Md. J. Uddin et al. / Bioorg. Med. Chem. Lett. 15 (2005) 439–442
441
significantly with (E)-10c (R1 = H; R2 = F; R3 =
tween the fluorine-atom present at the p-position of the
H; R4 = S OMe) (COX-2 IC50 = 0.0316lM; COX-2
C-2 phenyl ring and the OH of Ser530 (distance = 2.4A)
˚
2
selectivity index > 3164) being 2.2-fold more potent
and 6.7-fold more selective than celecoxib (1), or 16-fold
more potent and 15.8-fold more selective than rofecoxib
(2). However, the presence of an additional fluoro sub-
stituent at the C-2 phenyl ring as with compound
that is the acetylation site of aspirin. The geminal
unsubstituted C-1 phenyl ring was oriented toward
the mouth of the primary COX-2 binding site where
it interacts with Tyr355, Arg120, and Leu359
.
(E)-10d (R1 = R2 = F; R3 = H; R4 = S OMe) resulted
In conclusion, this investigation shows that, (i) a novel
group of 1,1,2-triaryl (E)-ethenes can be synthesized
via an (E)-selective Takeda olefination reaction, (ii)
COX-1/COX-2 isozyme inhibition structure–activity
studies identified (E)-2-(4-fluorophenyl)-1-(4-methyl-
sulfonylphenyl)-1-phenylethene (10c) as a highly potent
(IC50 = 0.0316lM), and selective (selectivity index
>3164), COX-2 inhibitor, (iii) COX-2 inhibitory potency
and selectivity for this 1,1,2-triarylethene template is
sensitive to appropriate placement of the olefinic substit-
uents and their relative stereochemistry with respect to
C@C, and (iv) the function of the carbon–carbon double
bond is to provide necessary substituent geometry for an
optimal enzyme–ligand binding interaction within the
COX-2 binding site.
2
in a reduction in COX-2 inhibitory potency (COX-2
IC50 = 0.97lM). The mono chloro analog (E)-
10e (R1 = H; R2 = Cl; R3 = H; R4 = S OMe) and the
2
p-methyl analog (E)-10b were equipotent COX-2 inhibi-
tors. It is interesting to note that, a significant reduction
in COX-2 potency was observed, when the SO2Me
COX-2 pharmacophore was placed at the p-position of
the C-2 phenyl ring of the central C@C. In this regard
10f and the related analogs 10g–h, having a C-2 p-meth-
ylsulfonylphenyl substituent, were much less potent
(IC50 = 2–32lM range), and less selective COX-2 inhibi-
tors (SI = >3 to >50 range) than regioisomeric com-
pounds 10a–e, having a C-1 p-methylsulfonylphenyl
substituent (COX-2 IC50 range = 0.0316–0.97lM range;
SI = 0.45 to >3164 range).
A molecular modeling (docking) study12 of the most sta-
ble ligand–enzyme complex of 10c (Fig. 3) showed that
this ligand binds in the center of the COX-2 binding site
such that the C-1 p-MeSO2-phenyl substituent is posi-
tioned in the vicinity of the COX-2 secondary pocket
Acknowledgements
We are grateful to the Canadian Institutes of Health Re-
search (CIHR) (MOP-14712) for financial support of
this research, to the Alberta Heritage Foundation for
Medical Research (AHFMR) for a postdoctoral fellow-
ship (to M.J.U.) and for a graduate scholarship (to
P.N.P.R.).
where it is surrounded by Phe518, Arg513, Gln192
,
Ser353, and Val523. One of the oxygen atoms of the
SO2Me group undergoes a H-bonding interaction with
the backbone NH of Phe518 (distance = 2.16A), whereas
˚
the other oxygen atom is close to the guanidine side
chain (NH2) of Arg513 (distance = 2.71A). The C-2
˚
References and notes
p-fluorophenyl substituent is oriented in a region com-
530
prised of Ala527, S er , Leu531, Leu534, Val349, and
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8. Synthesis of thioacetals 7. General procedure. Boron
trifluoride etherate (21.3g, 150mmol) was added slowly to
a solution of the aromatic aldehyde 5 (R1 = H, F; R2 = H,
Me, SMe, F, Cl) (150mmol) and thiophenol (34.6g,
314.5mmol) in CHCl3 (150mL) at 0ꢁC. The reaction
mixture was stirred for 1h at 25ꢁC prior to quenching with
H2O (150mL). The layers were separated, and the aqueous
layer was extracted with EtOAc (3 · 100mL). Washing the
combined organic extracts with an aqueous 1M NaOH
solution, drying the organic fraction (Na2SO4) and
Figure 3. Docking of (E)-10c in the binding site of murine COX-2.
Hydrogen atoms of the amino acid residues are not shown for clarity.