From Plant to Patient: Thapsigargin, a Tool for Understanding …
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10.4 Substitution at O-3
Removal of the lipophilic angelate group strongly decreased the affinity for SERCA
[79]. Inversion of the stereochemistry at C-3 also afforded an analog with severely
decreased affinity [153]. However, lipophilic acyl groups with chain lengths of the
same size as thapsigargin afforded potent analogs. The importance of the sizes of the
acyl groups at this position is illustrated by the observation that the affinities for 3O-benzoate, 3-methylbenzoate and 4-methylbenzoate severely drops with the length
of the side chain. The 3-O-p-phenylbenzoate ester shows no affinity in the range
measured. In contrast, the 3-O-p-phenylphenylacetate still possesses a significant
affinity [18].
10.5 The Carbonyl Group at C-12
The carbonyl group at C-12 of thapsigargin (1) is not essential for activity since the
reduction of this group to a methylene group affords a compound equipotent to 1
[70].
10.6 The Two Hydroxy Groups HO-7 and HO-11
Initial studies revealed that the epoxide of thapsigargin (16), as well as the 7,11-di-Oacetate, were unable to release histamine from mast cells [33]. This result indicated
that the 7,11-hydroxy groups are essential for provoking cellular responses. Later
results, however, have revealed that the 11-O-butanoate still has a significant affinity
for the SERCA pump [18]. Other experiments additionally have confirmed that the
epoxide 16 also has an affinity for the pump, although considerably poorer [69]. A
similar observation has been made for the epoxide of trilobolide [154]. Interestingly,
trilobolide (17) can inhibit SERCA activity up to 90% in vitro [138], and although 17
is unable to provoke histamine release from mast cells [29], it is able to induce growth
arrest, ER Ca
2+ depletion, UPR, and cell death at high concentrations in prostate and
breast cancer cells [129, 138].
Docking studies indicate that the ester carbonyl at O-8 forms a hydrogen bond to
Leu828 and Ile829 via a water molecule and HO-11 hydrogen bonding to Glu255
via two water molecules. These bindings might be of importance for the orientation
of the ligand in SERCA [69].
In conclusion, theoretical studies, as well as empirical studies using available
thapsigargin analogs and derivatives, have revealed the pharmacophore depicted in
Fig. 11.
87
10.4 Substitution at O-3
Removal of the lipophilic angelate group strongly decreased the affinity for SERCA
[79]. Inversion of the stereochemistry at C-3 also afforded an analog with severely
decreased affinity [153]. However, lipophilic acyl groups with chain lengths of the
same size as thapsigargin afforded potent analogs. The importance of the sizes of the
acyl groups at this position is illustrated by the observation that the affinities for 3O-benzoate, 3-methylbenzoate and 4-methylbenzoate severely drops with the length
of the side chain. The 3-O-p-phenylbenzoate ester shows no affinity in the range
measured. In contrast, the 3-O-p-phenylphenylacetate still possesses a significant
affinity [18].
10.5 The Carbonyl Group at C-12
The carbonyl group at C-12 of thapsigargin (1) is not essential for activity since the
reduction of this group to a methylene group affords a compound equipotent to 1
[70].
10.6 The Two Hydroxy Groups HO-7 and HO-11
Initial studies revealed that the epoxide of thapsigargin (16), as well as the 7,11-di-Oacetate, were unable to release histamine from mast cells [33]. This result indicated
that the 7,11-hydroxy groups are essential for provoking cellular responses. Later
results, however, have revealed that the 11-O-butanoate still has a significant affinity
for the SERCA pump [18]. Other experiments additionally have confirmed that the
epoxide 16 also has an affinity for the pump, although considerably poorer [69]. A
similar observation has been made for the epoxide of trilobolide [154]. Interestingly,
trilobolide (17) can inhibit SERCA activity up to 90% in vitro [138], and although 17
is unable to provoke histamine release from mast cells [29], it is able to induce growth
arrest, ER Ca
2+ depletion, UPR, and cell death at high concentrations in prostate and
breast cancer cells [129, 138].
Docking studies indicate that the ester carbonyl at O-8 forms a hydrogen bond to
Leu828 and Ile829 via a water molecule and HO-11 hydrogen bonding to Glu255
via two water molecules. These bindings might be of importance for the orientation
of the ligand in SERCA [69].
In conclusion, theoretical studies, as well as empirical studies using available
thapsigargin analogs and derivatives, have revealed the pharmacophore depicted in
Fig. 11.