Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology
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Perfl uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 307
Figure 11.12 Reactions of pyrido[2,3 - b ]pyrazine scaffolds [57] .
NF
F
PhSO
2
N
N
H
H
PhSH, NaH (4 equiv.)
THF, reflux, 7 d
NF
F
S
N
N
H
H
NF
F
PhSO
2
N
N
THF, reflux, 2 d
NF
F
N
N
N
Et
2
NLi
NF
F
PhSO
2
N
N
H
H
Reflux, 24 h
Ac
2
O
NF
F
PhSO
2
N
N
H
O
40a, 13%
40b, 13%
41, 66%
39
Figure 11.13 Synthesis of 2 - pyridone systems from pentafl uoropyridine.
N
F
F
F
FF
NaO
t
Bu
N
F
O
t
Bu
F
FF
N
F
O
t
Bu
F
F
Li OTBDMS
i)
ii) F
-
HO
70 %
63 %
i) NH
2
NH
2
ii)NaOH, O
2
N
F
O
t
Bu
FHO
NaH
N
O
t
Bu
FO
82 %
90 %
LDA
EMME
N
O
t
Bu
FO
O
OEt
O
EtO
i) DBU
ii) TFA
N
OH
FO
O
EtO O
POCl
3
/ DMF
N
Cl
FO
O
EtO O
42
308 Fluorine in Medicinal Chemistry and Chemical Biology
Fluoroquinolones have proved to be one of the most successful classes of antibacterial
agents both economically and clinically [59] and, as such, 2 - pyridones, as bio - isosteres of
quinolones, provide a valuable source of potential new therapeutic agents [60] .
11.3 Summary
The drug discovery arena requires the availability of an ever - increasing, diverse range of
polyfunctional heterocyclic core scaffolds based upon privileged structures with proven
biological activity from which to synthesize arrays of structurally similar analogues that
follow the Lipinski RO5 parameters with the aim of reducing the resources used in
hit - to - lead progression. In this chapter, we have outlined how perfl uorinated heteroaro-
matic systems such as pentafl uoropyridine and tetrafl uoropyrimidine can be utilized as
very effective core scaffolds for the synthesis of a diverse array of polysubstituted pyridine,
pyrimidine, [5,6] - and [6,6] - bicyclic fused - ring systems. Given the vast diversity of
mono - and difunctional nucleophiles that are readily available from commercial suppliers,
the core scaffolds and polyfunctional privileged structure systems that may be accessed
from perfl uorinated heteroaromatic starting materials offer, potentially, many great
opportunities.
Acknowledgments
We thank GlaxoSmithKline and EPSRC for funding our research in this area.
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12
gem - D i fl uorocyclopropanes as Key
Building Blocks for Novel Biologically
Active Molecules
Toshiyuki Itoh
12.1 Introduction
The cyclopropyl group is a structural element present in a wide range of naturally
occurring biologically active compounds found in both plants and microorganisms [1] .
Since substitution of two fl uorine atoms on the cyclopropane ring is expected to alter
both chemical reactivity and biological activity due to the strong electron - withdrawing
nature of fl uorine [2] , ge m - difl uorocyclopropanes are expected to display unique biological
and physical properties and a great deal of attention has been given to their chemistry
and singular properties [3,4] . This chapter describes the chemistry of these gem -
difl uorocyclopropanes that have unique biological activities. In particular, we focus on the
methodology for the synthesis of optically active gem - difl uorocyclopropanes as well as
our investigation into the novel biological activities of gem - difl uorocyclopropane
derivatives.
12.2 Biologically Active gem - D i fl uorocyclopropanes
The fi rst example of biologically active gem - difl uorocyclopropane derivative was reported
in 1986 by Johnson and his co - workers [5a] . Halogen - substituted analogues of DDT -
Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima
© 2009 Blackwell Publishing, Ltd. ISBN: 978-1-405-16720-8
314 Fluorine in Medicinal Chemistry and Chemical Biology
pyrethroid were synthesized and their insecticidal activity was examined. Subsequently,
it was found that gem - difl uorocyclopropane 1 possesses strong toxicity to some insects.
It was revealed that the optimum insecticidal activity required two fl uorine substituents at
the C - 2 position of the cyclopropane ring since chlorine - or monofl uorine - substituted
compounds, 2 and 3 , were less active than gem - difl uorocyclopropane 1 (see Figure
12.1 ).
The next important examples of biologically active gem - difl uorocyclopropane deriva-
tives were reported in 1995 – 1997 from several groups independently [6, 8, 9] . Pfi ster
and co - workers found a strong multidrug resistance (MDR) reversal activity of gem -
difl uorinated compound 5 , which is an analogue of the MDR reversal agent MS - 073. When
anti - ( R ) - 5 was used with the anticancer agent doxorubicin (1 µ g/mL) against the CHRC - 5
Chinese hamster cell line, expressing P - glycoprotein - mediated MDR, the cytotoxicity of
doxorubicin was substantially increased (EC
50
20.7 ± 3.8 nM), though anti - ( R ) - 5 alone did
not show any cytotoxicity [6] . gem - Difl uorocyclopropane anti - ( R ) - 5 exhibited an effect
∼ 2 - fold stronger than the corresponding nonfl uorinated compound, anti - H - 5 , and ∼ 3 - fold
stronger than MS - 073 (see Figure 12.2 ) [6] . In addition, anti - ( R ) - 5 was found to show
excellent stability in acidic medium ( t
1/2
= > 72 h at pH 2.0 and 37 ° C) compared with MS -
073 ( t
1/2
= ∼ 15 min at pH 2.0 and 37 ° C). Among four stereoisomers, anti - ( R ) - 5 possesses
the most potent activity. It is suggested that the superior activity of anti - isomers over syn -
isomers may be ascribed to effi cient π - stacking of the rigid anti - methanobenzosuberyl
group with the phenylalanine residue extending outwards in the α - helical backbone of
P - glycoprotein [6] . Barnett and co - workers recently reported an improved synthesis of
anti - ( R ) - 5 [7] .
Figure 12.1 Effect of substitution of fl uorine at the C - 2 position of the cyclopropyl ring on
insecticidal activity.
gem-Difl uorocyclopropanes as Key Building Blocks for Novel Biologically Active Molecules 315
Boger and Jenkins reported the synthesis of 9,9 - difl uoro - 1,2,9,9 a - tetrahydrocyclopr
opyl[ c ]benzo[ e ]indol - 4 - one (F
2
CBI) and its trimethylindolcarbonyl derivatives such as
F
2
CBI - TMI ( 6 ) as a fl uorinated analogue of CC - 1065, duocarmycin SA, and duocar-
mycin A, which are potent antitumor antibiotics exhibiting their cytotoxicities based on
sequence - selective DNA alkylation through the nucleophilic ring - opening of the cyclopro-
pane moiety [8] (see Figure 12.3 ). It was found that the introduction of two fl uorine atoms
onto the cyclopropane ring brings about enhanced reactivity in the acid - catalyzed
solvolysis ( ∼ 500 times compared with that of nonfl uorinated analogues) without altering
the inherent regioselectivity. Single - crystal x - ray structure analysis of the difl uoro
Figure 12.2 Effect of the gem - difl uorinated analogue of MS - 073 on the proliferation of mul-
tidrug resistant CH
R
C5 Chinese hamster cells in the presence of doxorubicin (1 m g/mL).
316 Fluorine in Medicinal Chemistry and Chemical Biology
analogues explained this enhanced reactivity and regioselectivity; that is, the cyclopropane
C – CF
2
– C bond angle was expanded and the carbon – carbon bond opposite to the
difl uoromethylene moiety was lengthened to induce additional strain energy. As a conse-
quence, the stability of F
2
CBI at pH 3 and 25 ° C ( t
1/2
= 4.2 h) was much lower than that
of nonfl uorinated counterpart, CBI, under the same conditions ( t
1/2
= 930 h). The
observed difference in the stability of the F
2
CBI structure as compared to the CBI
structure was refl ected to the cytotoxicity of their derivatives. Thus, 6 (IC
50
36 nM)
was ∼ 1000 times less cytotoxic than CBI - TMI (IC
50
30 pM). Also, the introduction of
the gem - difl uorocyclopropane moiety showed no perceptible effect on the DNA
alkylation selectivity with reduced effi ciency. Thus, in this case, fl uorinated analogues did
not provide better biological activity than the nonfl uorinated counterparts, although the
introduction of fl uorine induced substantial changes in chemical and biological
properties.
Taguchi and co - workers reported the potential of gem - difl uorocyclopropane as a
source of biologically active compounds [9] . gem - Difl uorinated methylenecyclopropane
(F
2
MCP) 7 was synthesized and its reactivity as a Michael acceptor was examined. The
crossover reaction of F
2
MCP 7 with 4 - aminophenylthiol in the presence of the nonfl uori-
nated methylenecyclopropane (MCP) 8 showed that F
2
MCP 7 reacted exclusively with the
thiol to give adduct 9 in excellent yield, while nonfl uorinated MCP did not react with the
thiol at all and 8 was recovered (see Figure 12.4 ) [9] . The result suggests that F
2
MCP
might act an irreversible inhibitor for certain enzymatic reactions such as acyl - CoA dehy-
drogenase - catalyzed reactions.
As described above, incorporation of fl uorine into bioactive compounds is well rec-
ognized to be very effective means for the enhancement of the physiological properties
of molecules [1 – 3] . Since fl uorine is the most electronegative element, its substitution
infl uences the acidity/basicity of neighboring groups and the lipophilicity of molecules
(see Chapter 1 ). Due to the isoelectronic nature of fl uorine to oxygen, a fl uorine substituent
can mimic a hydroxyl group in some biological responses [10] . Increased ring - strain
energy might be another important characteristic of fl uorine - substituted cyclopropanes
[3a, 11] . Cyclopropane ring - opening reactions are important for the mechanism of
cyclopropane - based enzyme inhibitors [12] and fl uorine - substitution may enhance the
Figure 12.3 Biologically active gem - difl uorocyclopropane F
2
CBI as a duocarmycin
analogue.
gem-Difl uorocyclopropanes as Key Building Blocks for Novel Biologically Active Molecules 317
inhibitory activity of these compounds. Examples are summarized in Figures 12.5 –
12.8 .
Figure 12.5 shows two examples of gem - difl uorocyclopropanes as a part of a rather
complex natural product framework. Koizumi and co - workers synthesized gem - difl uoro-
cyclopropane 10 as an analogue of the antiandrogenic agent, KNP 215 [13] and examined
its activity in terms of the suppressive effect on the androgen - stimulated weight gain.
Compound 10 exhibited an activity similar to that of KNP 215. Danishefsky and co -
workers reported the synthesis of the gem - difl uorocyclopropane analogue of anticancer
agent cycloproparadicicol 11 , but the potency of 11 was only ∼ 1/185 of that of the parent
compound [14] .
Various biological activities have been reported for simple gem - difl uorcyclopropane
molecules (see Figure 12.6 ). Conformationally restricted analogues of glutamate,
known as an excitatory neurotransmitter in mammals, have attracted much attention for
identifi cation of receptor subtype - specifi c agonists or antagonists (see Chapter 3 ). Intro-
duction of a cyclopropane moiety to such biologically active substances is one of the
key protocols in investigating an active conformer for the target receptor. It was anticipated
that the introduction of fl uorine would bring about little change in the steric size of the
molecule but would enhance the acidity of the neighboring carbonyl group and decrease
Figure 12.4 High reactivity of F
2
MCP as a Michael acceptor.
Figure 12.5 Examples of biologically active gem - difl uorocyclopropanes (complex
molecules).