The cubane paradigm in bioactive molecule discovery: Further scope, limitations and the cyclooctatetraene complement

Article abstract of DOI:10.1039/c9ob01238a

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

Full text of DOI:10.1039/c9ob01238a

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The cubane paradigm in bioactive molecule
discovery: further scope, limitations and the
Cite this: DOI: 10.1039/c9ob01238a
cyclooctatetraene complement†‡
Sevan D. Houston,a Tyler Fahrenhorst-Jones, a Hui Xing,a
Benjamin A. Chalmers, a Melissa L. Sykes, b Jeanette E. Stok,a
a
Clementina Farfan Soto,a Jed M. Burns, a Paul V. Bernhardt,
James J. De Voss,a Glen M. Boyle, c Maree T. Smith, d John Tsanaktsidis,e
G. Paul Savage,e Vicky M. Avery b and Craig M. Williams
*
a
The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide
range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G)
and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an
agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibar-
otene). This investigation highlights the scope and limitations of incorporating cubane into bioactive
molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane
maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was
less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene
(COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and
augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioi-
sosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these
have been specifically highlighted herein using failed examples. A summary of all templates prepared to
date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable
tool in bioactive molecule discovery and COT is a viable complement.
Received 28th May 2019,
Accepted 13th June 2019
DOI: 10.1039/c9ob01238a
rsc.li/obc
In 1992 Eaton theorised that cubane (1) had the potential to highly planar aromatic compounds arising from ease of sp2
act as a phenyl ring (benzene, 2) bioisostere, which was coupling,4 as opposed to increased three dimensionality
initially idealised by viewing the orientation of cubane from an inherent to cage hydrocarbons.5 Herein reported are extensive
apex (i.e. 3) and observing a phenyl ring map (Fig. 1).1 trials and tribulations associated with further prosecution of
Recently our group validated Eaton’s conjecture with a select
number of known pharmaceutical and agrochemical tem-
plates.2 This development bodes well for modern bioactive
molecule discovery, which is highly cognisant of the ensuing
perils that come with “flatland” chemical space.3 That is,
aSchool of Chemistry and Molecular Biosciences, University of Queensland (UQ),
Brisbane, 4072 Queensland (QLD), Australia. E-mail: c.williams3@uq.edu.au
bDiscovery Biology, Griffith Institute for Drug Discovery, Griffith University, Brisbane,
QLD 4111, Australia
cQIMR Berghofer Medical Research Institute, PO Royal Brisbane Hospital, Brisbane,
4029 QLD, Australia
dSchool of Biomedical Sciences, Faculty of Medicine, UQ, Brisbane, Australia
eCSIRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168 Victoria (VIC),
Australia
†Dedicated to Professor Phillip Eaton.
‡Electronic supplementary information (ESI) available. CCDC 1906221–1906224.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ob01238a
Fig. 1 Space filling models of cubane (1), and benzene (phenyl ring, 2)
with an apex view (3) comparison; bond distances given in angstroms
[M06-2X/6-311+G(d,p)], and angles in degrees.
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Scheme 1 Towards the synthesis of a cubane analogue of cefalocor
(14) via the Dane salt method, and synthesis of a cubane analogue of
penicillin G (16). [KOH = potassium hydroxide; EtOH = ethanol; 7-ACCA
= 7-amino-3-chloro cephalosporanic acid; HATU = 1-[bis(dimethyl-
amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexa-
fluorophosphate; TEA = triethylamine; DMF = N,N-dimethylformamide;
(+)-6-APA = (+)-6-aminopenicillanic acid.]
Fig. 2 Selected bioactive molecule templates; phenyl ring highlighted
in red.
cubane as a phenyl bioisostere, and strategic deployment of
1,3,5,7-cyclooctatetraene (COT) as a complementary (bio)motif.
A new set of pharmaceutical and agrochemical templates
were chosen to further delineate Eaton’s postulate. These
included the antibacterial compounds, cefaclor (4) and penicil-
lin G (5), the antihistamine diphenhydramine (DPH) (6), the
smooth muscle relaxant alverine (7), the anaesthetic agent
(R,S)-ketamine (8), the agrochemical insecticide triflumuron (9),
the antiparasitic benznidazole (10) and the anti-cancer agent
tamibarotene (11) (Fig. 2).
itself as a striking structural feature for investigation, allowing
for either double or single cubane substitution, and in the
case of the latter, introducing a asymmetric centre not present
in the parent pharmaceutical (Scheme 2).
Reaction of Weinreb amide18 17 with cubyl lithium (18) fol-
lowed by sodium borohydride reduction gave dicubylmethanol
(19). Despite forcing conditions, SN2 reaction between 19 and
chloride 20 was not successful in delivering bis-cubane ana-
logue 21 (Scheme 2). The observed lack of reactivity was specu-
lated to arise from the steric encumbrance of dicubylmethanol
(19) preventing backside attack on chloride 20. Substituting
cubyl lithium (18) for phenylmagnesium bromide and apply-
ing the same sequence of events was successful in furnishing
mono-cubane analogue 23 (Scheme 2).
Cefaclor (4) and penicillin G (5)
In light of the emerging antibiotic resistance crisis,6 the
β-lactam antibiotics cefaclor (4)7 and penicillin G (5)8 were
chosen as initial targets for investigation. Although recent
developments have allowed facile access to (R)-2-cubylglycine
(12),9 efforts to couple10 Dane salt (13)11 with 7-amino-3-chloro
cephalosporanic acid (7-ACCA) were ultimately unsuccessful in
giving the cubane analogue 14 (Scheme 1). Switching to peni-
cillin G (5) was more productive. Forging the amide bond
between 2-cubylacetic acid (15) and (+)-6-aminopenicillanic
acid [(+)-6-APA] using acid chloride12 or solution-phase peptide
coupling approaches13 were marred by issues with decompo-
sition and purification, so were quickly abandoned in favor of
a solid-phase approach14 (Scheme 1). Cubane analogue 16 was
reached, but proved highly unstable and difficult to purify,
decomposing during characterization presumably via hydro-
lysis of the labile β-lactam ring.15
DPH (6) is administered as the hydrochloride salt,16 and it
was in derivatisation of 23 to the hydrochloride salt where the
Diphenhydramine (DPH, 6)
Available in some countries as an over-the-counter pharma-
ceutical, DPH was originally developed as a first-generation
antihistamine16 but boasts a range of additional therapeutic
Scheme 2 Towards the synthesis of a bis-cubane analogue of diphen-
hydramine (21) and the successful synthesis of a mono-cubane ana-
logue of diphenhydramine (23). [THF
= tetrahydrofuran; DMSO =
properties as well.17 The benzhydrol motif in DPH presented dimethyl sulfoxide.]
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synthesis met difficulty. Upon treatment with methanolic hydro- researchers and medical professionals alike have called to
chloric acid, rapid decomposition of 23 was observed. have many re-evaluated for their untapped clinical poten-
Cubylmethanols are known to convert to their corresponding tial.23 The anaesthetic agent (R,S)-ketamine (8) has enjoyed
homocubanes via a Wagner–Meerwein type rearrangement, a particular attention,24 both for its ability to improve myriad
process accelerated in the presence of acidic media.19 Indeed, a core depressive symptoms at sub-anesthetic doses,25 and
neat sample of 23 left under ambient conditions was observed because of the identification of (2R,6R)-hydroxynorketamine,
to decompose in a similar manner in a matter of weeks, which a key metabolite that lacks ketamine-related side effects.26
prevented any notion of reliable biological testing.
ortho-Functionalisation of the cubane nucleus was achieved
using conditions developed by Eaton27 and Bashir-
Hashemi.28 N,N-Diisopropylamide 32 acted as a directing
group for LiTMP mediated ortho-lithiation, which was fol-
lowed by transmetallation with magnesium bromide diethyl
etherate, and quenching with iodine to deliver 2-iodo cubane
33. Despite facilitating access to the coveted 1,2-substitution
pattern, the transformation suffered from poor step economy
(i.e. directing group installation/removal), the use of super
stoichiometric reagents, and in our hands was capricious.
Oxidative displacement of 33 with iodobenzene dichloride29
resulted in 2-chloro cubane 34 which, after reduction and
oxidation to remove the directing group,30 gave 2-chlorocuba-
necarboxylic acid (35). Conversion to the Weinreb amide fol-
lowed by addition of cyclopentylmagnesium bromide gave
ketone 36, which was converted by a two-step Rubottom oxi-
dation31 into alpha-hydroxy ketone 37, thereby setting the
stage for a thermal isomerisation endgame as outlined in the
original synthesis of (R,S)-ketamine (8).32 Disappointingly,
numerous conditions to reach the cubane analogue 38 were
investigated, all of which failed to produce the target
(Scheme 4).
Alverine (7)
The smooth muscle relaxant alverine (7) is used to treat irrita-
ble bowel syndrome (IBS),20 a gastrointestinal disorder that
is prevalent in approximately 11% of the global population.21
Synthesis began with a lengthy homologation process, in which
sequential application of the Arndt–Eistert22 protocol to cubane
carboxylic acid (24) furnished cubylpropionic acid (25) in 42%
over 6 steps. DCC coupling of 25 with ethylamine hydrochloride
followed by borane reduction gave amine 26, which was
coupled again with 25, this time using PyBOP. A final borane
reduction delivered the bis-cubane analogue 28. Application of
a similar iterative peptide-coupling/borane reduction sequence
gave the mono-cubane analogue 31 (Scheme 3). Unfortunately,
conversion to ammonium salts required for evaluation were pro-
blematic (i.e. giving difficult to handle oils rather than solids)
thus biological testing was abandoned.
(R,S)-Ketamine (8)
Psychoactive substances have had a tumultuous history, but
nevertheless have been the subject of a recent renaissance as
Scheme 4 Towards the synthesis of a cubane analogue of (R,S)-keta-
mine (38). [LiTMP = lithium tetramethylpiperidide; THF = tetrahydro-
furan; DCM = dichloromethane; DMF = N,N-dimethylformamide; TEA =
triethylamine; LDA = lithium diisopropylamide; DMPU = N,N’-dimethyl-
Scheme 3 Mono- (28) and bis-cubane (31) analogues of alverine. [DMF =
N,N-dimethylformamide; DCM = dichloromethane; THF = tetrahydrofuran;
TEA = triethylamine; DCC = N,N’-dicyclohexylcarbodiimide; PyBOP =
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate.]
propyleneurea; TMSCl
dimethyldioxirane.]
=
trimethylsilyl chloride; DMDO
=
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analogue 43 had an IC50 value of 6.1 0.1 µM and an SI of >6,
indicating that cubane substitution maintained activity against
Triflumuron (9)
In order to determine whether the 2-chloro substitution T. cruzi.
pattern was a synthetic liability, given the above results, the
chemistry of this system was further explored using the ben-
zoylurea agrochemical insecticide triflumuron (9) as a test
Tamibarotene (11)
system.33 Schotten–Baumann reaction of 2-chlorocubanecar-
boxylic acid (35) with aqueous ammonia proceeded smoothly
to give amide 39 in high yield. This in turn was then success-
fully coupled, albeit in low yield, with p-(trifluoromethoxy)
aniline (40) in the presence of triphosgene to furnish the
desired cubane analogue 41 (Scheme 5). The relative ease of
synthesis suggested that the 2-chloro substitution pattern
should not be considered globally problematic.
The acute promyelocytic leukemia (APL) drug tamibarotene
(11) was recently launched in the clinic37 and has already
garnered interest from several medicinal chemistry pro-
grams.38 Cubane derivatisation involved coupling of acid-ester
44 with napthalenamine 45,39 followed by saponification of
the pendant ester to give the cubane analogue 46 in 70% yield
over three-steps (Scheme 7).
The IC50 values for both tamibarotene (11) and the cubane
analogue 46 were measured across four different cancer cell
lines and normal fibroblasts (see ESI‡). Disappointingly, the
cubane analogue was less active in all cases, generally resulting
in an IC50 value 3–6 times higher than that of the benzene
original.
Benznidazole (10)
Chagas disease is caused by the protozoan parasite
Trypanosoma cruzi, and is prevalent in Latin America where it
results in over 10 000 cases per year.34 Benznidazole (10) has
been deployed to treat Chagas disease since the early 1970s,
although its use remains controversial due to a poor toxicity
profile and lack of efficacy in treatment of the chronic phase of
the disease.35 The cubane analogue (43) was accessed in a two-
step sequence by coupling cubane amino hydrochloride 42
first with chloroacetyl chloride, and then again with 2-nitroi-
madazole (Scheme 6).
The IC50 (half-maximal inhibitory concentration) values of
T. cruzi intracellular amastigotes and selectivity indexes (SI)
against mammalian 3T3 cells were determined utilizing a well-
established image-based assay36 for both benznidazole (10)
and the cubane analogue 43. Compounds were tested in two bio-
logical replicates per experiment (see ESI‡). Benznidazole (10)
had an IC50 of 5.9 0.5 µM and an SI of >21, whilst the cubane
The COT complement
With the advent of strained hydrocarbon motifs such as
cubane (1)2 in bioactive molecule discovery, the toolbox of the
contemporary medicinal chemist is well equipped to address
steric replacement demands in a broad range of scenarios.40
An obvious shortcoming of this structural class, however, is its
lack of π character, an electronic property required for poten-
tial metabolic reactivity41 and/or π interactions.42 This short-
coming was recently addressed with the finding that 1,3,5,7-
cyclooctatetraene (COT) was able to fulfil both criteria (i.e.
provide steric and π components), where it was demonstrated
to behave as a viable bioactive motif.43 In the view that cubane
displayed bioisosterism in the case of the Chagas disease anti-
parasitic benznidazole (10), but exhibited diminished activity
in the case of the anticancer agent tamibarotene (11), the COT
complement was deployed to determine if activity could be
optimized in each system.
Facile access to the COT motif was achieved by treatment of
the cubane analogues 43 and 46 with rhodium(I) norborna-
diene chloride dimer [Rh(nbd)Cl]2 (Scheme 8).44
Scheme 5 Synthesis of a cubane analogue of triflumuron (41). [DMF =
N,N-dimethylformamide; DCM = dichloromethane.]
Scheme 7 Synthesis of a cubane analogue of tamibarotene (48). [DMF =
N,N-dimethylformamide; DCM = dichloromethane; ArNH2 = 5,5,8,8-tetra-
methyl-5,6,7,8-tetrahydronaphthalen-2-amine; TEA = triethylamine; THF =
tetrahydrofuran.]
Scheme 6 Synthesis of a cubane analogue of benznidazole (43). [TEA
= triethylamine; DCM = dichloromethane; C2H2Cl2O = chloroacetyl
chloride; DMF = N,N-dimethylformamide.]
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Table 1 Half-maximal inhibitory concentration standard error of the
mean (µM) values for tamibarotene (11) and cubane (46) and COT (48)
analogues across NFF fibroblasts and MCF7, MM96L, HT-29 and HeLa
cancer cell lines
Substrate
NFF
MCF7
<0.5
MM96L
HT-29
41
HeLa
Benzene (11)
Cubane (46)
COT (48)
21 10
93 30
51 20
25
70
70
1
5
4
5
48
3
30
8
5
1
251 70
113
107
93
7
8
3
Table 2 Log P values for the pharmaceutical templates tamibarotene
and benznidazole for all three scaffolds (benzene, cubane and COT)
Scheme 8 Functionalised cubane conversion to mono- and di-
substituted cyclooctatetraenes, through valence isomerisation. [Rh(nbd)
Cl2 = rhodium(I) norbornadiene chloride dimer.] a Reaction conditions:
Cubane derivative (0.2 mmol, 1 eq.), [Rh(nbd)Cl]2 (0.02 mmol, 0.1 eq.),
toluene (5 mL), 60–110 °C, 3–18 h; b isolated yield.
a
Template
Log PBenz
Log PCub b (Δ)
Log PCOT c (Δ)
Benznidazole
Tamibarotene
0.77d
3.49e
1.84e (+1.07)
1.30e (+0.53)
2.99e (−0.50)
3.30e (−0.19)
a Log P of benzene analogue. b Cubane analogue. c COT analogue.
d Literature value.47 e Measured using shake flask method. (Δ)
Difference relative to [a].
COT benznidazole (47)
Pleasingly, when evaluated against T. cruzi, the COT analogue
of benznidazole (47) displayed an IC50 of 2.3 0.2 µM and an measurements,5 is therefore essential. Log P values of the
SI of ≥16, indicating a two and a half fold improvement in tamibarotene and benznidazole templates were measured
activity compared to both the benzene original (10) (IC50 = 5.9 across all three systems using the traditional octanol water par-
0.5, SI > 21) and the cubane analogue (43) (IC50 6.1 0.1 µM, tition coefficient method (Table 2).43a In the case of tamibaro-
SI > 6).
tene, the cubane and COT scaffold both decreased log P rela-
tive to benzene, whereas for benznidazole an increase was
observed in both cases. Whilst there is no clearly discernible
trend, incorporation of either cubane or COT systems does
alter the log P, albeit not dramatically.
COT tamibarotene (48)
Overall, the COT (48) and cubane (46) derivatives of tamibaro-
tene were less active than the clinically used drug, although
the COT derivative was generally more active than the cubane
(46). In the case of the COT derivative 48, activity loss was gen-
erally by a factor of approximately 2–3 as observed for the mel-
anoma (MM96L), colon (HT-29), and cervical (HeLa) cancer
cell lines. However, for the breast cancer cell line (MCF7) the
COT derivative was an order of magnitude less active, but
nonetheless maintained reasonable activity. For the cubane
derivative little to no difference in activity was observed
between COT and cubane for MM96L and HeLa cell lines and
based on the standard error of the mean (SEM), there was also
little difference seen in activity for the healthy neonatal fore-
skin fibroblast (NFF) cell line. The larger differences in activity
between COT and cubane was observed with HT-29 and MCF7
cell lines (Table 1).
Metabolism
Previously we showed with the COT warfarin analogue43a that
this motif is not a particular metabolic liability. It appeared to
be metabolized by human liver cytochromes P450 to monooxy-
genated metabolites, albeit perhaps a little faster than the
phenyl analogues. In addition, it appeared to be bound to
plasma proteins equally compared with the phenyl com-
pounds. However, little if any work has been undertaken with
cubane metabolism by human enzymes. In order to explore
the metabolism of cubane containing molecules, the binding
and oxidation of a number of structurally simple cubyl/phenyl
pairs by cytochromes P450 was evaluated (Table 3). In this
initial screen the more active, readily available pure bacterial
P450s, P450cin and P450cam, were used as model systems. It
was expected that as their natural substrates are C10 oxyge-
nated hydrocarbons they would be good oxidants of small
cubane derivatives. All of the cubyl analogues evaluated bound
Log P
The tactic of scaffold hopping in drug discovery finds greatest more tightly to the P450 than the corresponding phenyl deriva-
utility in scenarios where a lead candidate displays satisfactory tive. This is perhaps indicative that the cube framework more
pharmacodynamic properties, but has an undesirable pharma- effectively occupies the active sites and participates in impor-
cokinetic profile.45 An understanding of how changing a tant hydrophobic interactions in these enzymes. In all cases a
scaffold or motif can affect key physical property measure- significant change in spin state of the heme iron was observed,
ments, for example log P46 and associated lipophilicity indicating binding at the active site of the enzyme. However,
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Table 3 Dissociation constants, high spin percentages and oxidation
products for benzene and cubane substrate pairs 49–56
lacks the π character of aromatic systems. Although this
deficiency has been addressed with the COT complement, a
thorough crystallographic study of protein-bound biologically
active cubanes would allow for the identification of active site
residues most favorable for cubane binding, and the instances
in which they align/differ with “aromatic” binding regions.
Solid state investigations into the unique range of three-
dimensional interactions displayed by cubanes have already
begun.49 With regards to pharmacokinetics, we have previously
utilized both log P and Clog P as measures of compound
hydrophobicity. Improved parameterization of computational
methods for accurately predicting the lipophilicity of cubanes
would be highly valuable.
A predictive approach to which targets are synthetically
viable, however, is more straightforward, and has been
informed by our extensive trials and tribulations associated
with inserting cubane into biologically active templates. Steric
limitations in extreme situations [i.e. dicubylmethanol (19)]
and the propensity of the cubylmethanol system to undergo
homocubane rearrangement [i.e. monocubane analogue of
DPH (23)] must both be taken into consideration. Accessing
homologated cubanes [i.e. mono- (28) and bis-cubane (31) ana-
logues of alverine] is cumbersome using traditional synthetic
approaches, although recent advances50 have expedited entry
to this area of chemical space. The dearth of practical pro-
cedures51 for functionalization of cubane in the 2-position can
place considerable downstream strain on arduous synthetic
sequences, both in terms of further chemical exploration [i.e.
cubane analogue of (R,S)-ketamine (38)] and of supplying
sufficient material for demanding agrochemical regimes [i.e.
cubane analogue of triflumuron (41)]. This exigency appears to
be general for other saturated hydrocarbon scaffolds with the
potential to act as ortho- (and meta-) benzene bioisosteres.52
Although candid synthetic limitations have been purpose-
fully highlighted herein, a selection of targets were indeed
completed, reinforcing cubane as a pharmaceutical building
block and a viable phenyl bioisostere. The cubane analogue of
benznidazole displayed biological efficacy on par with that of
its benzene progenitor, whereas for tamibarotene the cubane
analogue was less active than the benzene original. Facile
scaffold hopping to the corresponding COT motif improved
P450cam
P450cin
Substrate
Kd (μM)
% HS
48
[O]
Ya
Kd (μM)
% HS
90
[O]
Ya
639 71
542 87
6.1 0.4
NM
83
9
Yb
6.7 0.9
81
8
Yb
ND
ND
ND
ND
1550 250
ND
ND
ND
ND
41
1400 200
18
4
61
33
61
60
3
27
56
44
NM
3
2310 160
670 120
23
ND
ND
NM
25
ND
ND
—
—
—
—
Kd = dissociation constant. % HS = percentage high spin. [O] = oxi-
dation product. Y = yes. NM = not measurable. ND = not detected.
a Both CH3 and aromatic oxidation, see literature.41 b Only CH3 oxi-
dation, see literature.2b
oxidation products were only seen in the case of the t-butylcu-
bane/t-butylbenzene pair, as previously reported. This might
reflect the strength of the cubyl C–H bond, which would
inhibit hydrogen abstraction, the first step in P450 catalysed
oxidations. That said, the corresponding phenyl systems were
not substrates either and oxidation of such moieties is believed
to proceed via an aryl addition mechanism.41 The results cer-
tainly indicate that the cubyl moiety is an effective hydro-
phobic substituent and it is not easily oxidized by metabolic
P450s.
Discussion and conclusion
Now entering its fifty-fifth year,1 cubane is a readily available activity in both cases: the COT analogue of benznidazole out-
fine chemical48 and as predicted by Eaton, has been demon- performed both cubane and benzene counterparts (i.e. 47 > 43
strated to behave as a benzene bioisostere. The cubane plat- = 10), and the COT analogue of tamibarotene was better than
form facilitates both structural diversity (i.e. an escape from the cubane analogue (but not the benzene original) (i.e. 11 >
“flatland”) and scaffold hopping, and continued investigation 48 > 46). For the latter two pharmaceutical templates, log P
will allow practitioners to identify the cases where cubane values were measured across all three systems. Cubane and
inclusion can be deployed in the future. A predictive approach COT substitution altered log P relative to the benzene original,
of this nature is understandably non-trivial given the range of demonstrating that both of these frameworks have the poten-
factors which contribute to producing an effective compound, tial to modulate solubility profiles.
and is a significant challenge even in conventional bioactive
molecule design. Individual characteristics, however, may be the context of all the targets completed thus far, where the
addressed. complementarity between cubane and COT as viable scaffolds
Overall, the results presented herein are best considered in
From a pharmacodynamic perspective, although cubane and/or motifs for bioactive discovery is clearly evident
and benzene both facilitate similar placement of pharmaco- (Table 4). In eight out of the ten biological templates evalu-
phoric points in three-dimensional space, cubane notably ated, the incorporation of either cubane or COT resulted in
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Table 4 Summary of the relative bioactivity for phenyl, cubane and COT derivatives of ten different biological templates: SAHA, leteprinim, benzo-
caine, benzyl benzoate, diflubenzuron, moclobemide, warfarin, pravadoline, benznidazole and tamibarotene
Template
Activity
Relative Bioactivity
Template
Activity
Relative Bioactivity
Anticancer
Antidepressant
Neurotrophic
Anticoagulant
Anaesthetic
Acaracide
Analgesic
Antiparasitic
Insecticide
Anticancer
biological efficacy greater than or equal to the benzene parent. able discussion. J. M. B is indebted to the University of
This success across a multitude of different biological plat- Queensland Research Computing Centre, the Queensland
forms and the straightforward conversion of cubane to COT Cyber Infrastructure Foundation (QCIF) and the National
make the pair a highly practical tool for deployment in drug Computational Infrastructure (NCI, supported by the
discovery. Whilst there have been numerous recent develop- Australian Government) for access to supercomputing
ments in methodology concerning the cubane core,53 substan- resources. M. L. S gratefully acknowledges funding support
tial omissions from the field include a robust procedure for from the Griffith University Postgraduate Fellowship
functionalization at the 2-position (ortho), and a general pro- Award. V. M. A is grateful for financial support from the
cedure for functionalization at the 3-position (meta). Advances NHMRC and ARC.
such as these that will likely galvanize cubane in the bioisos-
tere landscape for years to come.
Notes and references
Conflicts of interest
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CSIRO (J. T. and G. P. S.) and UQ (C. M. W.) have a formal
relationship with Boron Molecular Pty Ltd who supply cubane
intermediates.
Acknowledgements
The authors thank the University of Queensland (UQ), Griffith
University (GU), the QIMR Berghofer Medical Research
Institute, Department of Agriculture and Water Resources for
financial support (CT-06), and the CSIRO (Melbourne) for
financial support. The Australian Research Council (ARC) for a
Future Fellowship award (grant number FT110100851) to
C. M. W. is also gratefully acknowledged, in addition, to the
National Health and Medical Research Council of Australia
(NHMRC). S. D. H. is grateful to the Northcote Trust and
Britain-Australia Society for their award of the Northcote
Graduate Scholarship, and to Dr Rachel Stephenson for invalu-
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