IC50 values
for each stimulus were within 5 lM and the listed value
is the average (Table 2).
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