Antitumour polycyclic acridines. Palladium(0) mediated syntheses of quino[4,3,2-kl]acridines bearing peripheral substituents as potential telomere maintenance inhibitors

Article abstract of DOI:10.1039/b305177n

Pd(0) mediated couplings between substituted 2-(pivaloylamino)benzeneboronic acids and 3,6-disubstituted-10-methylacridones 13 bearing a bromo or trifluoromethylsulfonyloxy substituent in the 1-position yield intermediate 1-arylacridones 16 which can be c

Full text of DOI:10.1039/b305177n

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Antitumour polycyclic acridines.† Palladium(0) mediated
syntheses of quino[4,3,2-kl]acridines bearing peripheral
substituents as potential telomere maintenance inhibitors
Robert A. Heald and Malcolm F. G. Stevens*
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham,
Nottingham, UK NG7 2RD. E-mail: malcolm.stevens@nottingham.ac.uk; Fax: (115) 951
3412; Tel: (115) 951 3414
Received 8th May 2003, Accepted 15th August 2003
First published as an Advance Article on the web 3rd September 2003
Pd(0) mediated couplings between substituted 2-(pivaloylamino)benzeneboronic acids and 3,6-disubstituted-10-
methylacridones 13 bearing a bromo or trifluoromethylsulfonyloxy substituent in the 1-position yield intermediate
1-arylacridones 16 which can be can be cyclised to new 8-methylquino[4,3,2-kl]acridines 17 with phosphorus
oxychloride or 6 M HCl in EtOH. Heck reactions between triflate-substituted substrates 17 and acrylic acid
derivatives afforded quinoacridines with unsaturated side-chains in the 6-position. Alkylboranes, prepared by
interaction of 9-borabicyclo[3,3,1]nonane (9-BBN) and allyl acetate or N-allyltrifluoroacetamide, participated in
Suzuki–Miyaura reactions with chloro-substituted 8-methylquinoacridines to form derivatives bearing functionalised
propyl groups in the 6- and 10-positions. Representative 8-methylquinoacridines were methylated with methyl iodide
to yield telomerase-inhibitory 8,13-dimethylquinoacridinium iodides 24.
One of the most potent telomerase inhibitors known, the nat-
Introduction
ural product telomestatin 2,10 has also been demonstrated to act
Basic research to understand the biological mechanisms of
via quadruplex stabilisation.11
tumour initiation and survival is unravelling the fundamental
distinctions between normal and cancerous cells: these
advances are leading to the identification of novel, drugable,
tumour-specific molecular targets. Activation of the enzyme
telomerase (hTERT), together with Simian Virus 40 large T
antigen (which disables the tumour suppressor proteins p53 and
RB), and activated Ras protein, are the minimal requirements
for immortalisation of human epidermal tumour cells.2 hTERT
is activated in >85% of tumours and has attracted much recent
attention as a potential target for therapeutic intervention.3,4 In
most ‘normal’ human cells telomeric DNA shortens by 50–200
bases per cell division and, after multiple cell divisions, the cell
reaches crisis (the ‘Hayflick’ limit) and enters senescence.5
In tumour cells this cellular clock mechanism is evaded, and
telomerase maintains telomere length and stability—and
hence cellular immortality—by annealing (TTAGGG)n repeat
sequences to the single-stranded terminus of the telomere, thus
maintaining telomere length in the region of 3 to 8 kb.6
In addition to the catalytic domain of the protein hTERT,
telomerase is a multicomponent structure comprising an RNA
template (hTR) and further protein components such as the
telomere-repeat-binding factors (TRF1 and TRF2). Telomeric
integrity is cemented by a range of functional and chaperoning
proteins which ‘cap’ the 3Ј single-stranded DNA overhang and
its associated telomerase enzyme:7 these structures present
numerous novel targets to inhibit telomerase function for anti-
cancer drug design.8 Some of the most potent small molecule
inhibitors promote and stabilise the guanine rich (TTAGGG)n
telomeric DNA in higher-ordered quadruplex form thereby
inhibiting the single-stranded DNA-dependent telomerase
enzyme.3 Recently G-quartet ligands with nanomolar inhibi-
tory potency against telomerase in the TRAP assay have been
reported. For example the anilinoacridine BRACO19 1 shows
good selectivity for telomerase inhibition over cytotoxicity, and
preferentially binds to quadruplex DNA over duplex DNA.9
Neidle et al.12 have completed an X-ray crystallographic
determination of parallel quadruplexes from human telomeric
DNA and shown that the structure adopts a radically different
folding arrangement from that deduced by NMR studies13 (and
formerly considered the gold-standard for molecular modelling
studies). Hurley and coworkers have shown that a cationic por-
phyrin TMPyP4, but not the isomeric TMPyP2, down-regulates
the c-myc oncogene by stabilising a G-quadruplex structure
within its promoter sequence.14,15 These advances, and others,16
have propelled DNA back into the limelight as a smart target
for anti-cancer drug design.
† Part 14 in the series ‘Antitumour polycyclic acridines’. Part 13 is
ref. 1.
Our laboratory has had a long-standing commitment to the
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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synthesis of natural product-related pyrido- and quino[4,3,2-
kl]acridinium salts as DNA interactive agents.17,18 Our interest
in quinoacridines was sparked by the testing of the salt 4
which is a weak telomerase inhibitor (IC50 2 µM) but exhibits
considerable collateral cytotoxicity.18 The initial route to
quinoacridinium salts, the ‘one-pot’ Oszczapowicz synthesis,19
involved heating the quinaldinium iodide (3: R = H, R1 = Et;
X = I) in ethanolic piperidine. The salt 4 crystallised from
the reaction mixture in a claimed 63% yield (Scheme 1) and
a possible mechanism for this remarkable reaction has been
proposed.18
manner. Molecular modelling investigations on the interaction
of RHPS4 and the intermolecular G-quadruplex structure
formed from the human (TTAGGG)n sequence based on the
published NMR structure,20 suggests that substituents in the
peripheral benzene rings of the pentacyclic framework at the 3-
or 6-, and to a lesser extent the 10-positions, would potentially
enhance binding interactions within the grooves of the quadru-
plex (Fig. 1). However, our ambition to introduce substituents
selectively on any given corner of the quinoacridine skeleton
demanded a fully regiospecific synthetic method.
We have developed radical cyclisation routes to 8-methyl-
quinoacridines (e.g. 6)21 and these substrates can be N-methyl-
ated to 8,13-dimethylquinoacridinium salts in good yield.18
Retrosynthetic analysis revealed that the required 8-methyl-
quinoacridine core might be accessible through a new cross-
coupling–deprotective cyclisation strategy: the planned
approach (Scheme 2) has convenient coupling partners in a
substituted 2-(pivaloylamino)benzeneboronic acid 7 and 10-
methylacridones 8 bearing a group X suitable for Pd(0)
mediated cross-coupling and is convergent and regiospecific.
Acridones 8 are readily available through classical Ullmann
coupling and Friedel–Crafts cyclisation procedures,22 followed
by N-methylation.
Scheme 1 Reagents and conditions: (i) piperidine in EtOH, reflux.
A limited number of analogues substituted with methyl or
halogen substituents in the 3- and 11-positions have been pre-
pared but yields, generally, were low: one such compound,
the quinoacridinium salt RHPS4 5, displays potent inhibition
of telomerase (IC50 0.3 µM) coupled with low cytotoxicity,
correlated to its preferential binding to quadruplex over duplex
DNA.18 An NMR study has confirmed that RHPS4 recognises
and stabilises a d(TTAGGGT)4 quadruplex in a 2 : 1 complex.20
Furthermore, RHPS4 provokes delayed, telomere length-
dependent cellular senescence and its cytotoxicity to tumour
cells is directly related to their intrinsic telomere lengths
(unpublished work). The intriguing biological properties of
RHPS4, coupled to its robust pharmaceutical properties
(stability in the pH range 5–11; fast cellular uptake; intra-
cellular stability),18 prompted us to investigate alternative
syntheses of quinoacridinium salts with a view to selecting a
potential clinical candidate.
Scheme 2
Synthesis of 1,3,6-trisubstituted 10-methylacridones 13
As a first approach to 3-substituted and 3,6-disubstituted
quinoacridines 13 2-chlorobenzoic acids 9 (R2 = H or Cl) were
reacted with 3-bromoaniline under Ullmann conditions to
afford the diarylamines 10 (R2 = H or Cl). Cyclisation of these
substrates to 1-bromoacridones 12a,b in sulfuric acid at 100 ЊC,
followed by methylation of the purified acridones with dimethyl
sulfate–sodium hydride, gave the 1-bromo-10-methylacridones
13a,b in poor yields, <20% overall (Scheme 3). This route
suffers inefficiencies due to the necessary separation of the
Chemistry
Neidle et al. have shown that the binding selectivity of 9-sub-
stituted acridines to quadruplex DNA can be modulated by
decorating the acridine ring with appropriate groove-interactive
groups9 and it was envisioned that the bioactivity of quino-
acridinium based compounds could be optimised in a similar
Fig. 1 A, NMR structure of two RHPS4 5 molecules (black) bound to the d(TTAGGGT)4 sequence (ref. 20) with T units (yellow), A–T units
(magenta) and G-tetrads (blue); B, end view looking down the quadruplex showing one molecule of RHPS4 (green) with fluoro groups (magenta);
G-tetrad (nitrogen atoms blue, oxygen atoms red).
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Scheme 3 Reagents and conditions: (i) K2CO3, Cu, PrOH or DMF, reflux; (ii) H2SO4, 100 ЊC; (iii) NaH, (MeO)2SO2, 25 ЊC; (iv) hexanol, cat. TsOH,
reflux; (v) MeI, acetone–K2CO3, reflux, 3 h; (vi) Tf2O, Hünig’s base, Ϫ40 ЊC; (vii) Tf2O, pyridine, DCM, 0 ЊC.
1- and 3-bromoacridone isomers formed in the Friedel–Crafts
cyclisation step prior to methylation.23
n-BuLi–trimethyl borate followed by acid quench.25 Optimum
conditions for the Suzuki coupling between bromoacridone 13a
and 2-(pivaloylamino)benzeneboronic acid 15 (R = H) used
Pd(PPh3)4 catalyst in aqueous DME with sodium bicarbonate
(3 mol. equiv.) as base. The 1-arylacridone 16a (88%) was
cyclised to pentacycle 17a with 6 M HCl in THF, or hot POCl3,
in yields >90%. Equi-efficient was a combined ‘one-pot’ cross-
coupling and cyclisation procedure from 13a,b which afforded
pentacycles 17a–d without isolation of the intermediate 1-aryl-
acridones 16 (Scheme 4). Conditions for the coupling of triflates
13g,h with boronic acids had to be more exacting to avoid
triflate hydrolysis. Investigation of a selection of recently dis-
covered active catalyst–phosphine ligand–base combinations,
such as Pd2(dba)3–P(t-Bu)3–KF or Pd(OAc)2–PCy3–KF,26 either
gave no coupling, very limited conversions, or hydrolysis.
Also, use of resin bound catalyst (Deloxan resin)27 under
aqueous conditions, which would have aided purification, again
gave hydrolysis of the triflate groups. Best results were obtained
with a Pd(PPh3)4–NaHCO3 combination in DME with minimal
water to furnish 1-arylacridones 16e–h which were cyclised
directly to pentacyclic quinoacridines 17e–h as above.
Product losses necessitated by separation of isomeric
acridones can be bypassed. Thus 1,3-dihydroxyacridones 12c,d
have been prepared by the condensation of methyl anthranilate
(11; R2 = H) or methyl 4-chloroanthranilate (11; R2 = Cl)
respectively, with phloroglucinol. Treatment of these acridones
with methyl iodide in acetone–potassium carbonate effected
methylation at both the NH-position and the 3-OH group to
furnish the 3-methoxy-10-methylacridones 13e,f on multigram
scales.24 Intramolecular H-bonding between the 1-hydroxy and
9-carbonyl groups disfavours methylation at C-1. Trifluoro-
methylsulfonyloxy (triflate) substituents make good leaving
groups in cross-coupling reactions and precise conditions for
the conversion of the mono-hydroxyacridones 13e,f to triflate
derivatives 13g,h were required. The nature of the base deter-
mined the outcome: when phenol 13e was derivatised with triflic
anhydride in the presence of Et3N or pyridine or at 0 ЊC the
required triflate 13g was accompanied by an isomer, tentatively
identified (1H NMR) as the 2-(trifluoromethylsulfonyl)acridone
14. This by-product could arise by direct electrophilic sub-
stitution into the activated 2-position of 13e or by a Fries-type
rearrangement from the triflate 13g. Employment of the hin-
dered bases DBU or DIPEA in DCM at Ϫ20 ЊC gave the triflate
13g in 66 and 77% yields, respectively, uncontaminated with by-
product; batch-scale (25 g) synthesis of 13g could be achieved
employing the base DIPEA in DCM at Ϫ40 ЊC.
To provide opportunities for further functionalisation of the
quinoacridines at C-6 the 6-methoxy-derivatives 17e–g were
efficiently demethylated with aluminium chloride in benzene to
afford the phenols 17i–k, respectively: derivatisation of 17j,k
with triflic anhydride–Hünig’s base in DCM then furnished the
triflates 17l,m in >60% overall yield (Scheme 4).
Substituted quino[4,3,2-kl]acridines from Suzuki reactions
Substituted quino[4,3,2-kl]acridines from Heck reactions
Protected 2-aminobenzeneboronic acids 15 were prepared from
N-pivaloylanilines in two steps via directed ortho-lithiation with
In order to gain greater insights into drug–quadruplex inter-
actions to, hopefully, obtain better telomerase inhibitors, we
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Scheme 4 Reagents and conditions: (i) 15, Pd(PPh3)4, NaHCO3, DME, H2O, 100 ЊC; (ii) POCl3 or HCl–EtOH; (iii) AlCl3, benzene, 80 ЊC, 4 h;
(iv) Tf2O, DIPEA, DCM, 0 ЊC.
required pentacyclic intermediates which could be functional-
ised with different side-chains at defined sites (e.g. the 3-, 6-
and 10-positions). Heck28 reactions can often be carried out
orthogonally on chlorides, bromides, iodides and triflates by
judicious choice of catalyst. After much experimental fine-
tuning, the 3-substituted quinoacridines 17n–q, respectively,
were isolated from reactions between 3-chloroquinoacridine
17b and the reactive alkenes methyl acrylate, acrylamide,
acrylonitrile and 4-acryloylmorpholine (Table 1). The 3-chloro-
6-methoxyquinoacridine 17f was similarly converted to 17r
with 4-acryloylmorpholine. The combination of Pd2(dba)3–P(t-
Bu)3–K3PO4 in dioxane at 150 ЊC in a pressure tube proved the
most successful coupling milieu. Only the trans linear alkenes
Substituted quino[4,3,2-kl]acridines from Suzuki–Miyaura
reactions
Application of alkylboranes, first reported by Suzuki and
Miyaura in the 1980s,29 have been shown to be an efficient,
selective, method for alkylating arenes30 and the scope of the
reaction has been extended to electron rich aryl chloride sub-
strates.31 Initially, various catalyst–ligand–base combinations in
varying stoichiometries were assessed to define conditions
facilitating coupling of the quinoacridine 17m and borane 18,
prepared in situ from 9-borabicyclo[3,3,1]nonane (9-BBN) and
allyl acetate (Scheme 5). Tuning the coupling conditions
[Pd(OAc)2–PPh3–Cs2CO3] using excess allyl acetate (relative
to substrate 17m) gave an optimum yield (63%) of product 19
(Table 2; entry 6), although other by-products (e.g. 17c) were
always detected (TLC). Using comparable conditions 17m
and the borane 20 derived from 9-BBN and N-allyltrifluoro-
acetamide gave the substituted 6-(3-aminopropyl)quinoacridine
21 (59%). Quinoacridine 17l was similarly converted to the
6-acetoxypropyl derivative 22 (60%).
In other work (to be published separately) we have shown
that it is possible to introduce a second alkyl substituent by
displacing the 10- and 3-chloro groups of 19 and 22, respect-
ively, by Suzuki–Miyaura reactions but yields were <20%.
However, the scope of the Pd(0) mediated transformations of
quinoacridines was extended to an example of a Sonogashira
coupling between 17l and N-propargyltrifluoroacetamide in
the presence of Pd(Ph3)4–CuI–NEt3 to yield the 6-alkynyl-
quinoacridine 23 (Scheme 5) in 83% yield. Attempts to replace
the 3-chloro substituent of 23 in a second Sonogashira alkynyl-
ation were unsuccessful.
were produced as evidenced by the large CH᎐CH coupling
᎐
1
constants (>15 Hz) in the H NMR spectra of the products.
Heck conversion of the 10-chloro-6-methoxyquinoacridine 17g
to 10-substituted quinoacridines 17s–u was achieved with the
same catalyst–ligand–base combination: in contrast, Pd(OAc)2–
PPh3 modification with triethylamine base in dioxane at 100 ЊC
was the best system for coupling the more reactive 6-(trifluoro-
methylsulfonyloxy)quinoacridine 17l with acryloylmorpholine
to yield 17v (98%). Similarly, triflate 17l coupled optimally
with the less reactive alkene N-allyltrifluoroacetamide in the
presence of a Pd(OAc)2–PPh3 catalyst and N-methyldicyclo-
hexylamine base (Cy2NMe) to give a product confirmed as the
1
trans olefin 17w (60%) by H NMR: an NOE experiment with
irradiation at the methylene absorption gave a 4.9% enhance-
ment of the alkenyl signals at 6.89 Hz. A by-product was identi-
fied (TLC) as the reduced starting material 17b. Particularly
noteworthy in the above couplings were the very high yields
(81–98%) obtained when introducing an acrylamide or 4-acry-
loylmorpholine group into all three sites of interest. Attempts
to substitute the 3-chloro group of the 6-acryloylmorpho-
linylquinoacridine 17v with a further acryloylmorpholinyl
group using a range of coupling conditions was not successful
and only reductive dechlorination was noted.
For the Heck reaction to be particular value, coupling
of quinoacridines and unactivated alkenes was required.
Discouragingly, the 3-chloroquinoacridine 17b failed to react
with allyl alcohol, allyl acetate or acrolein diethylacetal in the
presence of a range of catalyst–ligand–base variations. This
impasse led us to seek a more general coupling strategy for
introducing saturated substituents onto the quinoacridine
nucleus.
Synthesis of 8,13-dimethylquino[4,3,2-kl]acridinium iodides 24
Methylation of the unsubstituted quinoacridine 17a to the
quaternary salt 24a has been effected with methyl iodide in a
sealed tube at 100 ЊC.18 These conditions were also applied
to yield selected salts 24b–f from quinoacridines with representa-
tive substituents in the 3-, 6- and 10-positions (Scheme 6).
Physical properties of quino[4,3,2-kl]acridines
The neutral quinoacridines of type 13 and 17 are insoluble in
water. The original lead anti-telomeric compound 5 (RHPS4)
18
has appreciable water solubility (>5 mg mlϪ1
)
and the new
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 7 7 – 3 3 8 9
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Table 1 3-, 6- and 10-Substituted quino[4,3,2-kl]acridines 17 prepared by Heck reactions with alkenes in dioxane
Starting
compd. no.
Catalyst/
Liganda
Alkenea
Base
Temp./ЊC
Product No.
R
R1
R2
Yield (%)
17b
17b
17b
17b
17f
17g
17g
17g
17l
A
B
G
G
G
G
G
G
G
G
H
H
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NEt3
170b
170b
170b
170b
170b
170b
170b
170b
100c
170d
17n
17o
17p
17q
17r
17s
17t
17u
17v
17w
HC᎐CHCO2Me
H
H
H
H
OMe
OMe
OMe
OMe
H
H
H
H
H
66
91
62
92
81
54
86
61
98
60
᎐
HC᎐CHCONH2
᎐
C
D
D
A
D
E
HC᎐CHCN
᎐
HC᎐CHCON(CH2CH2)2O
᎐
HC᎐CHCON(CH2CH2)2O
᎐
H
H
H
Cl
Cl
HC᎐CHCO2Me
HC᎐CHCON(CH2CH2)2O
HC᎐CHCON(CH2CH2)2NAc
H
H
᎐
᎐
᎐
D
F
HC᎐CHCON(CH2CH2)2O
HC᎐CHCH2NHCOCF3
᎐
᎐
17l
Cy2NMe
a Alkenes: A, methyl acrylate; B, acrylamide; C, acrylonitrile; D, 4-acryloylmorpholine; E, 1-acetyl-4-acryloylpiperazine; F, N-allyl trifluoroacetamide. Catalyst/ligand: G, Pd2(dba)3–P(t-Bu)3; H, Pd(OAc)2–PPh3. b 48 h.
c 18 h. d 16 h.
e
Table 2 Optimisation of conditions for the Suzuki–Miyauraa conversion of 10-chloro-8-methyl-6-trifluorosulfonyloxy-8H-quino[4,3,2-kl]acridine 17m to 6-(3-acetoxypropyl)-10-chloro-8-methyl-8H-quino[4,3,2-kl]-
acridine 19 in dioxane
Experiment no.
Mol. equiv.b 9-BBN
Mol. equiv.b allyl acetate
Catalyst
Ligand
Base
Mol. equiv.b of base
Temp./ЊC
Yield (%)
1
2
3
4
5
6
7
8
1.8
1.8
1.8
1.2
2.3
3.0
3.0
3.0
1.8
1.8
1.8
1.2
2.3
4.8
4.8
4.8
4% Pd2(dba)3
4% Pd2(dba)3
4% Pd2(dba)3
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
20% Pd(OAc)2
8% P(t-Bu)3
8% P(t-Bu)3
8% P(t-Bu)3
20% PPh3
20% PPh3
20% PPh3
20% PPh3
40% PPh3
Cs2CO3
KF
2.0
2.0
2.0
1.3
1.3
2.0
2.0
2.0
100
100
150
100
100
100
80
0
0
0
26
37
63
36
57
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
100
a Refs. 29 and 30. b Referenced to starting material 17m.

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Scheme 5 Reagents and conditions: (i) allyl acetate, THF, 0 ЊC; (ii) N-allyltrifluoroacetamide, THF, 0 ЊC; (iii) 18, Pd(OAc)2, PPh3, Cs2CO3, dioxane,
100 ЊC; (iv) 20, Pd(OAc)2, PPh3, Cs2CO3, dioxane, 100 ЊC; (v) N-propargyltrifluoroacetamide, Pd(PPh3)4, Et3N, CuI, dioxane, 100 ЊC.
8,13-dimethylquino[4,3,2-kl]acridinium iodides 24b,c shared
this desirable property which facilitated biological evaluation.
However, quaternary compounds with unsaturated substituents
and polyalkylene side chains 24d–f were only sparingly soluble
in water.
The position and shape of the characteristic long wavelength
band (at λ > 400 nm) in the electronic absorption spectra of
quinoacridines has proven of value, in earlier work, for cluster-
ing different classes of compounds.17 Attachment of additional
conjugated substituents to the framework pentacyclic system
induced major bathochromic shifts: for example, the band at
436 nm in 8-methyl-8H-quino[4,3,2-kl]acridine 17a was shifted
to 479 nm by appending an acryloylmorpholine substituent in
the 3-position (in 17q). More marked still was the bathochromic
shift from 454 nm (in the 8,13-dimethylquinoacridinium salt
24a) to 524 nm in the comparably derivatised 24d.
(in 17e) (Fig. 2). Irradiation of the doublet for H-4 of 17b pro-
duced a large enhancement of the H-5 signal confirming their
1
close proximity. H–1H COSY spectra were used to identify
groups of coupled protons which facilitated full assignment
of the spectra (see Experimental section). The spectra of
8,13-dimethylquinoacridinium salts 24 were assigned in a
similar manner, aided by a full interpretation of the spectra
of salts prepared by the Oszczapowicz bimolecular reaction of
quinaldinium salts.32
The synthesis of examples of quinoacridines substituted in
the 3-, 6-, and 10-positions presented a good opportunity to
1
assign completely their H NMR spectra. Starting points were
the published proton assignments of 17a18 and 2D spectra of
the 3-chloro- (17b) and 6-methoxy- (17e) derivatives. NOE
enhancements from irradiation of the methyl peaks located
protons at H-7 and H-9 (in 17b) and at H-5, H-7 and H-9
Fig. 2 NOE enhancements in quinoacridines 17b and 17e.
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Scheme 6 Reagents and conditions: (i) MeI, 100 ЊC.
meter (accurate mass). NMR spectra were recorded on a
Biological results
Bruker ARX 250 instrument at 250.130 MHz (1H) and 62.895
MHz (13C) in [2H6]DMSO) or CDCl3; coupling constants are
in Hz. Merck silica gel 60 (40–60 µM) was used for column
chromatography. THF was distilled from sodium wire and
benzophenone. All commercially available starting materials
were used without further purification.
The ability of quinoacridinium salts to inhibit telomerase
activity (IC50 values) was determined by a PCR based TRAP
assay, with taq polymerase control.33 These results were com-
pared to the mean growth inhibitory activities (mean GI50
values) in the National Cancer Institute (USA) 60 tumour cell
line panel.34 The ratio mean GI50/IC50 (Selectivity Index; SI)
gives a measure of the potential usefulness of the compounds,
a higher value being indicative of a more selective telomerase
inhibitor. Taking the known salts 4 and 5 as benchmarks,18 the
salt 4 is a weak telomerase inhibitor (IC50 2.0 µM) and has a
mean GI50 of 1.1 µM; this gives a SI of 0.55. The salt 5 is a
significantly more potent telomerase inhibitor (IC50 0.33 µM)
and is less growth inhibitory (mean GI50 13.18 µM; SI 40).
Disappointingly, attaching potentially quadruplex groove-
binding substituents to the pentacyclic core does not enhance
telomerase-inhibitory activity, but does dramatically reduce
growth-inhibitory activity (a measure of overall cytotoxicity).
For example quinoacridinium salt 24d with an acryloyl-
morpholinyl group in the 3-position is a reasonably potent
telomerase inhibitor but with low growth inhibitory activity
(IC50 0.37 µM; mean GI50 68 µM; SI 183).
2-(3-Bromophenylamino)benzoic acid 10 (R2 = H),35 2-(3-
bromophenylamino)-4-chlorobenzoic acid 10 (R2 = Cl),36
1-bromoacridin-9(10H )-one 12a,35 1-bromo-6-chloroacridin-
9(10H )-one 12b,36 1,3-dihydroxyacridin-9(10H )-one 12c,24
6-chloro-1,3-dihydroxyacridin-9(10H )-one 12d,37 1-bromo-10-
methylacridin-9(10H )-one 13a,35 1,3-dihydroxy-10-methyl-
acridin-9(10H )-one 13c,24 6-chloro-1,3-dihydroxy-10-methyl-
acridin-9(10H )-one 13d37 and 1-hydroxy-3-methoxy-10-methy-
lacridin-9(10H )-one 13e24 were prepared by published
methods.
1-Bromo-6-chloro-10-methylacridin-9(10H)-one 13b
2-(3-Bromophenylamino)-4-chlorobenzoic acid (10b, 4.0 g, 12.2
mmol) was heated in sulfuric acid (50 ml) for 30 min then
allowed to cool to room temperature. Water was added slowly
and the precipitate collected, washed with water, and dried over
P2O5. The crude material was suspended in DMF (50 ml) and
added under nitrogen to sodium hydride (1.2 g, 50 mmol) in
DMF (50 ml). After 30 min dimethyl sulfate (3 ml, 18 mmol)
was added and stirring was continued for 1 h. Addition of water
gave a precipitate which was purified by column chromato-
graphy (EtOAc : hexane, 1 : 4) to give 13b as pale yellow needles
(0.625 g, 17%), mp 223–225 ЊC (Found: C, 51.8; H, 2.8; N, 4.0.
C14H9BrClNO requires C, 52.1; H, 2.8; N, 4.3%); UV (EtOH)
λmax 289, 298, 390, 404 nm; IR (KBr) νmax 1636, 1590, 1456,
1050, 933, 788 cmϪ1; δH ([2H6]DMSO) 8.24 (1 H, d, J 8.5), 7.92
(1 H, d, J 1.5), 7.86 (1 H, dd, J 1.5, 8.0), 7.67–7.51 (2 H, m), 7.36
(1 H, dd, J 1.5, 8.5), 3.89 (3 H, s, 10-Me).
Full biological results on an extended family of quino-
acridinium salts 24, and the relationship between DNA quad-
ruplex affinity and telomerase inhibition, will be published
separately.
Conclusion
Synthetic routes to new quino[4,3,2-kl]acridines have been
further developed through a practicable, convergent, cross-
coupling procedure. Positionally selective catalytic substitution
reactions have allowed structures with varied side-chains to be
accessed, the synthetic scope of which is considerable. The
salts 5 and 24d are undergoing further analysis as potential
therapeutic telomerase inhibitors, and the synthesis of further
analogues continues.
6-Chloro-1-hydroxy-3-methoxy-10-methylacridin-9(10H)-one
13f
6-Chloro-1,3-dihydroxy-10-methylacridin-9(10H )-one
13d37
Experimental
(52.0 g, 0.2 mol) in dry acetone (1750 ml) was refluxed (3 h)
with K2CO3 (80.0 g, 0.58 mol) and methyl iodide (175 ml,
0.74 mol). Removal of acetone and trituration of the product
with water gave 13f which was recrystallised from DMF to give
yellow crystals (37.0 g, 65%), mp 230–233 ЊC (Found: C, 59.0;
H, 4.7; N, 5.9. C15H12ClNO3ؒ0.5H2Oؒ0.5C3H7NO requires C,
59.1; H, 5.0; N, 6.3%); IR (KBr) νmax 1628, 1583, 1284, 1162,
1090, 824, 611 cmϪ1; δH ([2H6]DMSO) 14.65 (1 H, s, OH), 8.25
Melting points were measured on a Gallenkamp apparatus and
are uncorrected. IR spectra were recorded on a Mattson 2020
Galaxy series FT-IR spectrometer and UV spectra on a
Pharmacia Biotech Ultraspec 2000 UV/visible spectrophoto-
meter. Mass spectra were recorded on either a Micromass
Platform spectrometer, an AEI MS-902 (nominal mass), or a
VG Micromass 7070E or a Finnigan MAT900XLT spectro-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 7 7 – 3 3 8 9
3383

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(1 H, d, J 7.5, H-8), 7.93 (1 H, s, H-5), 7.37 (1 H, d, J 7.5, H-7),
6.68 (1 H, s, H-2), 6.30 (1 H, s, H-4), 3.92 (3 H, s, OMe), 3.83
(3 H, s, 10-Me).
95%), mp 212–214 ЊC (lit.21 210–211 ЊC); UV (EtOH) λmax 296,
420, 439 nm; δH ([2H6]DMSO) 8.80 (1 H, dd, J 1.3, 7.5, H-12),
8.56 (1 H, dd, J 1.0, 7.5, H-4), 8.12 (1 H, d, J 8.0, H-5), 7.94–
7.88 (2 H, m, H-1, H-6), 7.70–7.58 (4 H, m, H-2, H-3, H-9,
H-10), 7.38 (1 H, d, J 7.5, H-7), 7.23 (1 H, dt, J 1.5, 8.0, H-11),
3.71 (3 H, s, 8-Me).
3-Methoxy-1-trifluoromethylsulfonyloxy-10-methylacridin-
9(10H)-one 13g
The same quinoacridine 17a was formed in 91% yield by the
combined cross-coupling and cyclisation procedure (General
method A, below).
1-Hydroxy-3-methoxy-10-methyl-10H-acridin-9-one24
(13e,
28.0 g, 0.116 mol) and DIPEA (18.7 ml, 0.116 mol) were
partially dissolved in dry DCM (2000 ml) and the solution
was cooled to Ϫ40 ЊC under an atmosphere of nitrogen. Tri-
fluoromethylsulfonic acid anhydride (15.5 ml, 0.116 mol) was
slowly added as a solution in DCM (100 ml) and the mixture
was stirred and allowed to warm slowly to room temperature
over 18 h. The organic layer was dried (Na2SO4), filtered and
evaporated under reduced pressure to afford a crude residue
which was purified by column chromatography (EtOAc :
hexane, 1 : 4). The acridone 13g was eluted with CHCl3 and the
solvent evaporated to give white needles (25.4 g, 57%), mp 189–
191 ЊC (Found: C, 49.6; H, 3.1; N, 3.5. C16H12F3NO5S requires
C, 49.6; H, 3.1; N, 3.6%); UV (EtOH) λmax 299, 369, 387 nm;
δH (CDCl3) 8.55 (1 H, dd, J 1.5, 7.5, H-8), 7.70 (1 H, td, J 1.5,
7.0, H-6), 7.45 (1 H, d, J 8.5, H-5), 7.30 (1 H, m, H-7), 6.85
(1 H, d, J 2.5, H-2), 6.50 (1 H, d, J 2.5, H-4), 3.95 (3 H, s, OMe),
3.78 (3 H, s, 10-Me); δC ([2H6]DMSO) 173.0, 161.5, 148.2, 144.5,
140.8, 133.2, 125.2, 121.3, 121.0, 115.22, 107.0, 103.6, 98.2,
55.4, 34.1; m/z (EI) 387 (Mϩ).
Combined cross-coupling and cyclisation procedure for the
synthesis of 8-methyl-8H-quino[4,3,2-kl]acridines 17
General method A. The appropriate 10-methylacridin-
9(10H )-one 13, 2-(pivaloylamino)benzeneboronic acid (1.2
mol. equiv.), NaHCO3 (1.4 mol. equiv.), DME (100 ml gϪ1 of
substrate acridone), and distilled water (24 ml gϪ1 for bromines;
5 ml gϪ1 for triflates) (see synthesis of 16a, above) were mixed
and the suspension was flushed with nitrogen. Catalytic
Pd(PPh3)4 (10–12 mol%) was added, and the mixture heated to
reflux under nitrogen. When all starting material was consumed
(TLC), water was added to the cooled mixture, and organic
products were extracted into EtOAc. The organic layer was
dried (MgSO4), filtered, and evaporated under reduced pressure
to give the crude coupled product 16. Phosphorus oxychloride
(5 ml gϪ1) was added to the dry, crude coupling product and the
mixture was heated at 100 ЊC in an oil bath for 20 min giving a
red solid. The residual phosphorus oxychloride was removed
under reduced pressure, and the solid residue cautiously
quenched with an aqueous concentrated ammonia–ice mix.
The solid quinoacridine 17 was collected and either purified
by column chromatography (EtOAc : hexane, 1 : 4) or
crystallisation.
6-Chloro-3-methoxy-1-trifluoromethylsulfonyloxy-10-methyl-
acridin-9(10H)-one 13h
Similarly prepared from 13f in 57% yield, the acridone had mp
234–236 ЊC (Found: C, 45.8; H, 2.7; N, 3.2. C16H11ClF3NO5S
requires C, 45.6; H, 2.6; N, 3.3%); UV (EtOH) λmax 285, 317,
372, 387 nm; IR (KBr) νmax 1643, 1615, 1597, 1463, 1464, 1424,
1306, 1244, 1223, 1200, 1146, 1125, 1069, 995, 922, 833, 810
cmϪ1; δH (CDCl3) 8.46 (1 H, d, J 8.5, H-8), 7.45 (1 H, s, H-5),
7.27–7.24 (1 H, m, H-7), 6.84 (1 H, s, H-2), 6.6 (1 H, s, H-4),
3.98 (3 H, s, OMe), 3.81 (3 H, s, 10-Me); δC (CDCl3) 206.8,
174.8, 163.1, 150.4, 145.9, 142.7, 140.4, 129.5, 122.7, 121.8,
114.6, 104.6, 98.6; m/z (EI) 421, 423 (Mϩ).
General method B. The crude coupling product was prepared
as in General method A and cyclised by a refluxing mixture
of EtOH and 6 M HCl (1 : 1.5) for 18 h. The solvent was
evaporated and the quinoacridine free base was liberated with
aqueous NaHCO3 and purified (above) to give the 8-methyl-
8H-quino[4,3,2-kl]acridine 17.
3-Chloro-8-methyl-8H-quino[4,3,2-kl]acridine 17b
1-(2-Pivaloylaminophenyl)-10-methylacridin-9(10H)-one 16a
Acridone 13a (3.0 g, 10.9 mmol) and 5-chloro-2-(pivaloyl-
amino)benzeneboronic acid38 (3.2 g, 12.5 mmol) were coupled
and cyclised by General method B to give 17b as yellow needles
(2.5 g, 72%), mp 226–228 ЊC (Found: C, 74.6; H, 4.1; N, 8.7.
C20H13ClN2ؒ0.25H2O requires C, 74.8; H, 4.2; N, 8.7%); UV
(EtOH) λmax 296, 426, 445 nm; IR (KBr) νmax 3442, 2234, 1597,
1551, 1493, 1460, 1354, 1331, 1279, 1233, 1181, 1107, 1080,
1045, 831, 766, 741, 656, 548 cmϪ1; δH (CDCl3) 8.84 (1 H, dd,
J 1.5, 8.0), 8.25 (1 H, d, J 7.5), 7.90 (1 H, d, J 2.0), 6.85 (1 H, d,
J 8.0), 7.65 (1 H, t, J 6.3), 7.53 (2 H, m), 7.23–7.18 (2 H, m),
7.03 (1 H, d, J 8.5), 3.59 (3 H, s); δH ([2H6]DMSO) 8.77 (1 H, d,
J 7.5, H-12), 8.62 (1 H, d, J 2.5, H-4), 8.20 (1 H, d, J 8.3, H-5),
7.93–7.86 (2 H, m, H-1, H-6), 7.68 (1 H, dd, J 2.5, 9.0, H-2),
7.66–7.60 (2 H, m, H-9, H-10), 7.46 (1 H, d, J 8.0, H-7), 7.28
(1 H, t, J 7.5, H-11); δC (CDCl3) 150.0, 144.53, 142.02, 141.8,
133.99, 132.20, 132.14, 130.96, 129.83, 126.44, 124.51, 122.55,
122.47, 121.98, 116.5, 114.23, 111.63, 109.15, 34.12; MS (AP)
m/z 317.0, 319.1 (MHϩ).
A mixture of acridone 13a (0.1 g, 0.35 mmol), (2-pivaloyl-
aminobenzene)boronic acid25 (94 mg, 1.2 mol. equiv.), DME
(10 ml), water (2 ml), and NaHCO3 (88 mg, 1.05 mmol) were
mixed and flushed with nitrogen. Pd(PPh3)4 (10 mol%) was
added and the mixture was heated to reflux (5 h). Water (3 ml)
was added and the product extracted with EtOAc (20 ml).
The dried (MgSO4) organic fraction was filtered and evaporated
under reduced pressure to give a yellow oil which was purified
by column chromatography (DCM : MeOH, 99 : 1) to give 16a
(0.12 g, 88%) as a yellow solid, mp 160–162 ЊC; UV (EtOH) λmax
238, 299, 386, 404 nm; IR (KBr) νmax 3437, 2957, 1682, 1636,
1605, 1522, 1497, 1445, 1370, 1292, 1254, 1173, 1094, 766 cmϪ1
;
δH (CDCl3) 8.34 (1 H, d, J 8.0), 8.00 (1 H, d, J 8.0), 7.7–7.64
(3 H, m), 7.54 (1 H, d, J 8.0), 7.36–7.3 (2 H, m), 7.21–7.03 (2 H,
m), 7.17 (1 H, d, J 7.0), 7.03–7.0 (2 H, m), 3.93 (3 H, s), 0.83
(9 H, s); HRMS (FAB) m/z 385.1882 (MHϩ), C25H25N2O2
requires 385.1916.
8-Methyl-8H-quino[4,3,2-kl]acridine 17a
10-Chloro-8-methyl-8H-quino[4,3,2-kl]acridine 17c
Acridone 16a (50 mg, 0.13 mmol) was dissolved in a mixture
of THF and 6 M HCl (1 : 1, 20 ml) and the mixture was heated
to reflux for 5 days. The yellow–orange solution was basified
(aq. Na2CO3) and extracted with EtOAc (50 ml). The dried
(Na2SO4) organic layer was evaporated under reduced pressure.
The crude product was purified by column chromatography
(EtOAc : hexane, 1 : 4) to give 17a as a yellow solid (35 mg,
Acridone 13b (0.22 g, 0.68 mmol) and 2-(pivaloylamino)-
benzeneboronic acid (0.173 g, 0.78 mmol) were coupled and
cyclised by General method B. The quinoacridine 17c (0.147 g,
68%) had mp 272–274 ЊC; UV (EtOH) λmax 297, 427, 446 nm;
IR (KBr) νmax 2962, 2357, 1606, 1585, 1458, 1261, 1093, 1024,
804, 548 cmϪ1; δH ([2H6]DMSO) 8.8 (1 H, d, J 8.5, H-12), 8.58
(1 H, d, J 8.5, H-4), 8.2 (1 H, d, J 8.0, H-5), 7.94–7.87 (2 H, m,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 7 7 – 3 3 8 9
3384

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H-1, H-6), 7.73–7.76 (2 H, m, H-2, H-9), 7.54 (1 H, t, J 8.5,
H-3), 7.43 (1 H, d, J 8.5, H-7), 7.28 (1 H, dd, J 2.0, 8.5, H-11),
3.70 (3 H, s, 8-Me); HRMS (FAB) m/z 317.0860 (MHϩ),
C20H14N2Cl requires 317.0846.
requires C, 63.9; H, 4.0; N, 7.1%); UV (EtOH) λmax 296, 416,
438 nm; IR (KBr) νmax 1585, 1548, 1406, 1211, 1107, 1047, 871,
819, 650 cmϪ1; δH ([2H6]DMSO) 8.69–8.65 (2 H, m, H-4, H-12),
7.84 (1H, d, J 8.5, H-1), 7.66–7.60 (3 H, m, H-2, H-5, H-9), 7.25
(1 H, d, J 8.5, H-11), 6.87 (1 H, s, H-7), 4.04 (3 H, s, OMe), 3.62
(3 H, s, 8-Me); HRMS (EI) m/z 382.0429 (Mϩ), C21H14ClClN2O
(Mϩ) requires 382.0454.
3,10-Dichloro-8-methyl-8H-quino[4,3,2-kl]acridine 17d
From acridone 13b (0.22 g, 0.68 mmol) and 5-chloro-2-(pival-
oylamino)benzeneboronic acid (0.20 g, 0.78 mmol) by General
method B, the dichloroquinoacridine 17d (0.143 g, 60%) had
mp 273–275 ЊC; UV (EtOH) λmax 295, 427, 446 nm; IR (KBr)
νmax 1963, 1607, 1589, 1551, 1451, 1422, 1262, 1099, 1022, 820
cmϪ1; δH ([2H6]DMSO) 8.7 (1 H, d, J 8.5, H-12), 8.62 (1 H, s,
H-4), 8.22 (1 H, d, J 7.5, H-5), 7.89 (2 H, m, H-1, H-6), 7.70–
7.66 (2 H, m, H-2, H-9), 7.45 (1 H, d, J 8.0, H-7), 7.27 (1 H, dd,
J 1.5, 8.5, H-11), 3.69 (3 H, s, 8-Me); HRMS (EI) m/z 350.0365
(Mϩ), C20H12N2Cl2 requires 350.0378.
Procedure for the demethylation of 6-methoxy-8H-quino-
[4,3,2-kl]acridines
General method C. The appropriate 6-methoxyquinoacridine,
suspended in benzene containing anhydrous AlCl3 (3 mol.
equiv.), was heated to 80 ЊC for 4 h giving a red oily suspension.
To the cooled mixture was added MeOH to disperse the red oil.
The solvent was vacuum evaporated, and the residue basified
with aqueous NaHCO3. Organic products were recovered by
Soxhlet extraction with EtOAc and evaporation gave the follow-
ing 6-hydroxy-8H-quino[4,3,2-kl]acridines.
6-Methoxy-8-methyl-8H-quino[4,3,2-kl]acridine 17e
From 13g (4.5 g, 11.3 mmol) and 2-(pivaloylamino)benzene-
boronic acid (3.3 g) by General method A, the 6-methoxy-
quinoacridine 17e formed yellow needles (1.94 g, 55%), mp
214–216 ЊC (Found: C, 78.05; H, 5.1; N, 8.6. C21H16N2Oؒ
0.5H2O requires C, 78.5; H, 5.3; N, 8.7%); UV (EtOH) λmax 294,
409, 427 nm; IR (KBr) νmax 1606, 1589, 1556, 1464, 1417, 1359,
6-Hydroxy-8-methyl-8H-quino[4,3,2-kl]acridine 17i
General method C applied to 17e gave orange crystals 17i
(0.381 g, 1.27 mmol, 99%), mp 250 ЊC (decomp.) (Found:
C, 73.9; H, 5.1; N, 8.0. C20H14N2 requires C, 73.8; H, 5.3; N,
8.6%); UV (EtOH) λmax 298, 412, 428 nm; IR (KBr) νmax 2928,
1604, 1589, 1462, 1429, 1352, 1292, 1205, 760, 746 cmϪ1
;
1329, 1290, 1209, 1168, 1147, 1097, 1047, 821, 798, 752 cmϪ1
;
δH ([2H6]DMSO) 8.74 (1 H, d, J 7.5, H-12), 8.26 (1 H, d, J 7.0,
H-4), 7.8 (1 H, d, J 8.5, H-1), 7.57 (3 H, m, H-2, H-9, H-10),
7.39 (2 H, m, H-3, H-5), 7.21 (1 H, t, J 6.5, H-11), 6.75 (1 H, s,
H-7), 3.62 (3 H, s, 8-Me); MS (AP) 297 (Mϩ Ϫ 1).
δH ([2H6]DMSO) 8.76 (1 H, d, J 8.0, H-12), 8.52 (1 H, d, J 8.0,
H-4), 8.87 (1 H, d, J 8.3, H-1), 7.66 (1 H, t, J 8.3, H-2), 7.63–
7.58 (3 H, m, H-5, H-9, H-10), 7.47 (1 H, t, J 8.0, H-3), 7.24
(1 H, t, J 8.0, H-11), 6.80 (1 H, s, H-7), 4.02 (3 H, s, OMe), 3.63
(3 H, s, 8-Me); MS (AP) m/z 313.1 (MHϩ).
3-Chloro-6-hydroxy-8-methyl-8H-quino[4,3,2-kl]acridine 17j
Similarly prepared by demethylation of 17f (5.5 g, 15.9 mmol)
the yellow quinoacridine 17j (4.5 g, 88%) had mp 250 ЊC
(decomp.) (Found: C, 71.9; H, 3.95; N, 8.0. C20H13ClN2O
requires C, 72.2; H, 3.9; N, 8.4%); UV (EtOH) λmax 299, 415,
430 nm; IR (KBr) νmax 2928, 1595, 1460, 1288, 1180, 1107, 833
cmϪ1; δH ([2H6]DMSO) 10.56 (1 H, s, OH), 8.75 (1 H, d, J 7.0,
H-12), 8.31 (1 H, d, J 2.5, H-4), 7.83 (1 H, d, J 8.5, H-1), 7.65–
7.56 (3 H, m, H-2, H-9, H-10), 7.41 (1H, d, J 2.5, H-5), 7.25
(1 H, dt, J 1.0, 7.0, H-11), 6.82 (1 H, d, J 2.5, H-7), 3.64 (3 H, s,
8-Me).
3-Chloro-6-methoxy-8H-quino[4,3,2-kl]acridine 17f
From 13g (6.9 g, 17.4 mmol) and 5-chloro-2-(pivaloylamino)-
benzeneboronic acid (5.33 g), the chloromethoxyquinoacridine
17f crystallised from methanol as yellow needles (62% by
General method A; 70% by General method B), mp 205–207 ЊC
(Found: C, 67.8; H, 4.2; N, 7.6. C21H15ClN2Oؒ1.5H2O requires
C, 67.5; H, 4.85; N, 7.5%); UV (EtOH) λmax 304, 411, 432 nm;
IR (KBr) νmax 1601, 1554, 1462, 1415, 1327, 1288, 1209, 1157,
1105, 1057, 817, 746, 721, 651, 542 cmϪ1; δH ([2H6]DMSO) 8.76
(1 H, dd, J 1.5, 7.5, H-12), 8.70 (1 H, d, J 2.5, H-4), 7.87 (1 H, d,
J 8.5, H-1), 7.71–7.58 (4 H, m, H-2, H-5, H-9, H-10), 7.26 (1 H,
dt, J 2.0, 7.5, H-11), 6.92 (1 H, d, J 2.0, H-7), 4.07 (3 H, s,
OMe), 3.69 (3 H, s, 8-Me); HRMS (FAB) m/z 347.0951 (MHϩ),
C21H16ClN2O requires 347.0948.
10-Chloro-6-hydroxy-8-methyl-8H-quino[4,3,2-kl]acridine 17k
Similarly prepared by demethylation of 17g (2.6 g, 7.5 mmol)
the yellow quinoacridine 17k (2.43 g, 98%) had mp 255 ЊC
(decomp.) (Found: C, 68.55; H, 4.0; N, 7.55. C20H13ClN2Oؒ
1.0H2O requires C, 68.5; H, 4.3; N, 8.0%); UV (EtOH) λmax 293,
435 nm; IR (KBr) νmax 2922, 1620, 1560, 1477, 1440, 1365, 1232,
1041, 806, 746 cmϪ1; δH ([2H6]DMSO) 10.54 (1 H, s, OH), 8.72
(1H, d, J 7.5, H-12), 8.32 (1 H, d, J 7.5, H-4), 7.85 (1 H, d, J 7.5,
H-1), 7.68–7.62 (2 H, m, H-2, H-9), 7.53–7.44 (2 H, m, H-3,
H-5), 7.26 (1 H, dd, J 1.0, 7.5, H-11), 6.79 (1 H, d, J 1.0, H-7),
3.62 (3 H, s, 8-Me); HRMS (EI) m/z 334.0690, C20H13 37ClN2O
requires 334.0687.
10-Chloro-6-methoxy-8H-quino[4,3,2-kl]acridine 17g
Prepared from acridone 13h (3.5 g, 8.3 mmol) and 2-(pivaloyl-
amino)benzeneboronic acid (2.3 g, 10.4 mmol) by General
method A, the yellow quinoacridine 17g (1.45 g, 50%) had mp
240–242 ЊC (Found: C, 72.1; H, 4.4; N, 8.0. C21H15ClN2Oؒ
1.5H2O requires C, 72.7; H, 4.4; N, 8.0%); UV (EtOH) λmax 295,
412, 431 nm; IR (KBr) νmax 2933, 1606, 1587, 1440, 1284, 1211,
1168, 1058, 817, 761, 650 cmϪ1; δH ([2H6]DMSO) 8.72 (1 H, d,
J 8.5, H-12), 8.57 (1 H, d, J 7.5, H-4), 7.88 (1 H, d, J 8.3, H-1),
7.71–7.61 (3 H, m, H-2, H-5, H-9), 7.50 (1 H, t, J 7.5, H-3), 7.26
(1 H, d, J 8.5, H-11), 6.88 (1 H, s, H-7), 4.04 (3 H, s, OMe), 3.64
(3 H, s, 8-Me); MS (AP) m/z 347.4, 349.4 (MHϩ).
3-Chloro-8-methyl-6-trifluoromethylsulfonyloxy-8H-quino-
[4,3,2-kl]acridine 17l
Trifluoromethylsulfonic acid anhydride (1.14 ml, 6.4 mmol) was
added dropwise (over 1 h) to a stirred, cold (0 ЊC), suspension
of 17j (2.23 g, 6.4 mmol) in DCM (1 l) containing DIPEA
(6.4 mmol) under nitrogen. The mixture was warmed (to 25 ЊC)
and shaken with water (500 ml). The organic layer was dried
(MgSO4), filtered, evaporated to reduced volume and fraction-
ated on a silica column (hexane : EtOAc, 85 : 15). Evaporation
of the yellow band gave 17l as a yellow solid (2.0 g, 67%), mp
193–195 ЊC (Found: C, 53.1; H, 2.6; N, 5.7. C21H12ClF3N2O3ؒ
0.5H2O requires C, 53.2; H, 2.8; N, 5.9%); UV (EtOH) λmax 297,
414, 439 nm; IR (KBr) νmax 1597, 1554, 1421, 1327, 1222, 1205,
3,10-Dichloro-6-methoxy-8-methyl-8H-quino[4,3,2-kl]acridine
17h
Acridone 13h (0.287 g, 0.68 mmol) and 5-chloro-2-(pivaloyl-
amino)benzeneboronic acid (0.20 g, 0.78 mmol) were coupled
and cyclised by General method B. Purification of the crude
product by column chromatography gave the dichloroquino-
acridine 17h as yellow needles (0.113 g, 58%), mp 287–289 ЊC
(Found: C, 64.0; H, 3.9; N, 6.7. C21H14Cl2N2Oؒ0.75H2O
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 7 7 – 3 3 8 9
3385

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1136, 974, 925, 869, 841, 761, 599 cmϪ1; δH (CDCl3) 8.8 (1 H, d,
J 7.0, H-12), 8.16 (1 H, d, J 2.0, H-4), 7.96 (1 H, d, J 9.0, H-1),
7.61 (3 H, m, H-2, H-9, H-10), 7.32 (2 H, m, H-5, H-11), 6.9
(1 H, d, J 2.0, H-7), 3.66 (3 H, s, 8-Me); MS (AP) m/z 465.3,
467.3 (MHϩ).
H-5), 8.0–7.92 (3 H, m, H-1, H-2, H-6), 7.77 (1 H, d, J 17.0,
ethene CH), 7.71–7.63 (2 H, m, H-9, H-10), 7.48 (1 H, d, J 8.0,
H-7), 7.30 (1 H, dt, J 1.5, 7.5, H-11), 6.68 (1 H, d, J 17.0, ethene
CH), 3.78 (3 H, s, 8-Me); HRMS (FAB) m/z 334.1334 (MHϩ),
C23H16N3 requires 334.1344.
(E )-3-(8-Methyl-8H-quino[4,3,2-kl]acridin-3-yl)acrylic acid
(morpholin-4-yl)amide 17q
10-Chloro-8-methyl-6-trifluoromethylsulfonyloxy-8H-quino-
[4,3,2-kl]acridine 17m
General method D applied to 17b (0.10 g, 0.32 mmol) and 4-
acryloylmorpholine (0.08 ml, 1.5 mol. equiv.) gave 17q (0.125 g,
92%), mp 251–253 ЊC (Found: C, 75.3; H, 5.55; N, 9.9.
C27H23N3O2ؒ0.5H2O requires C, 75.3; H, 5.6; N, 9.8%); UV
(EtOH) λmax 322, 455, 479 nm; IR (KBr) νmax 1644, 1588, 1452,
1332, 1213, 1115, 826, 747 cmϪ1; δH ([2H6]DMSO) 8.86 (1 H,
s, H-4), 8.81 (1 H, d, J 8.0, H-12), 8.32 (1 H, d, J 8.0, H-5), 8.09
(1 H, d, J 9.0, H-2), 7.96–7.88 (2 H, m, H-1, H-6), 7.79 (1H, d,
J 15.5, ethene CH), 7.67–7.91 (2 H, m, H-9, H-10), 7.49–7.43
(2 H, m, H-7, ethene CH), 7.29 (1 H, dt, J 2.0, 7.5, H-11), 3.82
(2 H, br s, CH2), 3.75 (3 H, s, 8-Me), 3.65 (6 H, br s, 3 × CH2);
MS (AP) m/z 422.4 (MHϩ).
Prepared from 17k and trifluoromethylsulfonic acid anhydride
as above, the yellow quinoacridine 17m (64%) had mp 239–241
ЊC (Found: C, 51.5; H, 3.1; N, 5.4. C21H12ClF3N2O3Sؒ1.5H2O
requires C, 51.3; H, 3.1; N, 5.7%); UV (EtOH) λmax 295, 413,
427 nm; IR (KBr) νmax 1597, 1421, 1217, 1138, 983, 827, 746
cmϪ1; δH (CDCl3) 8.78 (1 H, dd, J 2.0, 7.0, H-12), 8.23 (1 H, d,
J 8.5, H-4), 8.02 (1 H, d, J 7.5, H-1), 7.72 (2 H, m, H-2, H-9),
7.54 (1 H, dt, J 1.5, 7.0, H-3), 7.17 (2 H, m, H-5, H-11), 6.81
(1 H, d, J 2.0, H-7); MS (AP) m/z 465.3, 467.3 (MHϩ).
Heck reactions on 3-, 6- and 10-substituted 8-methyl-8H-quino-
[4,3,2-kl]acridines
General method D. The chloro substituted 8-methyl-8H-
quino[4,3,2-kl]acridine, K3PO4 (2 mol. equiv.), Pd2(dba)3
(2 mol%), P(t-Bu)3 (0.05 M in dioxane, 8 mol%), and the
appropriate alkene were mixed in a screw-top tube and flushed
with nitrogen. The enclosed mixture was heated to 170 ЊC for
48 h. The reaction was allowed to cool to room temperature,
DCM was added and the suspension was filtered through Celite
and then vacuum evaporated. The residue was purified by
column chromatography on silica (5% MeOH in DCM), and
the products were recovered as orange–red solids.
(E )-3-(6-Methoxy-8-methyl-8H-quino[4,3,2-kl]acridin-3-yl)-
acrylic acid (morpholin-4-yl)amide 17r
General method D applied to 17f (0.20 g, 0.58 mmol) and 4-
acryloylmorpholine (0.15 ml, 2.0 mol. equiv.) gave 17r (0.21 g,
81%), mp 175–177 ЊC; UV (EtOH) λmax 296, 330, 440, 452 nm;
IR (KBr) νmax 1590, 1464, 1295, 1212, 1114, 1044, 826 cmϪ1
;
δH ([2H6]DMSO) 8.85 (1 H, s, 4), 8.78 (1H, dd, J 1.5, 7.5, H-12),
8.14 (1-H, d, J 8.5, H-2), 7.87 (1 H, s, H-5), 7.84–7.79 (2 H,
m, H-1, ethene CH), 7.64–7.58 (2 H, m, H-9, H-10), 7.43 (1 H,
d, J 15.5, ethene CH), 7.26 (1 H, dt, J 1.5, 6.0, H-11), 6.91 (1 H,
d, J 1.5, H-7), 4.08 (3 H, s, OMe), 3.83 (2 H, br s, CH2), 3.70
(3 H, s, 8-Me), 3.65 (6 H, br s, 3 × CH2); HRMS (EI)
m/z 451.1889 (Mϩ), C28H25N3O3 requires 451.1896.
(E )-3-(8-Methyl-8H-quino[4,3,2-kl]acridin-3-yl)acrylic acid
methyl ester 17n
Prepared by General method D from 17b (0.16 g, 0.5 mmol)
and methyl acrylate (0.064 ml, 1.5 mol. equiv.), 17n (0.12 g,
66%) had mp 252–254 ЊC; UV (EtOH) λmax 314, 457, 479 nm;
IR (KBr) νmax 1693, 1688, 1589, 1551, 1514, 1503, 1464, 1443,
1425, 1362, 1352, 1333, 1262, 1209, 1173, 1154, 1096, 1082,
1045 cmϪ1; δH ([2H6]DMSO) 8.87 (1 H, s, H-4), 8.76 (1 H, d,
J 7.0, H-12), 8.25 (1 H, d, J 8.0, H-5), 8.0 (1 H, d, J 8.5, H-2),
7.94–7.84 (3 H, m, H-1, H-6, ethene CH), 7.69–7.62 (2 H, m,
H-9, H-10), 7.38 (1 H, d, J 8.0, H-7), 7.24 (1 H, t, J 6.25, H-11),
6.78 (1 H, d, J 12.5, ethene CH), 3.79 (3 H, s, OMe), 3.72 (3 H,
s, 8-Me); HRMS (FAB) m/z 367.1446 (MHϩ), C24H19N2O2
requires 367.1447.
(E )-3-(6-Methoxy-8-methyl-8H-quino[4,3,2-kl]acridin-10-yl)-
acrylic acid methyl ester 17s
By General method D from 17g (1.0 g, 2.9 mmol) and methyl
acrylate (0.52 ml, 2.0 mol. equiv.), 17s (0.61 g, 54%) formed red
needles (from DMF), mp 237–239 ЊC (Found: C, 69.0; H, 5.3;
N, 6.7. C25H20N2O3ؒ2H2O requires C, 69.4; H, 5.6; N, 6.5%);
UV (EtOH) λmax 304, 434, 452 nm; IR (KBr) νmax 1701, 1604,
1434, 1169, 816, 617 cmϪ1; δH ([2H6]DMSO) 8.76 (1 H, d, J 8.0,
H-12), 8.57 (1 H, d, J 7.5, H-4), 7.92–7.88 (2 H, m, H-1, H-9),
7.83 (1 H, d, J 16.0, ethene CH), 7.71–7.62 (3 H, m, H-2, H-5,
H-11), 7.50 (1 H, t, J 7.5, H-3), 6.94–6.88 (2 H, m, H-7, ethene
CH), 4.06 (3 H, s, OMe), 3.79 (3 H, s, OMe), 3.72 (3 H, s, 8-Me);
HRMS (EI) m/z 396.1468 (Mϩ), C25H20N2O3 requires 396.1474.
(E )-3-(8-Methyl-8H-quino[4,3,2-kl]acridin-3-yl)acrylamide 17o
By method D from 17b (0.1 g, 32 mmol) and acrylamide (0.042
g, 2.0 mol. equiv.), 17o (0.10 g, 91%), had mp 284–286 ЊC; UV
(EtOH) λmax 312, 450, 471 nm; IR (KBr) νmax 2965, 1678, 1605,
1589, 1551, 1508, 1468, 1443, 1429, 1412, 1387, 1354,
1331, 1283, 1262, 1098, 1082, 1026, 831 cmϪ1; δH ([2H6]DMSO)
8.80 (1 H, d, J 7.0, H-12), 8.72 (1 H, s, H-4), 8.23 (1 H, d, J 8.0,
H-5), 7.94–7.88 (3 H, m, H-1, H-2, H-6), 7.73–7.64 (3 H, m,
H-9, H-10, ethene CH), 7.58 (1 H, br s, NH), 7.44 (1H, d, J 8.0,
H-7), 7.29 (1 H, dt, J 1.5, 7.0, H-11), 7.17 (1 H, br s, NH), 8.73
(1 H, d, J 16.0, ethene CH), 3.74 (3 H, s, 8-Me); HRMS (FAB)
352.1448 (MHϩ), C23H18N3O requires 352.1450.
(E )-3-(6-Methoxy-8-methyl-8H-quino[4,3,2-kl]acridin-10-yl)-
acrylic acid (morpholin-4-yl)amide 17t
By General method D from 17g (0.2 g, 0.5 mmol) and 4-acry-
loylmorpholine (0.15 ml, 2.0 mol. equiv.), 17t (0.226 g, 86%)
had mp 248–250 ЊC; UV (EtOH) λmax 312, 450 nm; IR (KBr)
νmax 1641, 1606, 1444, 1211, 1113, 815 cmϪ1; δH ([2H6]DMSO)
8.75 (1 H, d, J 8.0, H-12), 8.56 (1 H, d, J 8.0, H-4), 7.90 (1 H, d,
J 8.0, H-1), 7.83 (1 H, s, H-9), 7.73–7.64 (4 H, m, H-2, H-11, 2 ×
ethene CH), 7.52–7.43 (2 H, m, H-3, H-5), 6.88 (1 H, s, H-7),
4.05 (3 H, s, OMe), 3.81 (2 H, br s, CH2), 3.72 (3 H, s, 8-Me),
3.65 (6 H, br s, 3 × CH2); δC ([2H6]DMSO) 164.7, 162.8, 156.4,
148.1, 145.7, 143.0, 141.7, 138.5, 136.0, 129.5, 128.8, 127.6,
125.6, 124.8, 123.6, 122.8, 122.15, 120.4, 119.5, 115.2, 114.0,
111.7, 66.6, 55.9, 45.9, 34.0; MS (FAB) no molecular ion.
(E )-3-(8-Methyl-8H-quino[4,3,2-kl]acridin-3-yl)acrylonitrile
17p
By General method D from 17b (0.3 g, 94 mmol) and acrylo-
nitrile (0.15 ml, 2.0 mol. equiv.), 17p (0.19 g, 62%) had mp 262–
264 ЊC; UV (EtOH) λmax 317, 460, 488 nm; IR (KBr) νmax 2963,
2922, 2864, 1721, 1603, 1589, 1543, 1510, 1460, 1443, 1352,
1329, 1283, 1262, 1175, 1094, 1075, 1042 cmϪ1; δH ([2H6]DMSO)
8.84 (1 H, s, H-4), 8.8 (1 H, d, J 7.5, H-12), 8.22 (1 H, d, J 8.0,
(E )-3-(6-Methoxy-8-methyl-8H-quino[4,3,2-kl]acridin-10-yl)-
acrylic acid (4-acetylpiperazin-1-yl)amide 17u
By General method D from 17g (0.3 g, 0.87 mmol) and 4-acetyl-
1-acryloylpiperazine (0.31 g, 1.67 mol. equiv.), 17u (0.26 g, 61%)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 7 7 – 3 3 8 9
3386

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had mp 270–272 ЊC; UV (EtOH) λmax 311, 446 nm; IR (KBr)
νmax 1642, 1606, 1435, 1211, 1046, 984, 818, 751, 634 cmϪ1
HRMS (FAB) m/z 417.1371 (MHϩ), C25H22ClN2O2 requires
417.1370.
;
δH ([2H6]DMSO) 8.73 (1 H, d, J 8.0, H-12), 8.55 (1H, d, J 8.0,
H-4), 7.89 (1 H, d, J 8.0, H-1), 7.81 (1 H, s, H-9), 7.73–7.62
(4 H, m, H-2, H-11, 2 × ethene CH), 7.51–7.45 (2 H, m, H-3,
H-5), 6.85 (1 H, s, H-7), 4.04 (3 H, s, OMe), 3.78 (2 H, br s,
CH2), 3.67 (3 H, s, 8-Me), 3.54 (6 H, br s, 3 × CH2), 2.08 (3 H, s,
COCH3); HRMS (FAB) m/z 493.2268 (MHϩ), C30H29N4O3
requires 493.2240.
1-Trifluoroacetylamino-3-(10-chloro-8-methyl-8H-quino-
[4,3,2-kl]acridin-6-yl)propane 21. Similarly prepared, from
17m, 9-BBN, N-allyltrifluoroacetamide, Pd(OAc)2 (10 mol%),
PPh3 (20 mol%) and Cs2CO3 (2 mol. equiv.) in dioxane at
100 ЊC, the acridinylpropane 21 (59%) had mp 142–144 ЊC; UV
(EtOH) λmax 297, 441 nm; IR (KBr) νmax 1513, 1469, 1210, 831,
756 cmϪ1; δH (CDCl3) 8.87 (1 H, d, J 6.5, H-12), 8.22 (1 H, s,
H-4), 7.70–7.53 (3 H, m, H-2, H-9, H-10), 7.29–7.21 (2 H, m,
H-5, H-11), 6.85 (1 H, s, H-7), 6.44 (1 H, br s, NH), 3.61 (3 H, s,
8-Me), 3.50 (2 H, dt, J 6.5, 7.5, CH2), 2.87 (2 H, t, J 7.5 CH2),
2.09 (2 H, J 7.5, CH2); MS (FAB) 456.0 (MHϩ), C25H19-
ClF3N3O requires 455.0.
(E )-3-(3-Chloro-8-methyl-8H-quino[4,3,2-kl]acridin-6-yl)acrylic
acid (morpholin-4-yl)amide 17v
Chloroacridine 17l (0.20 g, 0.43 mmol), 4-acryloylmorpholine
(0.11 ml, 2 mol. equiv.), Pd(OAc)2 (10 mg, 10 mol%), PPh3
(22 mg, 20 mol%), Et3N (0.072 ml, 1.2 mol. equiv.) and dioxane
(2.0 ml) were mixed, flushed with nitrogen and the mixture
heated to reflux for 18 h. On cooling DCM (20 ml) was added,
the suspension filtered through Celite and the product purified
by silica column chromatography (EtOAc–hexane–MeOH).
Evaporation of the orange band gave 17v as an orange solid
(0.195 g, 98%), mp 284–287 ЊC; UV (EtOH) λmax 314, 462,486
nm; IR (KBr) νmax 2858, 1649, 1592, 1591, 1554, 1419, 1332,
1259, 1224, 1114, 1043 cmϪ1; δH ([2H6]DMSO) 8.76–8.73 (2 H,
m, H-4, H-12), 8.52 (1 H, s, H-5), 7.88 (1 H, d, J 8.5, H-1), 7.7–
7.6 (6 H, m, H-2, H-7, H-9, H-10, 2 × ethene CH), 7.28 (1 H, t,
J 7.0, H-11), 3.87 (2 H, br s, CH2), 3.78 (3 H, br s, 8-Me), 3.57
(6 H, br s, 3 × CH2); HRMS (FAB) m/z 456.1484 (MHϩ),
C27H23ClN3O2 requires 456.1479.
1-Acetoxy-3-(3-chloro-8-methyl-8H-quino[4,3,2-kl]acridin-
6-yl)propane 22. Similarly prepared (as above) from 17l and allyl
acetate, quinoacridine 22 (60%) had mp 152–154 ЊC; UV
(EtOH) λmax 297, 445 nm; IR (KBr) νmax 2930, 1740, 1613, 1590,
1553, 1462, 1358, 1339, 1233, 1098, 1044 cmϪ1; δH ([2H6]DMSO)
8.73 (1 H, d, J 7.5, H-12), 8.60 (1 H, d, J 2.0, H-4), 8.03 (1 H, s,
H-5), 7.86 (1 H, d, J 8.5, H-1), 7.7–7.55 (3 H, m, H-2, H-9,
H-10), 7.27–7.22 (2 H, m, H-7, H-11), 4.12 (2 H, t, J 6.5,
CH2OAc), 3.69 (3 H, s, 8-Me), 2.92 (2 H, t, J 7.5, CH2), 2.08
(2 H, m, CH2), 2.06 (3 H, s, CH3CO); δC ([2H6]DMSO) 170.0
(C), 148.9 (C), 146.0 (C), 143.4 (C), 140.8 (C), 140.6 (C), 132.5
(C), 131.7 (CH), 129.9 (CH), 128.8 (CH), 128.7 (C), 124.6 (CH),
123.5 (C), 122.1 (CH), 120.8 (CH), 120.4 (C), 114.5 (CH), 113.9
(C), 111.1 (CH), 109.8 (CH), 63.0 (CH2), 33.2 (CH3), 32.3
(CH2), 29.1 (CH2), 20.3 (CH3); HRMS (FAB) m/z 417.1344
(MHϩ), C25H22ClN2O2 requires 417.1370.
(E )-3-(3-Chloro-8-methyl-8H-quino[4,3,2-kl]acridin-6-yl)-
N-(trifluoroacetyl)allylamine 17w
Similarly prepared (as above) from 17l, using Pd(OAc)2, PPh3,
Cy2NMe and dioxane at 150 ЊC in a sealed tube, the allylamine
17w (60%) was crystallised from DCM and had mp 175–177 ЊC
(Found: C, 50.7; H, 3.45; N, 6.6. C25H17ClF3N3Oؒ2CH2Cl2
requires C, 50.35; H, 3.3; N, 6.6%); UV (EtOH) λmax 302, 434,
464 nm; IR (KBr) νmax 2858, 1649, 1592, 1591, 1554, 1419, 1332,
1259, 1224, 1114, 1043 cmϪ1; δH ([2H6]acetone) 8.65 (1 H, s),
8.63 (1 H, dd, J 2.0, 8.0), 8.29 (1 H, d, J 2.5), 7.9 (1-H, s), 7.71
(1 H, d, J 10.0), 7.44 (2 H, m), 7.32 (1 H, d, J 10.0), 7.13 (1 H, s),
7.07 (1 H, dt J 1.5, 8.0), 6.6 (2 H, m), 4.1 (2 H, t, J 7.5), 3.54
(3 H, s, 8-Me); δH ([2H6]DMSO) 9.91 (1 H, br s, NH), 8.51–8.45
(2H, m, H-4, H-12), 7.99 (1 H, s, H-5), 7.67–7.56 (4 H, m, H-1,
H-2, H-9, H-10), 7.0 (2 H, m, H-7, H-11), 6.74–6.60 (2 H, m,
2 × ethene CH), 4.14 (2 H, br s, CH2), 3.63 (3 H, s, 8-Me); MS
(FAB) no molecular ion.
N-[3-(3-Chloro-8-methyl-8H-quino[4,3,2-kl]acridin-6-yl)-
propargyl]trifluoroacetamide 23. The quinoacridine 17l (0.1 g,
0.22 mmol) and N-propargyltrifluoroacetamide (0.065 g, 2 mol.
equiv.), CuI (0.033 g, 0.17 mmol), Pd(Ph3)4 (0.053 g, 20 mol%)
and Et3N (2 mol. equiv.) were mixed in dioxane (10 ml) and the
flask purged with nitrogen. The mixture was refluxed (18 h),
diluted with DCM (20 ml), and the mixture fractionated on a
silica column (EtOAc–hexane). The trifluoroacetamide 23 was
recovered as a yellow solid (83%), mp 255–257 ЊC (Found:
C, 59.7; H, 3.1; N, 8.3. C24H15ClF3N3O2ؒ2H2O requires C, 59.8;
H, 3.8; N, 8.4%); UV (EtOH) λmax 301, 431, 457 nm; IR (KBr)
νmax 1710, 1606, 1589, 1554, 1462, 1207, 1184, 1184, 1151, 1105,
696, 653, 613 cmϪ1; δH ([2H6]DMSO) 10.23 (1 H, s, NH), 8.76
(1 H, d, J 8.0, H-12), 8.7 (1 H, J 2.5, H-4), 8.27 (1 H, s, H-5),
7.92 (1 H, d, J 7.5, H-1), 7.7 (3 H, m, H-2, H-9, H-10), 7.39
(1 H, s, H-7), 7.4 (1 H, dt, J 1.5, 8.0, H-11), 4.44 (2 H, s, CH2),
3.72 (3 H, s, 8-Me).
Suzuki–Miyaura and Sonogashira reactions on 3- and
6-substituted 8-methyl-8H-quino[4,3,2-kl]acridines
1-Acetoxy-3-(10-chloro-8-methyl-8H-quino[4,3,2-kl]acridin-
6-yl)propane 19. Allyl acetate (0.17 ml, 1.58 mmol) and a solu-
tion of 9-BBN (0.5 M) in THF (2 ml, 2.3 mol. equiv.) were
stirred together at 0 ЊC for 3.5 h. To the alkylborane solution
was added quinoacridine 17m (0.20 g, 0.43 mmol), Pd(OAc)2
(10 mol%), PPh3 (20 mol%), Cs2CO3 (2 mol. equiv.) and
dioxane (5 ml) and the mixture was heated at 100 ЊC for 16 h.
On cooling, DCM was added and the products were adsorbed
onto silica, and fractionated by column chromatography
(EtOAc–hexane). The orange band furnished an orange solid
when the combined fractions were evaporated and triturated
with hexane. The product 19 (0.11 g, 63%) had mp 162–164 ЊC;
UV (EtOH) λmax 298, 441 nm; IR (KBr) νmax 2955, 1736, 1607,
1586, 1489, 1364, 1250, 1036, 870 cmϪ1; δH ([2H6]DMSO)
8.74 (1 H, d, J 8.5, H-12), 8.57 (1 H, d, J 7.5, H-4), 8.06
(1 H, s, H-5), 7.90 (1 H, d, J 7.5, H-1), 7.68 (1 H, t, J 7.5,
H-2), 7.63 (1 H, s, H-9), 7.28–7.25 (2 H, m, H-7, H-11), 4.12
(2 H, t, J 6.5, CH2OAc), 3.69 (3 H, s, 8-Me), 2.95 (2H, t,
J 7.5, CH2), 2.10 (2 H, m, CH2), 2.06 (3 H, s, CH3CO);
Synthesis of 8,13-dimethylquino[4,3,2-kl]acridinium iodides
General method E. The appropriate substituted 8-methyl-
acridine was heated with excess methyl iodide in a sealed tube
at 100 ЊC for 3 days. The product was collected by filtration
and washed with Et2O. The following acridinium iodides were
prepared:
3-Chloro-8,13-dimethyl-6-methoxy-8H-quino[4,3,2-kl]acridin-
ium iodide 24b
Prepared (69%) from 17f by General method E, compound 24b
(69%) had mp 203–205 ЊC; UV (EtOH) λmax 287, 330, 420, 437
nm; IR (KBr) νmax 1618, 1580, 1470, 1310, 1229, 1192, 1121
cmϪ1; δH ([2H6]DMSO) 8.93 (1 H, d, J 2.5, H-4), 8.44 (1 H, d,
J 7.5, H-12), 8.1 (4 H, m, H-1, H-5, H-9, H-10), 7.94 (1 H, dd,
J 2.5, 9.0, H-2), 7.61 (1 H, t, J 7.5, H-11), 7.45 (1 H, d, J 2.0,
H-7), 4.33 (3 H, s, 13-Me), 4.2 (3 H, s, OMe), 4.06 (3 H, s, 8-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 3 7 7 – 3 3 8 9
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Me); δC ([2H6]DMSO) 165.7, 150.4, 143.2, 142.4, 137.9, 135.7,
132.8, 131.9, 131.7, 129.8, 124.1, 123.8, 122.8, 121.7, 117.4,
114.7, 112.2, 102.7, 99.0, 57.1, 46.0, 36.6; HRMS (FAB)
m/z 361.1116 (Mϩ Ϫ 1), C22H18ClN2O requires 361.1108.
human cell panel was conducted according to a published
method.34
Acknowledgements
10-Chloro-8,13-dimethyl-6-methoxy-8H-quino[4,3,2-kl]acridin-
ium iodide 24c
We thank Cancer Research UK for supporting this project
through a Studentship (to R. A. H.) and the EPSRC National
Mass Spectrometry Service Centre, University of Wales,
Swansea, UK for high resolution mass spectra. We also thank
Sharon Gowan and Dr L. R. Kelland (Institute of Cancer
Research, Sutton, Surrey, UK) for TRAP telomerase assays.
Prepared from 17g by General method E, compound 24c (60%)
had mp 177–179 ЊC; UV (EtOH) λmax 285, 330, 426, 443 nm;
δH ([2H6]DMSO) 8.80 (1 H, d, J 8.0, H-4), 8.44 (1 H, d, J 8.5,
H-12), 8.24 (1 H, s, H-9), 8.1 (2 H, m, H-1, H-5), 7.95 (1 H, t,
J 7.5, H-2), 7.5 (1 H, t, J 7.5, H-3), 7.61 (1 H, d, J 8.5, H-11),
7.42 (1 H, s, H-7), 4.3 (3 H, s, 13-Me), 4.16 (3 H, s, OMe), 4.03
(3 H, s, 8-Me); δC ([2H6]DMSO) 165.5, 150.8, 143.2, 142.4,
139.5, 138.2, 132.2, 130.8, 130.7, 126.1, 123.5, 122.1, 121.7,
117.8, 116.0, 112.8, 111.4, 102.0, 96.6, 56.1, 54.9, 36.5; HRMS
(FAB) m/z 361.1112 (Mϩ Ϫ I), C22H18ClN2O requires 361.1108.
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