Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.02.062

Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.

Full text of DOI:10.1016/j.bmcl.2005.02.062

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2033–2039
Design, synthesis, and activity of achiral analogs of
2-quinolones and indoles as non-thiol farnesyltransferase inhibitors
Qun Li,* Keith W. Woods, Weibo Wang, Nan-Horng Lin, Akiyo Claiborne,
Wen-zhen Gu, Jerry Cohen, Vincent S. Stoll, Charles Hutchins, David Frost,
Saul H. Rosenberg and Hing L. Sham
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA
Received 18 August 2004; revised 17 February 2005; accepted 18 February 2005
Available online 16 March 2005
Abstract—Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the
D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and
have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series.
The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.
Ó 2005 Elsevier Ltd. All rights reserved.
Farnesyltransferase (FTase) inhibitors have generated
much attention recently as anticancer agents because
of their potential for reduced intrinsic toxicity as com-
pared with the conventional cytotoxic agents.1 Among
the several inhibitors currently in Phase III clinical tri-
als, tipifarnib (R115777, 1) is perhaps the most potent
and selective non-thiol FTase inhibitor.2,3 Recently, we
reported a novel series of FTase inhibitors that contain
4-quinolone and pyridone cores resulting from struc-
tural modifications of tipifarnib.4 In this paper, we
report our continued efforts to utilize tipifarnib as a
template in designing novel classes of FTase inhibitors.
the relative position of N-3 which is essential for coordi-
nating with zinc (Fig. 1). Further structural refinement
replaces the 2-quinolone of 2 with other heterocycles
to yield compounds with an aromatic C-ring properly
positioned to occupy the same hydrophobic pocket as
in tipifarnib as represented by compound 4.
The synthesis of the 6-iodoquinolone (9) and subsequent
conversion to 3 is illustrated in Scheme 1. Thus
NC
Cl
Cl
H2N
Cl
D
C
D
C
The rationale for this series is based on analysis of the
X-ray structure of tipifarnib in complex with FTase,4,5
in which the D-ring is close to the methyl group on
the imidazole. Transposition of the D-ring to the methyl
group on the imidazole should not significantly affect its
binding to one of the hydrophobic pockets of FTase,
while leading to a novel series which may not have a chi-
ral center as seen in tipifarnib. This modification will
lead to two different series of compounds depending
on whether the D-ring is attached through a methylene
group to either N-1 (2) or C-5 (3). Both series conserve
W
N
N
Me
A
N
Me
B
N
D
A
N
Me
B
O
O
N
2
1
NC
W
NC
Cl
D
C
C
Y
N
N
N
N
A
N
Me
B
X
Het
N
O
4
3
Keywords: Tipifarnib; Zarnestra; R115777; Farnesyltransferase inhibi-
tors; Anticancer.
W=CH2, CHOH, CHNH2, CO; X=CH, N; Y=H, CN
*
Figure 1. Modifications of tipifarnib (1) lead to novel inhibitors of
FTase 2, 3, and 4.
Corresponding author. Tel.: +1 847 937 7125; fax: +1 847 936
1550; e-mail: qun.li@abbott.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.062

2034
Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2033–2039
Cl
Cl
N
Cl
Cl
CH3
I
I
Me
NC
I
a
c
a
b
Me
Cl
O
c
O
b
O
O
O2N
F
N
N
H2N
HN
Me
F
N
14
5
6
7
13
15
Cl
Cl
Cl
Cl
N
Cl
OH
Br
I
I
Me
d
e
e
O
d
N
O
N
Me
O
N
Me
N
HN
Me
O
N
N
O
N
Me
O
N
Me
N
10
9
Me
8
3d
16
17
NC
NC
Cl
Cl
Scheme 2. Reagents and conditions: (a) (i) LDA, THF, À78 °C, 2 h,
then 3-chlorobenzaldehyde, rt, overnight, 66%; (ii) MnO2, dioxane,
reflux, 1 h, 94%; (b) MeNH2, EtOH, rt, 5 h, 93%; (c) (i) AcOBut, LDA,
THF, À78 °C to rt, overnight; (ii) toluene, reflux, 1 h, 84%; (d) NBS,
AIBN, CCl4, reflux, 5 h, 44%; (e) 12, AcOEt, 55 °C, 5 days, then
MeOH, reflux, 2 h, 55%.
X
Br
X
N
f
N
N
12
Tr
N
O
N
Me
O
N
g
Me
3a, X=H
3b, X=OAc
3c, X=OH
11
h
provided the desired monobromide (17) in a respectable
yield (44%). Alkylation of 12 with bromide 17 using the
same conditions used for 3a furnished the desired naph-
thyridone 3d in 55% yield.
Scheme 1. Reagents and conditions: (a) 3-chlorobenzonitrile, NaOH,
MeOH, 0 °C to rt, 2 days, 93%; (b) Fe, AcOH, rt, 2 h, 49%; (c)
Me2SO4, n-Bu4NBr, THF, 60 °C, 3.5 h, 86%; (d) (i) Ac2O, toluene,
reflux, 21 h; (ii) NaOH, EtOH/H2O, reflux, 1.5 h 96%; (e) (i) iso-
PrMgBr, THF, À25 °C, 50 min, then N-formylmorpholine, rt, over-
night, 80%; (ii) NaBH4, MeOH, À78 °C to rt, overnight, 87%; (f) PBr3,
LiBr, DMF 0 °C to rt, 2 h, 96%; (g) (i) AcOEt, 55 °C, 4 days; (ii)
MeOH, reflux, 2 h, 42–46%; (h) LiOH, THF/H2O, rt, overnight, 100%.
The bioisosteres of 3 (2b and c) were prepared as de-
scribed in Scheme 3. Addition of the Grignard reagent
of 9 to aldehyde 184 provided alcohol 2a12 (38% yield).
Our attempt to eliminate the chiral center by deoxygen-
ating alcohol 2a utilizing the Barton–McCombie proto-
col10 was unsuccessful. Thus 2a was converted to ketone
b, amine c, and formamide 2d as indicated in Scheme 3.
4-iodonitrobenzene (5) was reacted with 3-chlorophenyl-
acetonitrile in the presence of NaOH in methanol6 to
produce benzisoxazole 6 (93% yield), which was reduced
with iron powder in acetic acid to give aminobenzophe-
none 7 in 49% yield.7 Methylation of 7 with dimethyl
sulfate utilizing conditions of Mouzin et al.8 provided
N-methylamine 8 in 86% yield. Compound 8 underwent
acetylation and base-catalyzed cyclization to furnish the
quinolone (9) in 96% yield. Formation of alcohol 10 was
accomplished by an iodine–magnesium exchange reac-
tion of 9 with magnesium isopropylmagnesium bro-
mide.9 The reaction of the resulting anion with N-
formylmorpholine and subsequent reduction of the alde-
hyde with sodium borohydride gave 10 in 70% yield.
Reaction of 10 with PBr3 produced bromide 11 (96%).
The desired compounds 3a and b were prepared in 42–
46% yield by regioselectively alkylating tritylimidazole
1210 with bromide 11 using the reaction conditions
developed by Anthony et al.11
Syntheses of analogs with variable D-rings and linker
lengths connecting the D-rings were executed as outlined
in Scheme 4. Alkylation of 1913 with bromide 11 as de-
scribed above followed by hydrolysis provided alcohol
20, which was converted to 21, 22, and 25a,b as de-
scribed in Scheme 4. Compounds 26 and 27 (Table 1)
were prepared from bromide 11 using similar methods
described in the literature.4,18
Compounds with modified AB- and C-rings of 2 were
prepared as depicted in Schemes 5 and 6. Thus aldehyde
28 underwent the Wadsworth–Emmons reaction to af-
ford acrylonitrile 29 (100% yield), which was converted
NC
NC
W
NC
Cl
Cl
Preparation of the bioisosteric 2-naphthyridone analog
3d is shown in Scheme 2. 2-Fluoropyridine 13 was
ortho-lithiated and reacted with 3-chlorobenzaldehyde.
The alcohol was then oxidized with MnO2 to form ke-
tone 14 in 66% yield. Conversion of the fluoroketone
(14) to naphthyridone 16 was achieved through nucleo-
philic displacement of the fluorine by methylamine (93%
yield). Condensation of the resulting aminoketone (15)
with tert-butyl acetate in the presence of LDA followed
by thermal cyclization gave 16 in 84% yield. NBS bro-
mination of methyl-naphthyridone 16 produced a mix-
ture of dibromo and monobromo compounds, but
OH
N
N
N
N
a
OHC
N
N
O
N
Me
O
N
Me
2a
18
b: W=CO (2b)
c: W=CHNH2 (2c)
d: W=CHNHCHO
(2d)
Scheme 3. Reagents and conditions: (a) 9, iso-PrMgBr, THF, À25 °C,
30 min, then 18, rt, overnight, 38%; (b) MnO2, dioxane, reflux, 1 h,
80%; (c) (i) SOCl2, CH2Cl2, rt, 2 h; (ii) NH4OH, THF/H2O, rt, 1 h,
32%; (d) HCONH2, AcOH, reflux, 5 h, 100%.

Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2033–2039
2035
37b in 59% yield. Descyano compound 37a was pre-
pared in 37% yield by Suzuki coupling of 5-bromoindole
(36) with 1-naphthylboronic acid. N-Alkylation of in-
doles 37 with chloride 31a yielded the 4c and d in 20–
22% yield.
NC
Cl
CN
Cl
O
O
N
N
N
N
O
N
The compounds were evaluated for their activities
against bovine Ftase17 and cellular Ras processing in
H-ras transformed cells.17 Selectivity against geranylger-
anyl transferase (GGTase I), a closely related enzyme
that is responsible for prenylating the majority of the
prenylated proteins, was also tested.18 Because FTIs
have been shown to be sufficient for achieving growth
inhibition in tumors and that this effect is not enhanced
with co-application of GGTase inhibitors, selective FTIs
are sought to avoid potential undesirable toxicity.19
These results are summarized in Tables 1–3.
O
N
Me
c
Me
b
21
22
Cl
Cl
AcO
HO
Cl
a
d
N
N
N
N
N
O
N
N
O
N
Tr
Me
Me
19
20
23
f
e
O
R
Cl
Cl
N
N
Compounds 2a–d that have the D-ring attached to the
N-1 of imidazole are potent FTase inhibitors, with
IC50 values ranging from 2.1 nM to 29 nM (Table 1).
Note that the chloro group in D ring has been replaced
by a cyano group in the new series because the cyano
group has been shown to dramatically boost the activity,
particularly in the Ras processing assay.4b,11,13,18 In the
X-ray structure4a and the model (Fig. 2), the D-ring cya-
no group fits into a small pocket and accepts H-bonds
from the main chain NH of both Tyr361 and Phe360
of the b-subunit. The most potent analogs are the amine
(2c) and corresponding formamide d. Alcohol 2a is only
slightly less active as compared with amine 2c. Oxida-
tion of the alcohol (2a) to the ketone (2b) resulted in a
6-fold drop in activity. Bioisostere 3a, in which the D-
ring is attached to C-5, versus N-1 in 2, displays an
IC50 of 7.2 nM, which is 2- and 11-fold higher respec-
tively compared to 2b and tipifarnib (racemic, same be-
low). The activity is markedly impaired when the linker
N
N
N
O
N
Me
25a, R=CN; 25b, R=
N
O
N
Me
O
N
O
24
Scheme 4. Reagents and conditions: (a) (i) 11, AcOEt, 60 °C,
overnight; (ii) MeOH, reflux, 1 h; (iii) LiOH, THF/H2O, rt, 14 h,
57%; (b) 4-fluorobenzonitrile, NaH, DME, rt, overnight, 80%; (c) 4-
cyanobenzyl bromide, NaH, DME, rt, 3 h, 40%; (d) SOCl2, rt, 1 h,
100%; (e) 4-hydroxypyridine, NaH, DME, rt, 14 h, 79%; (f) the
pyrroles,14 NaH, THF, rt, overnight, 36–37%.
to pyrrole 30 in 75% yield by treatment with tosylmethyl
isocyanide (TosMIC) utilizing the reaction conditions
developed by Pavri and Trudell.15 Displacement of chlo-
ride 3116 with pyrrole 30 furnished the desired com-
pounds 4a and b in 75–88% yield.
Formylation of phenol 32 by the Duff reaction afforded
33 (8% yield). Phenol 33 was converted to the triflate
(87% yield), which then underwent the Suzuki coupling
with 1-naphthylboronic acid to form aldehyde 34 in 46%
yield. Transformation of aldehyde 34 to nitrile 35 was
achieved in 93% through dehydration of the oxime inter-
mediate. Reaction of 35 with DMF dimethyl acetal and
subsequent reduction of the nitro group produced indole
HO
OHC
HO
a
b
NO2
NO2
CH3
33
CH3
32
OHC
34
NO2
CH3
c
d
37a, X=H
b
a
X
NC
NO2
NH
37b, X=CN
CH3
NH
CN
CHO
35
b-ii
(X=H)
NC
e
29
28
30
NC
R1 R2
R1 R2
c
Br
NH
4c, X=H
N
N
X
N
4d, X=CN
N
N
N
N
N
36
Cl
.HCl
NC
Scheme 6. Reagents and conditions: (a) hexamethylenetetramine, TFA,
reflux, 60 h, 8%; (b) (i) Tf2O, Et3N, CH2Cl2, rt, overnight, 87%; (ii) 1-
naphthylboronic acid, Pd(PPh3)4, NaHCO3, EtOH/toluene, reflux, 3 h,
37–46%; (c) (i) NH2OH, NaOAc, EtOH, reflux, overnight; (ii) Ac2O,
reflux, 4 h, 93%; (d) (i) DMF–DMA, DMF, 100 °C, 3 h; (ii) Fe, AcOH/
EtOH, reflux, 0.5 h, 59%; (e) 31a, NaH, DMF, rt, overnight, 20–22%.
31a, R1=CN, R2=H
31b, R1,R2=OCH2O
4a, R1=CN, R2=H
4b, R1, R2=OCH2O
Scheme 5. Reagents and conditions: (a) CNCH2PO(OEt)2, DBU,
CH3CN, rt, overnight, 100%; (b) TosMIC, t-KOBu, THF, reflux, 2 h,
75%; (c) NaH, THF, rt, 5 h, 75–88%.

2036
Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2033–2039
Table 1. Activity of 2-quinolone farnesyltransferase inhibitors
NC
Cl
X
B
A
N
O
N
Me
Z
Compd
X
Z
A
C
B
IC50 (nM)
EC50 (nM)
Rasc processing
FTa
4.7
GGTb
HO
O
2a
CH
N
17,000
32%d
2b
2c
CH
CH
C
C
N
N
29
<10,000
22,000
30%d
42%d
NH2
3.8
HN
28%d
57%d
39%d
nte
O
2d
3a
3d
26
CH
CH
N
C
N
N
C
N
C
C
N
2.1
7.2
10
>10,000
>10,000
4000
CH
89
nte
O
CN
Cl
27
80
nte
nte
Me
N
O
O
N
N
Me
1
Tipifarnibf
Lonafarnibf,20
0.65
8.3
1100
>10,000
1.6
100
a Bovine farnesyltransferase.
b Bovine geranylgeranyltransferase.
c In H-ras NIH-3T3 cells.
d Inhibition at 100 nM.
e Not tested.
f Data from racemic mixtures.
between the AB-ring and the imidazole is extended to
three atoms (26–27).
group. Activity of the compounds with other linkers,
including substituted methyl (3b and c), two-atom linker
(21) and three-atom linker (22), are markedly impaired.
All compounds in Table 1 demonstrate excellent selec-
tivity against GGTase I18 with IC50 values equal to or
greater than 4 lM. However, none of the compounds
showed good cellular activity in the Ras processing as-
say, with the best one being 3a, which induced 57% inhi-
bition of the Ras processing at 100 nM. Addition of a
nitrogen atom to the B-ring (3d) has little effect on either
enzymatic or cellular activities.
With the optimal D-ring seemingly being the cyanophenyl
group, we focused our attention on modification of the
2-quinolone part of compound 2. There are two impor-
tant structural features of this part of the molecule in its
interaction with FTase. First, it must have an aromatic
D-ring which increases the binding affinity through
interaction with a hydrophobic pocket. Second, the Ôhet-
erocycleÕ containing either a carbonyl group as in 1 or a
cyano group provides a significant potency enhancement
by binding to the main chain loop consisting of residues
Asp359, Phe360, and Tyr361 through a combination of
electrostatic and van der Waals interactions, although
the exact role is not clear.4
In an effort to take advantage of the easily available alco-
hol 20, several compounds with various D-rings and
linkers connecting the D-ring were synthesized. Pyridone
24 and amide 25b were prepared with the hope that the
cyano group in 3a is replaceable by a carbonyl group.
Unfortunately, replacing the cyanophenyl group in 3a
with 4-pyridone (24), 3-cyanopyrrole (25a), or 3-mor-
pholinylcarbonyl-pyrrole (25b) all resulted in significant
loss in activity, with IC50 values ranging from 560 nM
to over 1000 nM (Table 2). The optimal linker between
the cyanophenyl group and the imidazole is the methyl
Our goal was to design moieties that can be alkylated by
the easily available chloride 33. Pyrrole 3221 seemed to
be the ideal candidate for this purpose. Compound 4a
turned out to be a very potent inhibitor of FTase with
an IC50 of 0.58 nM (Table 3). It also potently inhibits

Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2033–2039
Table 2. Activity of 2-quinolone farnesyltransferase inhibitors
2037
Cl
Ar
Y
N
N
O
N
Me
Compd
Ar
Y
IC50 (nM)
EC50 (nM) Rasc processing
FTa
GGTb
17,000
NC
3a
4.7
57%d
NC
NC
NC
NC
O
3b
3c
>1000
44
>1000
>10,000
nte
nte
nte
nte
nte
nte
nte
OAc
OH
O
O
21
22
24
25a
>1000
>1000
>1000
560
nte
nte
N
NC
nte
N
O
nte
nte
N
25b
>1000
O
N
a Bovine farnesyltransferase.
b Bovine geranylgeranyltransferase.
c In H-ras NIH-3T3 cells.
d Inhibition at 100 nM.
e Not tested.
cellular Ras processing displaying an EC50 of 34 nM.
Despite being more active than the 2-quinolone analogs
against GGTase, the selectivity is still 240-fold. Substi-
tuting 31b for 31a resulted in compound 4b that shows
a 10-fold drop in potency, further confirming the cyano-
phenyl group as the optimal D-ring in this series.
farnib (1)4 are shown in Figure 2. The models of 3a and
4d superimpose very well with tipifarnib in which the
methyl imidazole is interacting closely with the active
site Zn2+ and the imidazole nitrogen. The A-ring extends
out over the loop of residues Asp359-Phe360 forming
good van der Waals contact with the loop. The C-ring
is stacked against Trp106 and Trp102 and the D-ring
stacks along the hydroxy farnesyl pyrophosphate
(HFP). The C- and D-rings also stack together forming
a strong p–p interaction.
Further modification led to the discovery of the most po-
tent compounds in this series. Indole analog 4c shows
subnanomolar activity against FTase. More importantly,
4c demonstrates dramatically improved cellular potency
with an EC50 of 5.7 nM. The activity of the correspond-
ing cyano-containing analog (4d) improves 6-fold as
compared with 4c. It displays an IC50 of 0.15 nM, which
is about 4-fold more active than tipifarnib. 4d is nearly
equipotent to tipifarnib as measured in Ras processing
assay, with an EC50 of 2.1–1.6 nM for tipifarnib.
In summary, beginning with the structure of tipifarnib, a
series of inhibitors of FTase have been synthesized by
transposition of the D-ring to the imidazole and subse-
quent modification of the 2-quinolone motif. The new
2-quinolone-containing compounds demonstrate sin-
gle-digit nanomolar activity against FTase and are
highly selective against GGTase with IC50 values of over
10 lM in most cases. Although inferior to tipifarnib
with respect to cellular activity, the easier and more con-
vergent synthesis allows for preparation of a large
Stereoviews of overlays of models of 3a and 4d, which
were modeled based on the crystal structure of a close
chemical analog18 and the X-ray crystal structure of tipi-

2038
Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2033–2039
Table 3. Activity of pyrole and indole farnesyltransferase inhibitors
Ar2
N
N
Ar1
Compd
Ar1
Ar2
IC50 (nM)
EC50 (nM) Rasc processing
FTa
GGTb
140
NC
4a
0.58
6.1
34
NC
N
N
O
O
4b
520
68%d
NC
NC
NC
4c
4d
0.93
0.15
270
110
5.7
2.1
N
N
NC
a Bovine farnesyltransferase.
b Bovine geranylgeranyltransferase.
c In H-ras NIH-3T3 cells.
d Inhibition at 1000 nM.
Figure 2. Stereoviews of overlays of models of (A) compound 3a (in green) and (B) compound 4d (in white) over the X-ray crystal structure of
tipifarnib (1)4 (in purple) in complex with FTase in the active site. Zn+2 is shown in grey and hydroxy farnesylpyrophosphate in blue.
number of achiral analogs including 4-quinolones and
their bioisosteres,4 pyrrole, indole, and other heterocy-
cles, many of which would be difficult or impossible to
make in the original tertiary carbon-based tipifarnib ser-
ies. One such example is the indole analog 4d as dis-
cussed in this paper, which shows superior in vitro

Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2033–2039
2039
7. Hester, J. B.; Ludens, J. H.; Emmert, D. E.; West, B. E. J.
Med. Chem. 1989, 32, 1157–1163.
8. Mouzin, G.; Cousse, H.; Autin, J. Synthesis 1981, 6, 448–
449.
enzymatic activity to tipifarnib. These encouraging re-
sults warrant further efforts to optimize the properties
of the molecules in this series.
9. Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 1701–1703.
References and notes
10. Aslanian, R.; Brown, J. E.; Shih, N.-Y.; Mutahi, M. W.;
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1. For a recent reviews on FTIs see: (a) Sebti, S. M.; Adjei,
A. A. Semin. Oncol. 2004, 31(suppl. I), 28–39; (b)
Mazieres, J.; Pradines, A.; Favre, G. Cancer Lett. 2004,
206, 159–167; (c) Doll, R. J.; Kirschmeier, P.; Bishop, W.
R. Curr. Opin. Drug Discov. Devel. 2004, 7, 478–486; (d)
Bell, I. M. J. Med. Chem. 2004, 47, 1869–1878.
2. (a) van Cutsem, E.; van de Velde, H.; Karasek, P.; Oettle,
H.; Vervenne, W. L.; Szawlowski, A.; Schoffski, P.; Post,
S.; Verslype, C.; Neumann, H.; Safran, H.; Humblet, Y.;
Perez Ruixo, J.; Ma, Y.; von Hoff, D. J. Clin. Oncol. 2004,
22, 1430–1438; (b) Venet, M.; End, D.; Angibaud, P. Curr.
Top. Med. Chem. 2003, 3, 1095–1102; (c) Caponigro, F.;
Casale, M.; Bryce, J. Expert Opin. Investig. Drugs 2003,
12, 943–954; (d) Norman, P. Curr. Opin. Invest. Drugs
2002, 3, 313–319.
3. Relevant studies using tipifarnib as a template: (a)
Angibaud, P.; Bourdrez, X.; End, D. W.; Freyne, E.;
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