Benzo[b]thiophene-based histone deacetylase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.05.091

Benzo[b]thienyl hydroxamic acids, a novel class of histone deacetylase (HDAC) inhibitors, were identified via a targeted screen of small molecule hydroxamic acids. Various substitutions were explored in the C5- and C6-positions of the benzo[b]thiophene co

Full text of DOI:10.1016/j.bmcl.2007.05.091

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4562–4567
Benzo[b]thiophene-based histone deacetylase inhibitors
David J. Witter,a,* Sandro Belvedere,b Liqiang Chen,c J. Paul Secrist,a
Ralph T. Mosleyd and Thomas A. Millera
aMerck Research Laboratories, Departments of Drug Design & Optimization and Cancer & Biology Therapeutics,
33 Avenue Louis Pasteur, Boston, MA 02115, USA
bARMGO Pharma, Inc., 3960 Broadway 3rd Floor, New York, NY 10032, USA
cCenter for Drug Design, University of Minnesota, 516 Delaware St. SE, Minneapolis, MN 55455, USA
dDepartment of Medicinal Chemistry, Merck Research Laboratories, 126 Lincoln Avenue, Rahway, NJ 07065, USA
Received 5 April 2007; revised 29 May 2007; accepted 30 May 2007
Available online 6 June 2007
Abstract—Benzo[b]thienyl hydroxamic acids, a novel class of histone deacetylase (HDAC) inhibitors, were identified via a targeted
screen of small molecule hydroxamic acids. Various substitutions were explored in the C5- and C6-positions of the benzo[b]thio-
phene core to characterize SAR and develop optimal inhibitors. It was determined that substitution at the C6-position of the
benzo[b]thiophene core with a three-atom spacer yielded optimal HDAC1 inhibition and anti-proliferative activity in murine eryth-
roleukemia (SC-9) cells.
Ó 2007 Elsevier Ltd. All rights reserved.
Class I/II histone deacetylase (HDAC) enzymes are an
emerging therapeutic target for the treatment of cancer
O
H
N
OH
N
and other diseases.1 These enzymes, as part of multipro-
tein complexes, catalyze the removal of acetyl groups
from lysine residues on proteins, including histones,
affecting gene expression, differentiation, growth arrest,
and/or apoptosis in transformed cell cultures.2 HDAC
inhibitors have been shown to bind directly to the
HDAC active site and thereby block substrate access
and cause the accumulation of acetylated histones
in vitro.2 In vivo xenograft studies2 have further demon-
strated many of these agents to be effective in the inhibi-
tion of tumor growth, and most recently, ZolinzaTM
(SAHA, vorinostat)3 was approved for the treatment
of the cutaneous manifestations of cutaneous T-cell lym-
phoma. A wide range of structures have been shown to
inhibit the activity of Class I/II HDAC enzymes and,
with few exceptions, these can be broadly characterized
by a common pharmacophore comprised of a metal
binding domain, a linker domain, and a surface recogni-
tion domain (Fig. 1).4
H
O
ZolinzaTM
Surface
Metal
Binding
Linker
Recognition
Figure 1. Pharmacophoric summary of HDAC inhibitors.
As part of an ongoing effort to identify novel HDAC
inhibitors, a panel of small molecules containing
hydroxamic acid metal binding moieties was screened
for inhibitory activity against a crudely purified HDAC1
enzyme preparation.5 These hydroxamic acids contained
both the metal binding and linker domains but lacked
the surface recognition domain, thereby allowing maxi-
mal conformational freedom and highest potential for
obtaining the most favorable interaction between the
active site zinc and the hydroxamic acid. Once active
hydroxamic acid-based scaffolds were identified, the
strategy was to perform subsequent modifications to
the surface recognition domain to optimize potency
and pharmacokinetic properties. During the initial scaf-
fold ‘scan’ it was determined that there was a 30-fold
increase in HDAC inhibitory activity progressing from
aceto- to benzoyl hydroxamic acid, with IC50 values of
625 and 20 lM, respectively (Fig. 2). Further increases
in HDAC inhibitory potency were realized by replace-
ment of the aromatic phenyl moiety with a thiophene
Keywords: HDAC; Histone deacetylase inhibitor; HDAC inhibitor;
Anticancer drug; SAHA; Hydroxamic acids; Benzo[b]thiophene.
*
Corresponding author. Tel.: +1 617 992 2067; e-mail: David_
Witter@merck.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.091

D. J. Witter et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4562–4567
4563
OH
OH
O
HN
HN
H
N
H
O
OH
N
<
<<
<<
OH
S
S
O
O
HDAC1 IC50 = 625 μM
20 μM
C2 = 6.6 μM
C3 = 9.7 μM
C2 = 0.67 μM
C3 = 38% inh. @ 10 μM
Figure 2. Representative SAR from initial scaffold ‘scan’.
or benzo[b]thiophene (Fig. 2). The position of the
hydroxamic acid on the core scaffold was determined
to be important for both heterocycles, with the 2-substi-
tution being optimal in both cases. The C3-hydroxamic
acid on the benzo[b]thiophene exhibited 38% inhibition
at 10 lM compared to 670 nM for the 2-substituted ana-
log. Based on the 30-fold improvement in IC50 with the
benzo[b]thiophene analogs relative to the phenyl, an
exploration into benzo[b]thiophene substitutions was
initiated.6
of remaining di-methylester 3 and the corresponding dia-
cid. Unfortunately, when di-methylester 4 was subjected
to similar conditions, two inseparable monoacids were
observed (ca. 2:1). In order to obtain a differentially
substituted benzothiophene 2,5-dicarboxylate, the use
of a tert-butyl protecting group was employed via a
condensation reaction between benzaldehyde 2 and
tert-butyl thioglycolate, which was prepared in situ from
tert-butyl chloroacetate. Even though diester 6 was
formed in low yield, subsequent deprotection of tert-bu-
tyl ester quantitatively afforded desired monoacid 7. With
both mono-acids in hand, trityl-protected hydroxylamine
was used to afford the protected hydroxamic acids, which
were converted to the free acids. Various amides were
then constructed via standard amide coupling and the
hydroxamic acids were deprotected (Scheme 1).
The benzo[b]thiophene moiety represents an important
core structure found in biologically active small mole-
cules ranging from protease inhibitors7 to modulators
of GPCRs8 exemplified by marketed drugs such as
ZileutonTM,9 and RaloxifeneTM.8c Like many other het-
erocyclic aromatic structures, the benzo[b]thiophene
core provides numerous avenues for further chemical
modifications and there has been an increasing interest
in the development of methodologies for its construc-
tion.10 In the present communication, we describe part
of these SAR studies modifying the C5- and C6-posi-
tions of the benzo[b]thiophene core, focusing on the
identification of the optimal substitution pattern.
Acylated amino-benzo[b]thiothiophene analogs, 13a–g,
were prepared from commercially available nitro-benzo-
thiophenes via hydrogenolysis to the amines, subsequent
acylation, and conversion of the remaining ester to the
hydroxamic acids (Scheme 2).11 In order to generate
the homologated aminomethyl analogs (Scheme 4), the
formyl-benzo[b]thiophenes were synthesized as shown
in Schemes 2 and 3. The 5-formyl benzo[b]thiophene
16 was made from diazonium salt formation followed
by displacement with iodide which furnished the iodo
derivative 14 in a modest yield (Scheme 2). Formation
of a carbanion was accomplished by the action of iso-
propylmagnesium bromide at À40 °C in the presence
of the ethyl ester. Subsequent formylation was initially
attempted with DMF, but with little success. When
the more reactive Meyer’s reagent was used, the formy-
Commercially available benzaldehyde 1 underwent cycli-
zation with methyl thioglycolate to give benzo[b]thio-
phene di-methylester 3, which was successfully
converted into the desired monoacid 5 in excellent yield
under standard saponification conditions (Scheme 1).
Even though more than stoichiometric amount of so-
dium hydroxide (1.3 equiv) was used, this method
yielded only one monoacid, together with small amounts
O
5
O
O
H
a
b
O
OH
6
O
O
NO2
S
S
O
O
O
O
1
3 = 6-C(O)OMe
4 = 5-C(O)OMe
5
2 (see below)
O
O
O
O
O
O
e
c, d
O
H
OH
O
NO2
S
S
O
O
2
6
7
R1
N
O
f, g
h, i
H
R2
5 or 7
Trityl
H
N
O
O
N
O
OH
S
S
O
O
8a-g
Scheme 1. Reagents: (a) MeOC(O)CH2SH, K2CO3, DMF; (b) NaOH, THF/MeOH; (c) t-BuOC(O)CH2Cl, NaSH, DCM; (d) K2CO3, DMF; (e)
TFA, DCM; (f) Trityl-ONH2, EDC, HOBt, DCM; (g) NaOH, THF/MeOH; (h) HNR1R2, EDC, HOBt, DCM; (i) TFA, DCM.

4564
D. J. Witter et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4562–4567
H
NO2
b or c
d
a
H2N
N
H
OEt
OEt
R
N
OH
S
S
S
O
O
O
9 = 5-NO2
10 = 6-NO2
11 = 5-NH2
12 = 6-NH2
13a-g; R = C(O)R1,
OR
S(O)2R1, C(O)NHR1, C(O)NHR1
e
H
O
I
f
OEt
OEt
S
S
O
O
14
16
Scheme 2. Reagents and conditions: (a) H2, Pd/C, EtOH; (b) R1C(O)Cl or R1S(O)2Cl, Et3N, DCM; (c) R1-NCO, DCM; (d) NH2OH (aq), MeOH;
(e) NaNO2, H2O, HCl, then NaI; (f) i-PrMgBr, THF, À40 °C, then Meyer’s reagent.
O
O
HO
H
b
d
a
OEt
OEt
O
NO2
S
O
S
O
O
O
O
1
19
20
18
HO
H
c
OEt
OEt
S
S
O
O
O
21
Scheme 3. Reagents and condition: (a) EtOC(O)CH2SH, K2CO3, DMF; (b) LiI, pyr, reflux; (c) BH3, THF; (d) MnO2, DCM.
R
N3
H
N
H
N
OEt
c, d or e
f
OH
a, b
g
S
S
O
O
O
H
24a-g; R = C(O)R1,
OR
22 = 5-CH2N3
23 = 6-CH2N3
OEt
S(O)2R1, C(O)NHR1, C(O)NHR1
S
O
16 = 5-C(O)H
18 = 6-C(O)H
R2
R2
N
N
f
R3
H
R3
OEt
N
OH
S
S
O
O
17a-g
Scheme 4. Reagents: (a) NaBH4, THF/EtOH; (b) (PhO)2P(O)N3, DBU; (c) H2, Pd/C, MeOH; (d) R1C(O)Cl or R1S(O)2Cl, Et3N, DCM;
(e) R1-NCO, DCM; (f) NH2OH (aq), MeOH; (g) NaBH(OAc)3, HNR2R3, DCE.
lation provided 5-formyl benzo[b]thiophene 16 in a 48%
yield after crystallization. It should be noted that prep-
aration of compound 16 from 9 using this sequence
required no column chromatography.
methyl analogs were generated from reduction of the
aldehyde and subsequent conversion to the methyl
azides, 22 and 23. Hydrogenolysis of the azides gener-
ated the free amines, which were acylated and converted
to the hydroxamic acids with aqueous hydroxylamine.
The 2° and 3° amines were generated via reduction
alkylation and conversion of the ester to hydroxamic
acids as above.
For the preparation of 6-formyl benzo[b]thiophene 18, a
different approach was taken (Scheme 3). Condensation
of benzaldehyde 1 with ethyl thioglycolate gave the
benzo[b]thiophene 19, containing both a methyl and
an ethyl ester. Selective deprotection of methyl ester
was accomplished using KI in refluxing pyridine gener-
ating monoacid 20 in 53% yield. Clean reduction of
monoacid 20 with borane provided 6-hydroxymethyl
21, which was subsequently oxidized to 6-form-
ylbenzo[b]thiophene 18 in high yield. Both the 5- and
6-formyl benz[b]thiophenes, 16 and 18, were used as
intermediates.
All compounds were tested for the ability to inhibit
HDAC1 activity and erythroleukemia cell proliferation.
The initial series tested were the bis-oxo analogs repre-
sented in Table 1.5 The data reveal that optimal surface
recognition domain constituents are hydrophobic aro-
matic moieties residing in the benzo[b]thiophene C6-po-
sition. Moving from the methyl ester 8a to the anilide 8c,
the HDAC1 potency is maintained, but there is an in-
crease in cellular potency from 14 to 2.8 lM. Moreover,
there appears to be an optimal chain length between the
heterocycle and the phenyl moiety. A single methylene
Multiple analogs were generated from the common alde-
hyde intermediates (Scheme 4). The acylated amino-

D. J. Witter et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4562–4567
Table 1. SAR of bis-oxo benzo[b]thiophene analogs Table 2. SAR of amide substituted benzo[b]thiophenes
4565
O
H
N
H
N
H
R
OH
N
R
OH
S
O
S
O
O
R
Benzo[b]-thiophene HDAC1 SC9
substitution
R
Benzo[b]thiophene HDAC1 SC9
substitution IC50 (nM) IC50 (nM)
IC50
(nM)
IC50
(nM)
8a OMe
8c PhNH
8d PhNH
6
6
5
6
5
6
5
6
630
615
600
55
13880
2775
6135
1105
1705
2075
5330
2960
13a Ph
13b Bn
13c Bn
6
6
5
6
6
6
6
6
6
205
10
30
55
20
20
40
20
60
2900
220
1165
5575
230
8e (Ph)CH2NH
8f (Ph)CH2NH
8g Ph(CH2)2NH
8h Ph(CH2)2NH
8i (Ph)2CHNH
13d Dihydro-cinnamoyl
13e (4-F)Ph–CH2
75
60
13f (4-OMe)Ph–CH2
13g (Ph)(Et)CH
205
225
155
285
13h (Ph)((S)-Et)CH
13i (Ph)((R)-Et)CH
140
530
Values are means of three experiments.
Values are means of three experiments.
spacer between these moieties results in an increase in
cell potency as seen when comparing 8c, 8e, and 8g.
The maximal activity of the benzyl amide 8e is reduced
as the chain length increases to the phenethyl analog 8g.
Additional branching did not improve activity, as seen
with biphenyl analog 8i. In almost all cases the enzy-
matic and cellular inhibitory activities were superior
for the 6-substituted benzothiophenes relative to the 5-
position. The relatively poor cellular activity of the
bis-oxo class of compounds prompted the search for
alterative substitutions.
investigated. The initial analogs tested, the aminomethyl
amines, displayed a similar trend as the amide series,
with a three-atom linker being the optimal length
(Table 3). Within the 6-substituted amines, optimal
cellular activity (IC50 = 160 nM) is observed with the
benzyl amine 17c, relative to the corresponding aniline
17a and phenethyl amine 17e. The activity trend is sim-
ilar for the 5-substituted amines, however, they are ꢀ3-
fold less potent than the corresponding 6-substituted
analogs (13b vs 13c).
The next series of benzo[b]thiophene modifications
investigated were aniline-based analogs of the
benzo[b]thiophene core (Table 2). Acylations of the ami-
no-benzo[b]thiophene yielded sulfonamides, ureas, car-
bamates, and amides. The sulfonamides, ureas, and
carbamate analogs were shown to be active HDAC
inhibitors (IC50 < 200 nM), but lacked the desired cellu-
lar activity (IC50 > 1 lM; data not shown). However,
improvements in cellular activity were seen in the corre-
sponding amide series. As seen with the bis-oxo series,
hydrophobic aromatic moieties are preferred in the sur-
face recognition domain and a similar SAR for linker
length is observed. As the aromatic group is extended
from the benzoylyl 13a, phenylacetyl 13b, to dihydrocin-
namoyl 13d, HDAC1 and cellular activities are maximal
with an optimal three-atom linker 13b. The enzymatic
and cellular IC50s for the phenylacetyl amide, 13b, are
sub-micromolar, 11 and 220 nM, respectively. Substitu-
tion of the pendent phenyl group had little effect on
either activities as seen with 13e and 13f. Branching in
the alpha-position of the phenylacetyl group revealed a
mild dependence on stereochemistry as seen with the
two enantiomers, 13h and 13i, where the S-enantiomer
is threefold more active than its R-counterpart. Similar
modifications were made in the 5-position, however 6-
substitution offers superior HDAC1 and cellular activi-
ties (13b vs 13c). The sub-micromolar SC9 activity seen
with 13b prompted analysis of the aniline-homologated
amino-methyl benzo[b]thiophenes (Table 3).
Acylated aminomethyl analogs (Table 3), such as sul-
fonamides, carbamates, and ureas, exhibited HDAC
enzymatic inhibition, but lacked potent cellular activity
(data not shown; >1 lM). However, amide analogs pos-
sess both HDAC enzymatic and cellular activity. The
benzoylamide 24a, for example, possesses similar cellu-
lar activity compared to 17c (190 vs 160 nM), suggesting
the linker length between the hydrophobic aromatic
group is an important driver of potency and not neces-
sarily the functionality contained in the linker. As seen
in the bis-oxo, amides, and amino-methyl analogs, there
is a preference for C6-benzo[b]thiophene substitution
with a linker length of three atoms between the terminal
aromatic group and the benzothiophene core.
Table 3. SAR of homologated analogs
R
NH
H
N
OH
S
O
R
Benzo[b]thiophene HDAC1 SC9
substitution IC50 (nM) IC50 (nM)
17a Ph
17b Ph
6
5
6
5
6
5
6
6
45
175
50
1780
4870
160
17c PhCH2
17d PhCH2
17e Ph(CH2)2
17e Ph(CH2)2
24a PhC(O)
24b PhCH2C(O)
145
128
200
10
475
455
945
190
To further investigate the enzymatic and cellular inhibi-
tory activity of nitrogen-linked HDAC inhibitors, the
homologated amino-methyl benzo[b]thiophenes were
70
1220
Values are means of three experiments.

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D. J. Witter et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4562–4567
In order to better understand the increased HDAC1
activity of the benzo[b]thiophenes, compounds 13a–c
were docked into a homology model of hHDAC1 the
construction of which is described elsewhere.12 A set of
150 conformers of 13a–c were generated13a and energy
minimized using MMFF94 with a distance-dependent
dielectric of 2r.13b Due to the rigidity afforded by the
amide linker in conjunction with the planar nature of
the 2-hydroxyamyl benzo[b]thiophene, these effectively
reduced to eight conformers which were docked into
the homology model by superposition of the hydroxy-
mate moiety onto that of trichostatin A (TSA) as
observed in the hHDAC8 crystal structure (PDB entry
1T64).14 This was followed by energy minimization as
above within context of the hHDAC1 homology model
tors, 13a–c, as well as the crystallographic structure of
TSA as complexed with hHDAC8. The dimethylami-
no-phenyl and adjacent carbonyl of TSA form a planar
structure that makes contacts with residues at the rim
and adjacent shallow groove. The rigidity and regio-
chemistry of the pendant amides of the benzo[b]thioph-
enes appeared to preclude this same type of interaction
with the enzyme during the modeling studies. During
the energy minimization process, the aromatic ring of
Phe205 proximate to the methyl group in TSA rotates
ꢀ110° toward the solvent-exposed surface away from a
position orthogonal to the S of the docked benzo[b]thio-
phene ring. Thus, it appears to stack with the aromatic
linker rather than clash with it in a face to edge fashion.
This also results in a larger opening for the linker. It is
interesting to note that this rotation occurred during
minimization of the conformer which made the most sta-
bilizing interactions with the protein with the least
amount of internal strain. This conformer is one of the
eight considered for 13b, the most potent of the three
inhibitors studied in this fashion, and is depicted in ma-
genta in Figure 3. The main difference among the
benzo[b]thiophene inhibitors arises from the pendant
aromatic moiety. In 13b, the phenyl group can achieve
close contact to the Glu98 backbone maximizing van
der Waals interactions. The orientation of the pendant
phenyl moiety of 13c is toward the surface groove occu-
pied by TSA’s dimethylamino-phenyl group, but is
packed less snugly and makes fewer contacts. For the
least active inhibitor, 13a, which is the truncated analog,
the phenyl group is unable to utilize either of the above
surface interactions.
˚
wherein residues falling within 10 A of each conformer
were held rigid while the sidechains of residues within
˚
5 A were energy-minimized in conjunction with the
inhibitor. Figure 3 contains surface representations of
the modeled HDAC1 enzyme and one of the lowest
energy conformers for each of the three HDAC inhibi-
H
Ph
O
N
N
H
N
H
Ph
H
OH
O
N
N
N
OH
S
H
OH
S
O
O
O
O
C5 = 13c; yellow
C6 = 13b; magenta
TSA; green
13a; blue
Panel a
Glu98
Phe205
In conclusion, we have identified a series of novel
benzo[b]thiophene HDAC inhibitors that are character-
ized by high potency in HDAC and cellular proliferation
assays. C5- and C6-substituted benzothiophenes were
synthesized and the most active compounds were pheny-
lacetyl amide, 13b, benzylamine, 17c, and benzoylamide,
24a, which are C6-substituted. Moreover, all three struc-
tural series described herein were found to exhibit the
same SAR with regard to the distance between the ter-
minal aromatic moiety and the benzothiophene core.
A three-atom linker proved to be optimal for HDAC1
activity and homology models revealed a favorable
interaction for the C6-substitution pattern and linker
length. Further studies of these agents and related ana-
logs will be reported in due course.
Panel b
Glu98
Phe205
References and notes
1. (a) Huang, L. J. Cell. Physiol. 2006, 209, 611; (b) Liu, T.;
Kuljaca, S.; Tee, A.; Marshall, G. M. Cancer Treat. Rev.
2006, 32, 157; (c) Sadri-Vakili, G.; Cha, J.-H. J. Curr.
Alzh. Res. 2006, 3, 403.
2. (a) Rodriquez, M.; Aquino, M.; Bruno, I.; De Martino,
G.; Taddei, M.; Gomez-Paloma, L. Curr. Med. Chem.
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Biochem. 2005, 96, 293.
3. Grant, S.; Easley, C.; Kirkpatrick, P. Nat. Rev. Drug
Discov. 2007, 6, 21.
Figure 3. Panels
a and b contain surface representations of a
homology model of HDAC1 based on HDLP with docked HDAC
inhibitors, TSA and 13a–c. Each panel a and b represent a different
spatial orientation of the HDAC1 surface to illustrate the binding
differences among the four inhibitors. TSA is labeled in green, 13a is in
blue, 13b is in magenta, and 13c is in yellow. Preferred orientations of
13a–c illustrate the optimal fit of 13b.
4. Miller, T. A.; Witter, D. J.; Belvedere, S. J. Med. Chem.
2003, 46, 5097.

D. J. Witter et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4562–4567
4567
5. HDAC activity (enzymatic) was evaluated with epitope-
tagged human HDAC1 complex immuno-purified from
stably expressing mammalian cells and substrate from
Biomol Research Laboratories, Inc., Plymouth Meeting,
PA. Cell-based HDAC activity was studied in a MTS
assay using murine erythroleukemia cells (SC-9) incubated
with vehicle or increasing concentrations of compound for
48 h. For full details, see: Miller, T. A.; Witter, D. J.;
Belvedere, S. Preparation of thiophene and benzothioph-
ene hydroxamic acid derivatives as histone deacetylase
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11. General experimental for acylated 6-amino-benzothioph-
enes. To a solution of 6-amino-benzo[b]thiophene-2-car-
boxylic acid methyl ester (75 mg, 0.36 mmol) and NMM
(51.7 lL, 0.47 mmol) in THF/CH2Cl2 (2/1 mL) was added
acid chloride (0.434 mmol). After 24 h, the solvent was
removed. To the resultant mixture were added DMA
(2 mL) and NH2OH (50% aq, 1 mL). The solution was
stirred until the disappearance of starting material as
indicated by LC/MS. After removal of solvent, MeOH/
H2O was added until a precipitate formed. The solid was
filtered yielding the desired amide (13b; 65% yield). 1H
NMR (DMSO-d6) d 11.38 (br s, 1H), 10.42 (br s, 1H), 9.21
(br s, 1H), 8.38 (s, 1H), 7.90–7.75 (m, 2H), 7.50–7.15 (m,
6H), 3.65 (s, 2H). MS (EI): calcd (MH+) 327.07, exp
(MH+) 327.28. Additional experimental details and spec-
tral data can be found in Ref. 5.
6. Structure–activity relationships of additional scaffolds will
be highlighted in due course.
7. (a) Liang, A. M.; Light, D. R.; Kochanny, M.;
Rumennik, G.; Trinh, L.; Lentz, D.; Post, P.; Morser,
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J. Tetrahedron 1999, 55, 11641; (d) Yamashita, D. S.;
Dong, X.; Oh, H.-J.; Brook, C. S.; Tomaszek, T. A.;
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