Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

Fluorinated Moieties for Replacement of Amide and Peptide Bonds 287

10.4 Conclusion

Recent advances in the bioorganic and medicinal chemistry of ﬂ uoropeptide mimetics and

related compounds are reviewed. The ﬂ uoro - oleﬁ n dipeptide isosteres Ψ [CF = CH] have

been studied extensively. Although steady advances in synthetic methods should be noted,

the development of more efﬁ cient and selective methods that tolerate various substitution

patterns and produce products in enantiomerically pure forms with a short - step procedure

is still required. Such development in synthetic methods will undoubtedly promote appli-

cations of ﬂ uoropeptide mimetics and related compounds to medicinal research. Weak or

lack of hydrogen bond - forming ability of ﬂ uorinated isosteres as amide mimics has been

suggested to explain the observed weak enzyme – substrate interactions or low biological

activities. On the other hand, their enhanced in vivo stability and/or enhanced afﬁ nity to

enzymes have also been experimentally veriﬁ ed. Fluorinated dipeptide isosteres and

nucleobase mimics also provide new and useful tools for bioorganic chemistry research,

as exempliﬁ ed in their use in molecular recognition of oligonucleotides.

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11

Perﬂ uorinated Heteroaromatic Systems

as Scaffolds for Drug Discovery

David Armstrong , Matthew W. Cartwright , Emma L. Parks , Graham Pattison ,

Graham Sandford , Rachel Slater , Ian Wilson John A. Christopher , David D. Miller ,

Paul W. Smith , and Antonio Vong

11.1 Introduction

The drug discovery process within the pharmaceutical industry has undergone many sig-

niﬁ cant changes over the past 40 years in order to decrease the high attrition rate of drug

candidates in the highly resource intensive discovery and development phases [1 – 3] .

Advances in technology brought about by the introduction of high - throughput screening

(HTS) in 1989 now allow hundreds of thousands of compounds to be assessed for biologi-

cal activity by a variety of in vitro assays within a very short time frame [4] . The subse-

quent introduction of combinatorial chemistry techniques [1] allowed the synthesis of

compound collections comprising around a million different entities for biological screen-

ing purposes [5] . However, despite some early promise, the production of such large

numbers of new molecules did not lead to the desired increase in the number of suitable

candidates for hit - to - lead generation [6, 7] .

Consequently, medicinal chemists have begun to pay closer attention to the structure,

nature and function of molecules synthesized and screened as drug candidates in order to

be able to recognize and, crucially, predict drug - like entities to aid the medicinal chemist

in their choice of synthetic target molecules. Approaches to predict drug - likeness have

been developed in recent years and include simple counting schemes, functional group

methods and the analysis of the multidimensional “ chemical space ” occupied by drugs

and neural network learning systems, and all these differing strategies have been discussed

Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima

292 Fluorine in Medicinal Chemistry and Chemical Biology

at length [5, 8] . In general, however, molecular “ drug - like ” properties can be deﬁ ned as

being a combination of favourable physiochemical (e.g. solubility, stability) and biological

parameters (e.g. absorption, distribution, metabolism, elimination and toxicity; ADME -

Tox) [2] .

In a seminal publication that outlines one popular approach, published in 1997,

Lipinski [1] analysed the physiochemical properties that are required for determining

whether a molecule will be orally bioavailable, and a statistical analysis of existing

successful drug systems was formalised as simple heuristic guidelines known as the

“ Rules of ﬁ ve ” (RO5) (see Table 11.1 ). These “ rules ” were intended to be “ conservative

predictors ” [9] to aid medicinal chemists to synthesize and select compounds that would

possess suitable physiochemical drug - like properties and, therefore, help reduce com-

pound attrition rates during clinical stages because, in principle, resources would not be

utilized on the synthesis of molecules that would not have drug - like characteristics.

The research by the Pﬁ zer group resulted in a paradigm shift of thinking for the

medicinal chemist [12] and has been cited well over a thousand times in the literature [9] .

Subsequently, similar analysis was carried out by scientists at other major pharmaceutical

companies such as GSK [11] , Boehringer Ingelheim [13] , Astra Zeneca [14] , Bayer [15]

and Lilly [16] , and very similar conclusions were formulated. From these further inves-

tigations, two notable extensions [11] to the RO5 (see Table 11.1 ) were established and

are now widely used as additional predictive ﬁ lters to identify suitable drug - like

structures.

The RO5 have proved to be an extremely useful set of physiochemical parameters in

the decision - making process in hit - to - lead generation and have been applied to the syn-

thesis and analysis of many libraries of drug - like molecules that contain low - molecular -

weight systems that possess diverse structural features [1] . If a particular compound has

structural features that lie outside these guidelines, it is highly probable that solubility and

permeability problems will occur in subsequent stages of drug development [9] . There are,

however, exceptions to these rules [1] , such as various medicinally important antibiotics,

antifungals, vitamins and cardiac glycosides, and it is very important to note that RO5 -

compliant molecules are not, of course, automatically good drugs. Additionally, the

RO5 do not give any indication as to the types of molecular structures that should be

synthesized. They are merely a guideline as to whether a particular structural class of

compound may possess drug - like features [9] .

Consequently, it falls to the medicinal chemist to identify and design the structures

of suitable drug - like entities using the RO5 as predictive guidelines, and subsequent con-

Table 11.1 Lipinski parameters ( RO 5) for predicting “ drug - likeness ” of potential

molecular targets

Rule of 5 [10]

• Molecular weight ≤ 500

• The calculated log of the octanol/water partition coefﬁ cient, Clog P

≤ 5

• Hydrogen - bond donors ≤ 5

• Hydrogen - bond acceptors (sum of N and O atoms) ≤ 10

Extensions [11]

• The polar surface area ≤ 140 Å

2

or sum of hydrogen - bond donors and

acceptors ≤ 12

• Rotatable bonds ≤ 10

Perﬂ uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 293

struction of libraries or arrays of appropriate drug - like molecules has been increasingly

based upon the concept of privileged structures. First proposed by Evans in 1988 [17] ,

privileged structures can be described as molecules that possess versatile binding

properties so that, through modiﬁ cation of various structural features, they are selective

for a variety of different biological receptors. The parameters deﬁ ned when choosing a

privileged structure system can be summarized as in Table 11.2 [18] .

Once a suitable privileged structure has been identiﬁ ed, rapid analogue synthesis

(RAS) techniques are used to produce arrays of compounds containing the required privi-

leged structure as the “ heart ” of the molecule and these methods can have a powerful

impact within the drug discovery arena [19, 20] . Methodology that may be applied to RAS

must be highly selective and high - yielding to allow the synthesis of libraries of privileged

polyfunctional entities [21] . Most importantly, RAS requires the synthesis of “ core scaf-

folds ’ , that is, molecules that themselves have privileged structure features and possess

many functional groups that allow rapid and selective functionalization, to give an array

of analogues based upon the privileged core system. The design and synthesis process

from identiﬁ cation of privileged structure to the RAS of many analogues of drug - like

systems and identiﬁ cation of lead compounds by high - throughput screening is shown

schematically in Figure 11.1 .

It can reasonably be argued, therefore, that the key to the hit - to - lead generation

process is the construction of a range of readily available “ core scaffolds ” possessing

multiple functionality that may be processed by efﬁ cient, regioselective and stereoselec-

tive, versatile, short and high - yielding RAS methodology.

Based on the criteria outlined above, low - molecular - weight, polyfunctional hetero-

aromatic compounds should make excellent candidates for privileged structures because

heteroaromatic structural subunits are present among many natural products and in about

70% of all pharmaceutical products that may be administered orally (some examples are

shown in Figure 11.2 ).

Table 11.2 Features of “ privileged structures ”

• Obeys RO5 (particularly MW ≤ 500) [3]

• Present in a large amount of natural products with varied biological activities

• Contains one or more rigid ring system and easily chemically modiﬁ ed to produce a

diverse library range

Figure 11.1 Privileged structures, core scaffolds and RAS in the drug discovery process.

Privileged structure

Designed to obey RO5

Functional groups

Core scaffold

Rapid

analogue

synthesis

A

1-n

C

1-n

B

1-n

A,B, C - reagents of maximal

structural diversity

Array or library

Reaction with:

A

1-n

, B

1-n

, C

1-n

High

throughput

screening

A

4

C

6

B

13

'Hit' compound

for 'Lead'

development

294 Fluorine in Medicinal Chemistry and Chemical Biology

Generally, rigid, polycyclic heteroaromatic systems, such as quinazolinones, are

excellent privileged structures and many heterocyclic systems that have been assessed and

developed as privileged structures have been thoroughly reviewed [3] . One key structural

feature exhibited by heteroaromatic systems is their ability to contain a diverse range

of substituents in a well - deﬁ ned three - dimensional space around a core structural

scaffold which, in comparison with their acyclic analogues, results in the constriction of

conformational freedom [22] . In order to be more exploitable, heterocyclic “ core scaf-

folds ” must bear several reactive sites that may be readily functionalized in a controlled

manner in high yield and with high regioselectivity. Unfortunately, scaffold and subsequent

analogue synthesis of many polyfunctionalized heterocyclic systems is hampered by the

Figure 11.2 Examples of biologically active heteroaromatic systems.

N

S

N

NMe

2

Antihistamine

N

S

N

Antipsychotic

NMe

2

N

Br

Me

H

O

Me Me

NHR

CRF antagonist

N

Cl

Br

H

O

Glycine antagonist

N

H

N

S

O

CH

3

H

3

CO

Inotropic agent

N

Me

S

N

Me

CO

2

Et

CH

2

i

Pr

O O

Anti-inflammatory

N

Me

NH

2

Immune response

modifier

N

H

2

N N

H

OH

Antiviral (HIV)

Perﬂ uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 295

inherent low reactivity and low regioselectivity of many aromatic heterocyclic systems

[23, 24] and there exists, therefore, a continuing requirement in the life science industries

for accessible, novel, heterocyclic scaffolds that bear multiple functionality and can be

processed into systems that possess maximally diverse structural features.

In this chapter, we describe the use of highly ﬂ uorinated heteroaromatic systems as

effective core scaffolds for the synthesis of an increasingly wide range of polyfunctional

heterocyclic systems.

11.2 Perﬂ uorinated Heterocycles as Core Scaffolds

Perﬂ uoroheteroaromatic compounds [25, 26] , in which all the hydrogen atom substituents

of the heterocyclic ring have been replaced by ﬂ uorine atoms, were ﬁ rst synthesized in

the 1960s by reaction of potassium ﬂ uoride with appropriate perchlorinated heteroaromatic

precursors [25, 26] and a range of perﬂ uorinated heteroaromatic systems may be accessed

by halogen exchange (Halex) techniques as shown in Figure 11.3 .

Perﬂ uorinated heteroaromatic derivatives are highly susceptible towards nucleophilic

attack owing to the presence of several highly electronegative ﬂ uorine atoms attached

to the heteroaromatic ring; consequently, the chemistry of perﬂ uoroheteroaromatic

systems is dominated by nucleophilic aromatic substitution processes and new chemistry

continues to emerge [25, 26] . Highly halogenated heteroaromatics are not merely of aca-

demic interest: a variety of such systems are commercially available from the usual

research chemical suppliers and, indeed, some are prepared on the industrial scale for use

in the ﬁ bre reactive dye industry and as intermediates for life - science products; for

example 3,5 - dichloro - 2,4,6 - triﬂ uoropyridine is a precursor for a herbicide manufactured

by the Dow company [27] . No special handling procedures are required for syntheses

Figure 11.3 Synthesis of perﬂ uoroheteroaromatic systems [25, 26] .

NCl

Cl

KF, 350

o

C

autoclave

NF

F

N

Cl

Cl Cl

Cl

KF, 350

o

C

autoclave

N

F

F F

F

N

Cl

KF, 350

o

C

autoclave

N

F

ClCl

Cl

Cl F

F

F F

68%

95%

73%

296 Fluorine in Medicinal Chemistry and Chemical Biology

involving perhaloheterocyclic derivatives; for example, pentaﬂ uoropyridine is a readily

available, inexpensive, colourless liquid that has a boiling point of 100 ° C. Consequently,

their chemistry can be used by the general organic chemistry community and can be scaled

up if required.

11.2.1 Pentaﬂ uropyridine as a Core Scaffold

Reactions between pentaﬂ uoropyridine 1 and a variety of nucleophiles have been estab-

lished [25, 26] and are found to be regioselective in the vast majority of cases, giving

products 2 arising from nucleophilic aromatic substitution of the ﬂ uorine atom located at

the 4 - position of 1 via the corresponding well - known Meisenheimer intermediate as shown

in Figure 11.4 , although a few exceptions to this general rule occur [28] . The regioselec-

tivity of these processes is due to (i) the presence of the ring nitrogen, which activates

para positions preferentially, and (ii) maximizing the number of activating ﬂ uorine atoms

that are located ortho to the site of nucleophilic attack [25, 26] .

Monosubstituted systems 2 are, of course, still activated towards nucleophilic

attack and, indeed, all ﬁ ve ﬂ uorine atoms can be replaced upon reaction with an excess

quantity of suitably reactive sulfur nucleophile species to give 3 [29] (see Figure 11.4 ),

demonstrating the feasibility of using highly ﬂ uorinated heterocycles as scaffolds where

the carbon – ﬂ uorine bond acts as the readily substituted functional group.

The order of nucleophilic attack for pentaﬂ uoropyridine 1 is established [25] to be

4 > 2 > 3, for monosubstitution reactions involving a range of nucleophiles. The order of

substitution for a succession of ﬁ ve nucleophilic substitution steps, where Nuc

1

is the ﬁ rst

nucleophile, and Nuc

2

is the second, etc., can therefore be postulated to occur as outlined

in Figure 11.4 to give 4 ultimately, although the outcome of successive reactions may

depend upon the nature and effect of the substituent that is installed onto the pyridine ring

in each nucleophilic substitution step. The wide range of functional nucleophiles available

Figure 11.4 Nucleophilic aromatic substitution of pentaﬂ uoropyridine [25, 26, 29] .

N

F

F F

F

+ Nuc

N

F

F Nuc

N

Nuc

F

F F

F

Meisenheimer

complex

NF

F

Nuc

1

NF

F

Nuc

1

F

Nuc

2

NNuc

3

F

Nuc

1

F

Nuc

2

Nuc

4

Nuc

3

Nuc

5

NNuc

3

Nuc

5

Nuc

1

Nuc

4

Nuc

2

NF

F

NPhS

PhS

SPh

Excess PhSNa

DMEU, r.t., 6 d

1

2

3, quantitative

4

Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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