Multiply–linked cyclodextrin–aromatic hybrids: Caps, hinges and clips

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Mul iply–linked cyclodex in–a oma ic hyb ids: caps, hinges
and clips
Jou nal:
Jou nal o Ca bohyd a e Chemis y
Manusc ip ID
LCAR-2019-0023.R1
Manusc ip Type:
Re iew
Da e Submi ed by he
Au ho :
n/a
Comple e Lis o Au ho s:
Ne a, Tania; CSIC, Ins i u e o Chemical Resea ch
O iz-Melle , Ca men; Uni e si y o Se ille, Depa men o O ganic
Chemis y
Ga cía Fe nández, José; CSIC, Ins i u e o Chemical Resea ch
Beni o, Juan; CSIC, Ins i u e o Chemical Resea ch
Keywo ds:
sel -assembling, hos -gues , ansi ion me al ca alysis, sup amolecula
chemis y, capped cyclodex ins
No e: The ollowing iles we e submi ed by he au ho o pee e iew, bu canno be con e ed o PDF.
You mus iew hese iles (e.g. mo ies) online.
Figu e 2.cdx
Scheme 1.cdx
Scheme 2.cdx
Scheme 3.cdx
Scheme 4.cdx
Scheme 5.cdx
Scheme 6.cdx
Scheme 8.cdx
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Jou nal o Ca bohyd a e Chemis y
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Mul iply–linked cyclodex in–a oma ic hyb ids: caps, hinges and clips.
Tania Ne aa, Ca men O iz Melle b, José M. Ga cía Fe nándeza and Juan
M. Beni oa*
aIns i u o de In es igaciones Químicas (IIQ), CSIC - Uni e si y o Se ille, Se ille,
Spain; bDepa men o O ganic Chemis y, Facul y o Chemis y, Uni e si y o Se ille,
Se ille, Spain
Co espondence:
D . J. M. Beni o, Ins i u o de In es igaciones Químicas (IIQ), CSIC−Uni e si y o
Se ille, A . Ame ico Vespucio 49, 41092 Se ille, Spain; email: [email p o ec ed]
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Mul iply–linked cyclodex in–a oma ic hyb ids: caps, hinges and clips.
The judicious combina ion o shaping and ecogni ion elemen s in cage- ype
a chi ec u es ep esen s a powe ul s a egy o access molecula de ices wi h
ailo ed ecep o p ope ies and con olled abili ies o o m sup amolecula
assemblies. A oma ic modules a e pa icula ly a ac i e o hese endea ou s:
hey can play he ole o igid walls o build pe manen ca i ies, olding sc eens
be ween p eexis ing compa men s and/o ac as unc ional componen s
p omo ing nonco alen sel -in e ac ions as well as associa ions wi h hi d species,
allowing se e al le els o o ganiza ion o be implemen ed. The ield o
cyclodex ins has eno mously bene i ed om he amalgama ion wi h a oma ic
building blocks o gi e bi h o hyb ids wi h a much b oade spec um o
p ope ies and applica ions. The p og ess in p ecision chemis y has u he
enabled he e icien p epa a ion o mul iply-linked cap, hinge o clip
cyclodex in-a oma ic chime as wi h unp eceden ed le el o con ol, which has
ansla ed in o new de elopmen s in ields like sup amolecula ca alysis, sel -
assembly o gene deli e y. This e iew a icle ocuses speci ically in hese ype
o compounds, highligh ing he in ima e ela ionship be ween s uc u e,
sup amolecula p ope ies and pe o mance in he a ge applica ion.
Keywo ds: capped cyclodex ins; sup amolecula chemis y; ansi ion me al
ca alysis; hos -gues ; sel -assembling
G aphical abs ac
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In oduc ion
The cyclomal ooligosaccha ides (cyclodex ins, CDs) a e iconic cage molecules ha
ha e been ins umen al in he bu s and de elopmen o sup amolecula chemis y.[1]
Thei α-(1→4)-linked α-D-glucopy anosyl backbone ea u es a unca ed-cone o oidal
shape ha exhibi s inne -ou e amphiphilici y, enabling he inclusion o hyd ophobic
gues molecules on a size- i basis (Figu e 1). Upon con inemen in he CD ca i y, he
p ope ies o he gues (e.g. i s luo escence beha io , spec oscopic p ope ies, s abili y,
chemical eac i i y o accessibili y o enzymes o ecep o s) become al e ed, which
ha e gi en ise o a b oad a ie y o echnological applica ions. The implemen a ion o
e icien me hodologies o he unc ionaliza ion o he hyd oxyl g oups in he na i e
cyclodex ins h ough p ecision chemis y s a egies has exponen ially expanded he
ca alogue o a ailable CD de i a i es beyond he s aigh -jacke ed hexa (αCD), hep a
(βCD) and oc ame (γCD) ep esen a i es.[2] Cu en ly, ailo ed-made CDs can be
accessed in single dias e eome ic o m wi h a p ecise o ien a ion o unc ional elemen s,
wi h he only limi a ion o one’s imagina ion.[3] Chemical elabo a ion allows, o
ins ance, o e coming he limi o he in e nal ca i y o molecula hos ing, impa ing
ca aly ic ac i i ies, p og amming sel -assembly o p omo ing he associa ion wi h
biomolecula pa ne s. A oma ic appendages a e pa icula ly a ac i e o hose
channels: hey can play he ole o igid walls and p obe elemen s, con eying addi ional
nonco alen in e ac ion and sensing abili ies and allowing se e al le els o o ganiza ion
o be implemen ed. In mos epo ed examples, howe e , he a oma ic componen in
a oma ic-CD hyb ids is a ached o he cyclooligosaccha ide co e h ough a single
posi ion and e ains subs an ial mobili y, which limi s accu a e h ee-dimensional
de ini ion.[4] Mul iply-linked de i a i es wi h es ic ed con o ma ional eedom,
eachable a e poin -speci ic posi ioning o he componen s, a e be e sui ed o
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p ecise con ol o ecep o opology. Depending on he ela i e disposi ion o he
ancho ing poin s, “cap”-, “hinge”- and “clip”-like a chi ec u es wi h di e se deg ees o
lexibili y ha e been epo ed. This e iew cen e s speci ically on such kind o
molecula nanosized hyb ids, wi h a ocus on he po en ial o a oma ic modules o
igge con o ma ional changes and sel -assembling modes impac ing he CD
sup amolecula and unc ional p ope ies. Ra he han a comp ehensi e discussion, we
will commen on selec ed ep esen a i e examples ha highligh he igo o he ield.
No e ha capped CD dime s inco po a ing a oma ic segmen s in he e he ing a m a e
no co e ed he e. Fo an all-inclusi e in o ma ion, he eade is add essed o excellen
e iews and ecen epo s.[5]
OH HO OH
HO OH
HO
HO
HO OH
OH
OHOH
OO
O
O
O
HO
HO OH OH
OH
OH
OH
OH
HO
n
O
OH
O
O
HO
HO
O
OH
O
HO
HO
OHO
O
OH
HO
O
HO
O
OH
OH
O
HO
O
OH
OH
O
OH
HO
OH
i. d. (Å)
4.7 - 5.2
6.0 - 6.4
7.5 - 8.3
CD
CD (n = 1)
CD (n = 2)
CD (n = 3)
o. d. (Å)
14.2 - 15.0
15.0 - 15.8
17.1 - 17.9
heigh (Å)
7.9 - 8.0
7.9 - 8.0
7.9 - 8.0
cyclodex in
(CD)
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Figu e 1. Gene al s uc u e and dimensions o na i e cyclodex ins ( he ac onyms i. d.
and o. d. e e o inne and ou e diame e , espec i ely).
Doubly-linked he e oa oma ic caps: me al chela ion and ca alysis
The igid s uc u e o CDs, wi h hyd oxyl g oups egula ly disposed a p ecise
dis ances, p o ides a e sa ile amewo k o p og amming conce ed me al chela ion
a e poin -selec i e unc ionaliza ion. The mo e eadily accessible p ima y posi ions
ha e been gene ally a ge ed o hese channels. In o de o limi he con o ma ional
mobili y, Ma , A mspach and cowo ke s de eloped syn he ic me hodologies, based in
he use o i yla ing eagen s, o access diamines o he inco po a ion o capping
he e oa oma ic ligands doubly ancho ed a C-6 posi ions in I/II, I/III o I/IV ela i e
disposi ion in ei he  o βCD.[6] In a pionee ing wo k, hese au ho s desc ibed he
syn hesis o he 2,2’-bipy idyl-capped αCDs 1 and 2. These hyb ids exhibi ed dis inc
me al chela ing p ope ies ha we e go e ned by he o ien a ion o he a oma ic
agmen : endo-o ien ed bipy idyl moie ies p e e en ially s abilized me als wi h plana
coo dina ion geome y me als, such as Pd(II),[7] while he exo-o ien ed analog be e
adap ed o oc ahed al me al cen e s, such as Ru(II),[8] (Scheme 1).
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MeOMeO OMe
OMe
MeO
H2N
OMe
NH2
OMe n
o CD
6I,6IV-CD, 16I,6IV-CD, 26I,6IV-CD, 3
6I,6IV-CD, 3
m
m + n = 4 o 5
( o - and CD,
espec i ely) 6I,6III-CD, 4
6I,6III-CD, 4
6I,6IV-CD, 5
6I,6IV-CD, 5
NHN
N N
MeOMeO OMe
OMe
MeO
O
OMe
O
OMe n
CD
m
m + n = 4
NH HN
H2N
H2N
NaBH3CN
HC(OE )3
HCl
Cl
AuCl
N N
Cl
N N
ClOC COCl
i) E 3N, ol, 80 ºC
ii) [PdCl2]
N N
ClOC COCl
i) E 3N, ol, 80 ºC
ii) [Ru(bpy)2]
plana -squa e
1:Pd coo dina ion
oc ahed al 2:Ru
coo dina ion
N
O
O
ii) FeCl2
i)
igonal-py amidal
3:Fe coo dina ion
OO
AcOH, ol, e lux
6I,6III-CD, 6; 6I,6IV-CD, 7
MeOMeO OMe
OMe
MeO
MeOMeO OMe
OMe
MeO MeOMeO OMe
OMe
MeO
MeOMeO OMe
OMe
MeO
Pd(II) Ru(II) Fe(II)
Au
N N
HN
O
N
O
N N
HN
O
NH
O
N
N N
Pd
Cl
(bpy)2
Ru
Fe
Cl
Cl
MeOMeO OMe
OMe
MeO MeOMeO OMe
OMe
MeO MeOMeO OMe
OMe
MeO
H
MeOMeO OMe
OMe
MeO
H2N
OMe
NH2
OMe n
o CD
6I,6IV-CD, 1
NN
HN
O
N
O
6I,6IV-CD, 2
NN
HN
O
NH
O
N
N N
6I,6IV-CD, 3
6I,6IV-CD, 3
m
m + n = 4 o 5
( o - and CD,
espec i ely)
6I,6III-CD, 4
6I,6III-CD, 4
6I,6IV-CD, 5
6I,6IV-CD, 5
NHN
N N
MeOMeO OMe
OMe
MeO
O
OMe
O
OMe n
CD
m
m + n = 4
NH HN
H2N
H2N
NaBH3CN
HC(OE )3
HCl
Cl
AuCl
N N
Cl
N N
ClOC COCl
i) E 3N, ol, 80 ºC
ii) [PdCl2]
Pd
Cl
N N
ClOC COCl
i) E 3N, ol, 80 ºC
ii) [Ru(bpy)2](bpy)2
Ru
plana -squa e
coo dina ion
oc ahed al
coo dina ion
N
O
O
ii) FeCl2
i)
Fe
Cl
Cl
igonal-py amidal
coo dina ion
OO
AcOH, ol, e lux
6I,6III-CD, 6; 6I,6IV-CD, 7
MeOMeO OMe
OMe
MeO MeOMeO OMe
OMe
MeO
MeOMeO OMe
OMe
MeO
MeOMeO OMe
OMe
MeO
MeOMeO OMe
OMe
MeO MeOMeO OMe
OMe
MeO
MeOMeO OMe
OMe
MeO
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Scheme 1. Di e en app oaches o p ima y im N-he e ocyclic a oma ic-capped CDs
epo ed by Ma , A mspach and cowo ke s and hei me al chela ion capabili ies
(me hoxyls a he p ima y im we e omi ed o cla i y in some o he s uc u es).
The same labo a o y epo ed he syn hesis o α and βCD de i a i es equipped
wi h a igid py idine-bisimine cap b idging he dis al 6I and 6IV posi ions (3α and 3β).
This a chi ec u e p o ided a sui able en i onmen o igonal bipy amidal chela ion o
Fe(II)[9] (Scheme 1), which is ema kable conside ing ha in he absence o he CD
sca old he py idine-bisimine mo i a o ds oc ahed al Fe(II) complexes. The app oach
has been la e ex ended o he ins alla ion o a oma ic caps h ough 6I/6III and 6I/6IV
unsymme ical imine-enamine (4 and 5) and benzimidazole (6 and 7) b idges in a
egioselec i e manne . The inal compounds ha e induce inwa d-o ien ed ni ogen
a omscoo dina ion, o e ing new oppo uni ies o conduc ing ca aly ic eac ions in a
highly c owded chi al en i onmen .[10] The concep has been ecen ly demons a ed o
he asymme ic cycloisome iza ion o 1,6-enynes p omo ed by complexes o Au(I) and
benzimidazolium ca bene-capped CDs[11] (Scheme 1).
Sollogoub and co-wo ke s de eloped an e icien syn hesis o N-he e ocyclic
ca bene (NHC)-capped CD de i a i es (8α and 8β) and o hei complexes wi h g oup
11 ansi ion me als, i.e. Cu(I), Ag(I) o Au(I), and in es iga ed he s iking e ec s o
con inemen o he me al inside he CD ca i y in he chemical p ope ies. A unique C-
H···M coo dina ion sphe e was e idenced ha se ed as insula ion shield om
elec ode su aces and go e ned he ca aly ic ac i i y. Thus, he egioselec i i y o he
Au(I)-ca alyzed cycloisome iza ion o 1,6-enynes e e ed upon swi ching om α o
βCD-based NHC ligands.[12] Simila CD ing size e ec s on he egioselec i i y we e
obse ed o he Cu(I)-ca alyzed hyd obo a ion eac ion, which led he au ho s o
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p oposed di e en ca aly ic pa hways o αCD- and βCD-de i ed NHC/Cu(I)
complexes[13] (Scheme 2).
HO
OBn
OH
BnO
BnO OBn 1 o 2
o CD
i) MsCl
ii)
N
N
H
OBn
BnO
BnO OBn 1 o 2
o CD
N NCl
OBn
BnO
BnO OBn 1 o 2
N N
Ag2O, CuCl
o AuCl
MeO2C
CO2Me
[8·M]+·Cl-
M = Cu, Ag, Au
[8·Au]+·Cl-
MeO2CCO2Me MeO2CCO2Me
MeO2CCO2Me
[8·Au]+·Cl-
1 : 0.65 : 0
63-52%
++
DCM
1 : 0 : 3.3
A
B
C
82-71%
BuOK, MeOH
O
H
B
O
[8·Cu]+·Cl-
[8·Cu]+·Cl-
0.94 : 0.06
0.12 : 0.88
MeO
BO
O
MeO
B
O
O
MeO
+
BnO
BnOBnO OBnOBn
OBn
OBn BnO
BnOBnO OBnOBn
OBn
OBn BnO
BnOBnO OBnOBn
OBn
OBn
6I,6IV-CD, 8
6I,6IV-CD, 8
Cl
HO
OBn
OH
BnO
BnO OBn 1 o 2
o CD
i) MsCl
ii)
N
N
H
OBn
BnO
BnO OBn 1 o 2
o CD
N NCl
OBn
BnO
BnO OBn 1 o 2
N N
Cl
Ag2O, CuCl
o AuCl
MeO2C
CO2Me
[8·M]+·Cl-; M = Cu, Ag, Au
6I,6IV-CD, 8  6I,6IV-CD, 8
[8·Au]+·Cl-
MeO2CCO2Me MeO2CCO2Me
MeO2CCO2Me
[8·Au]+·Cl-
1 : 0.65 : 0
63-52%
++
DCM
1 : 0 : 3.3
A
B
C
82-71%
BuOK, MeOH
O
H
B
O
[8·Cu]+·Cl-
[8·Cu]+·Cl-
0.94 : 0.06
0.12 : 0.88
MeO
BO
O
MeO
B
O
O
MeO
+
BnO
BnOBnO OBnOBn
OBn
OBn BnO
BnOBnO OBnOBn
OBn
OBn BnO
BnOBnO OBnOBn
OBn
OBn
Scheme 2. (A) Syn hesis o NHC-capped CDs 8α and 8β desc ibed by Sollogoub and
cowo ke s and hei pe o mance in 1,6-enyne cycloisome iza ion (B) and
hyd obo a ion eac ions (C) ca alysed by Au(I) and Cu(I), espec i ely.
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O
MeO
MeO
OMe
O
O
O
O
OMe
O
O
MeO
MeO
OMe
O
O
O
OMe
OMe
MeO
O
OMe
OMe
MeO
O
O
OMe
OMe
MeO
O
n
O
HO
HO
OH
O
O
O
O
OH
O
O
HO
HO
OH
O
O
O
OH
OH
HO
O
OH
OH
HO
O
O
OH
OH
HO
O
n
-, -, o CD
LDA, DMSO
28-33%
B
B
MeI, NaH
DMF
O
MeO
MeO
OMe
O
O
HO
HO
OMe
O
O
MeO
MeO
OMe
O
O
O
OMe
OMe
MeO
O
OMe
OMe
MeO
O
O
OMe
OMe
MeO
O
n
O
MeO
MeO
OMe
O
O
O
O
OMe
O
O
MeO
MeO
OMe
O
O
O
OMe
OMe
MeO
O
OMe
OMe
MeO
O
O
OMe
OMe
MeO
O
n
B
B
NaH, DMF
hyd oxyls in he
same Glc uni
Pd/C, H2
HCO2H
28-30
n = 1, 19,22,25, and 28
n = 2, 20,23,26, and 29
n = 3, 21,24,27, and 30
22-24
19-21
25-27
Scheme 6. Syn hesis o hinged- ype cyclodex in-a oma ic hyb ids by di ec 2I,3I-O-(o-
xylylena ion) o na i e CDs desc ibed by O iz Melle , Ga cía Fe nández and
cowo ke s.
The 2I,3I-O-(o-xylylene)-equipped pe me hyla ed CD de i a i es 22-24
exhibi ed nega i e solubili y empe a u e coe icien s in wa e : when hea ed, clea (25
°C) solu ions became immedia ely u bid, e u ning o he limpid o iginal s a e upon
cooling. This was asc ibed o e e sible dime iza ion p ocesses: in he dime s a e, he
hyd ophobic a oma ic moie y is likely sandwiched be ween he wo sel -assembling CD
monome s, becoming shielded om he bulk. This a angemen acili a es sol a ion and
p e en ing unspeci ic clus e iza ion a low empe a u es, whe eas hea ing esul s in
dime dis up ion, unco e ing o he a oma ic ing and p ecipi a ion. The he modynamic
pa ame e s o he monome - o-dime equilib ium was ex ensi ely cha ac e ized by
s eady-s a e and ime- esol ed luo escence echniques (based on he luo escence o
he biden a e xylylene moie y), NMR and compu a ional s udies (molecula mechanics
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and molecula dynamics; MM and MD). The da a we e consis en wi h a es ic ed
mobili y o he xylylene hinge, which can adop close and open con o ma ions ela i e
o he CD ca i y, bu do no unde go sel -inclusion. The o ma ion o head- o-head
(HH) dime s in semi-open con o ma ion is hen s ongly a o ed.[36] A simila beha io
was obse ed o α, β and γCD de i a i es inco po a ing he 2I,3I-O-(1,8-
dime hylnaph hylene) hinge 28-30, ob ained om he co esponding diols by eac ion
wi h 1,8-dib omome hylnaph halene[37] (Scheme 6). In e es ingly, he p esence o he
a oma ic hinge in he CDs enhances he 1:1 associa ion cons an s owa ds hyd ophobic
gues s such as oc yl β-D-glucopy anoside o me hyl 2-naph haleneca boxyla e (2MN; a
luo escen p obe sensi i e o medium pola i y), by abou h ee- old as compa ed wi h
he ully me hyla ed hos s, by p o iding addi ional a o able con ac s. I is wo h no ing
ha inclusion o he gues equi es dime dis up ion, which could be used o he
spa io empo al con ol o he sel -assembling p ope ies (Figu e 2).
OO
OO
O
O
O
O
< T
> T
Kdime 200 M-1
insoluble monome soluble dime
OO
OH
HO
HO
OH
oc yl -D-glucopy anoside
CO2Me
2MN
K1:1 ( o 23, M-1) 350 281
OMe
MeO
OMe
OMeOMe
OMe
23
OMe
OMe
MeO
OMe
OMe OMe
OMe
OMe
MeO
OMe
MeO
MeO
MeO
MeO
OMe
OMe
Figu e 2. Schema ic ep esen a ion o he con o ma ional and agg ega ion equilib ia o
2I,3I-O-(o-xylylena ed)-βCD 23.
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The possibili y o con olling he p opensi y o CD de i a i es o o m HH-
dime s in aqueous en i onmen s o e s new oppo uni ies o p og amming e e sible
hie a chical p ocesses equi ing he an ipa allel o ien a ion o unc ional elemen s
loca ed a he p ima y ace o he cyclooligosaccha ide pla o m. The co-assembly o
cyclodex in-based mul ihead/mul i ail amphiphiles wi h nucleic acids o a o d
nanocomplexes wi h ans ec ious capabili ies ep esen s an a che ypic example.[38,39]
Nanome ic molecula gene deli e y sys ems (molecula nanopa icle-based
ec o s)[40,41] o his amily spon aneously o m bilaye s be ween quasi-pa allel nucleic
acid chains (DNA o RNA) by he in e play o elec os a ic in e ac ions be ween he
ca ionic clus e s and he polyphospha e backbone[42] and hyd ophobic in e ac ions
in ol ing he lipophilic domains,[43] conce edly leading o desol a ion and compac ion
o he gene ic ma e ial. HH-dime s wi h ca ionic clus e s o ien ed in opposi e di ec ions
emula e he smalles s uc u al elemen o a bilaye and a e he e o e p e-o ganized o
unde go nucleic acid- empla ed nanocondensa ion[44] (Figu e 3).
Figu e 3. Schema ic ep esen a ion o he p ocess leading o nucleic acid condensa ion
in he p esence o polyca ionic CD amphiphiles emphasizing on he ele ance o he
spon aneous o ma ion o CD amphiphile bilaye s.
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As a p oo o concep , O iz Melle , Mendicu i, Ga cía Fe nández and cowo ke s
p epa ed he polyca ionic 2I,3I-O-(o-xylylene)-βCD de i a i es 32 and 34 by
xylylena ion o he pe -(C-6)-azido βCD ollowed ei he by educ ion o he azido
g oups o by coppe (I)-ca alyzed azide-alkyne coupling (CuAAC) eac ion wi h he
p opa gyl- unc ionalized amine dend on 33 and inal dep o ec ion[45] (Scheme 7). NMR,
luo escen decay measu emen s and compu a ional s udies suppo ed he exis ence o
pH-dependen dime iza ion equilib ia in wa e : whe eas he dime s a e a he s able a
neu al pH, dec easing he pH esul s in highe p o ona ion deg ees o he polyamine
domains and, consequen ly, s onge coulombic epulsion o he CD cons i uen s. Upon
o mula ion wi h plasmid DNA (pDNA), mul ilaye co-assemblies endowed wi h pH-
esponsi eness we e ob ained. This is concep ually e y in e es ing o applica ions in
gene he apy, since he weakening o he dime s a e nanopa icle cell up ake
des abilizes he whole CD-DNA sup amolecula edi ice, acili a ing endosome escape
and DNA ca go elease. Indeed, e alua ion o he ans ec ion capabili ies in COS-7
( enal epi helial g een monkey) cells, using a luci e ase-encoding epo e pDNA,
a o ded e iciencies ha pa alleled (32) o o e passed by 10- old ha o he non i al
ec o gold s anda d polye hyleneimine [45].
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Scheme 7. Syn hesis o polyca ionic 2I,3I-O-(o-xylylene)-βCD de i a i es 32 and 34
and p oposed mechanism o he pH-sensi i e hie a chical condensa ion and elease o
DNA. A neu al pH, he xylylene g oup p omo es dime iza ion h ough hyd ophobic
in e ac ions, p eo ganizing he sys em o he nex DNA condensa ion s ep.
Acidi ica ion leads o inc eased elec os a ic epulsion, des abilizing he condensa e and
acili a ing DNA elease.
Cyclic e he a oma ic clips: con ol o e molecula opology
Yamada and cowo ke s de eloped an elegan s a egy o achie e comple ely β-selec i e
glycosyla ion by using a glycosyl luo ide dono bea ing an o-xylylene b idge be ween
he 3-O and 6-O posi ions o D-glucopy anose.[46] The a ionale behind is ha he igid
e he connec ing he nonconsecu i e posi ions in he monosaccha ide o ces a dis o ed
con o ma ion o he six-membe ed ing ha de e mines he s e eochemical ou come o
he eac ion. Mo ing o he ield o cyclodex ins, O iz Melle , Mendicu i, Ga cía
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Fe nández and cowo ke s concei ed ha a oma ic “clips” could simila ly be inse ed
be ween nonconsecu i e hyd oxyls o o ce a con o ma ional change in he
cyclooligosaccha ide mac o ing, he eby modi ying he opology o he ca i y.[47]
S a ing om he βCD diol de i a i e 35, accessed by egioselec i e bis-deme hyla ion
o pe me hyla ed βCD wi h diisop opylaluminum hyd ide (DIBAL·H) ollowing he
me hodology o Sollogoub and cowo ke s,[48] he eac ion wi h 1,2- o 1,3-
dib omome hylbenzene, a o ded he co esponding 2I,3II-di-O-(o- o m-xylylene)-βCD
de i a i es 36 and 37, espec i ely (Scheme 8). As p edic ed om heo e ical
calcula ions, he o-xylylene “clipped” isome 36 p ese ed he 4C1 chai con o ma ion
o he glucopy anosyl esidues and he o oidal shape cha ac e is ic o CDs. Sha ply
di e en ly, he m-xylylene clip in 37 p o oked a shi o he 1C4 con o ma ion in he (O-
3)-subs i u ed monosaccha ide esidue, which esul s in a subs an ial al e a ion o he
o e all shape o he hos o an ellip ic geome y.
O
MeO
MeO
OMe
O7
O
O
DIBAL·H
oluene
O
HO MeO
O
OMe
O
MeO
MeO
O
OMe
O
MeO
MeO
OMe
O
OMe
OMe
OO
MeO
O
OOMe
OMe
MeO
O
OMe
OMe
MeO
O
OMe
OH
O
MeO
O
35
O
MeO
O
OMe
O
O
OMe
O
MeO
O
O
O
MeO
O
OMe
O
O
OMe
O
MeO
O
O
O
MeO
O
OMe
O
O
OMe
O
MeO
OO
O
OMe
O
MeO
OO
OOMe
MeO
B
B
B B
B
B
B
B
NaH, DMF
NaH, DMF
NaH,
DMF
36
37
38 39
NaH,
DMF
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Scheme 8. Syn hesis o O-2I,O-3II-xylylene- (36 and 37) and dime hylnaph hylene-
clipped (38 and 39) βCD de i a i es. The MM-op imized 3D-s uc u es o 36 and 37
(seconda y im iew) o hei s uc u es a e depic ed a he igh hand side.
P ea anging he CD opology h ough a oma ic clipping enables he con ol
o e he inclusion p ope ies. Thus, ci cula dich oism expe imen s es ablished ha he
o-xylylene module in 36 adop s a semi-open con o ma ion ha pe mi s he inclusion o
hyd ophobic molecules i ing he size o he βCD ca i y. The gues can addi ionally
bene i om a o able con ac s wi h he a oma ic clip in he complex, as con i med o
adaman ane-1-ca boxyla e (AC). Dissimila ly, he ellip ic ca i y o 37 is unable o hos
globula molecules, e en hough he m-xylylene moie y adop s a ully open
a angemen , selec ing ins ead plana gues s such as me hyl 2-naph hoa e. Fluo escence
decay measu emen s and compu a ional calcula ions u he e idenced a di ec
ela ionship be ween molecula shape and sel -assembling beha io : compound 36
o med an HH-dime in wa e solu ion whe eas he con o ma ionally dis o ed analogue
37 exis ed in monome ic o m a any concen a ion.[47]
The po en ial o a oma ic clips o modula e he sel -assembling p ope ies o
CDs has been u he demons a ed by p epa ing he O-2I,O-3II-linked 1,8- and 2,3-
dime hylnaph hylene de i a i es 38 and 39, espec i ely. In bo h cases he
con o ma ion o he glucopy anosyl uni s and he CD mac o ing emain essen ially
unal e ed. Howe e , he ela i e o ien a ion o he a oma ic pla o m signi ican ly
di e s: he 1,8-dime hylnaph halene module in 38 adop s a a he igid open
con o ma ion whe eas he mo e lexible 2,3-dime hylnaph halene appendage in 39 can
accommoda e a semi-open a angemen . Bo h compounds o m a he s able HH-dime s
in wa e solu ion, bu whe eas he a oma ic mo i s ac as ex ension walls in he case o
38-dime , hey beha e as olding sc eens be ween he seconda y ims o he monome
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cons i uen s in he case o 39-dime . Rema kably, he dime a chi ec u e has a s ong
impac in he inclusion capabili ies. Thus, he AC gues was ound o en e he 38-dime
ex ended ca i y h ough he bulk-exposed βCD na owe im o o m a e na y complex
AC/38-dime . In o he wo ds, 38-dime can accep hyd ophobic ca gos while p ese ing
he sel -assembled s uc u e. Con a ily, inclusion o AC igge ed 39-dime dis up ion
o gi e he bimolecula AC/39 complex species (Figu e 4). The possibili y o
implemen ing di e en sup amolecula o ganiza ion le els (e.g., sel -assembly and/o
inclusion and/o spa io empo al con olled dissocia ion) wi h a oma ic clips o e s hen
a a ional s a egy o p og am he beha io o CD-based de ices in biological
en i onmen s o (bio)molecula encapsula ion and con olled elease.[49]
Figu e 4. Schema ic ep esen a ion o he s uc u e o AC/38 and AC/39 complexes
illus a ing he dispa a e molecula inclusion dime o ma ion capabili ies imposed by
hei co esponding dime hylnaph halene appendages.
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Concluding ema ks
The ensemble o con ibu ions commen ed in he abo e sec ions illus a es he po en ial
o s a egies based in combining CD hos s and a oma ic modules o gene a e p ecise
molecula opologies and p og amming se e al le els o sup amolecula o ganiza ion.
Beyond p ede ining in e ac ions wi h a ge gues o sensing pu poses, a oma ic
moie ies can d i e sel -assembly as well as co-assembly wi h biomolecula pa ne s o
a o d nanocomplexes capable o pe o ming speci ic asks. Poly unc ional CD-
a oma ic hyb ids can u he be designed o e e sibly sel -a ange in o s imuli
esponsi e mul i alen cons uc s wi h p edic able o ien a ions and densi ies o he key
appended mo i s. The cu en applica ions ha e ocused mainly in sup amolecula
ca alysis[50] and molecula ec o s o non- i al gene deli e y[51] because o he c i ical
dependence o he e iciency o hese p ocesses on molecula and sup amolecula
p eo ganiza ion.[52] Cyclodex ins ha e been b oadly used o syn hesize mul i alen
ligands in o he esea ch a eas such as ca bohyd a e-p o ein in e ac ions,[53] po e-
o ming oxin blocke s[54] o enzyme inhibi ion[55] ha a e also expec ed o bene i om
simila app oaches. New de elopmen s will ce ainly a ise in he nea u u e om he
in ima e me ging o cyclodex in and a oma ic uni s in pu pose-concei ed hyb id
a chi ec u es.
Disclosu e s a emen
No po en ial con lic o in e es was epo ed by he au ho s.
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Funding
The au ho s acknowledge he inancial suppo o he Spanish Minis e io de Economía y
Compe i i idad (con ac numbe s CTQ2015-64425-C2-1-R and SAF2016-76083-R),
he Jun a de Andalucía (con ac numbe FQM2012-1467) and he Eu opean Regional
De elopmen Funds (FEDER and FSE). TN acknowledges he Jun a de Andalucía o a
doc o al ellowship.
Re e ences
[1] C ini, G. Re iew: A His o y o Cyclodex ins. Chem. Re . 2014, 114, 10940-10975.
DOI: 10.1021/c 500081p.
[2] Beni o, J.M.; Ga cía Fe nández, J.M. Cyclodex in Chemis y ia Selec i e
Hyd oxyl G oup Manipula ions. In P o ec ing G oups: S a egies and
Applica ions in Ca bohyd a e Chemis y; Vidal, S., Ed. Wiley-VCH: Weinheim,
Ge many, 2019; pp. 371-393.
[3] Wang, B.; Zabo o a, E.; Guieu, S.; Pe illo, M.; Gui e , M.; Blé io , Y.; Ménand,
M.; Zhang, Y.; Sollogoub, M. Si e-Selec i e Hexa-He e o-Func ionaliza ion o
α-Cyclodex in an A che ypical C6-Symme ic Conca e Cycle. Na . Commun.
2014, 5, 5354. DOI: 10.1038/ncomms6354.
[4] Gamieldien, M.R.; Maes e, I.; Jaime, C.; Naidoo, K.J. Op imal Con igu a ions o
“Capped” β-Cyclodex in Dime s in Wa e Maximise Hyd ophobic Associa ion.
ChemPhysChem 2010, 11, 452-459. DOI: 10.1002/cphc.200900541.
[5] (a) Engeldinge , E.; A mspach, D.; Ma , D. Capped Cyclodex ins. Chem. Re .
2003, 103, 4147-4173. DOI: 10.1021/c 030670y. (b) Ogoshi, T.; Ha ada, A.
Chemical Senso s Based on Cyclodex in De i a i es. Senso s 2008, 8, 4961-
4982; DOI: 10.3390/s8084961. (c) I o, S.; Kogame, C.; Akashi, M.; Kida, T.
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mul iply-linked
CD-a oma ic hyb ids
sel -
assembling
hos -gues
chemis y ca alysis
s uc u al
sca old
M
M
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OH HO OH
HO
OH
HO
HO OH
OH
OO
O
O
O
HO HO OH
OH
OH
OH
OH
HO
OH
n
cyclodex in
(CD)
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DNA
paCD
lipid-like�
bilaye
hyd ophobic�
compac ion
elec os a ic�
in e ac ion
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38-dime :AC
39:AC
complexes
he�ex ended�38-dime �
ca i y�accommoda es�AC.
AC�accesses� he�ca i y�
h ough� he�na owe �
im
AC
38-dime 39-dime
ype�I ype�II
39-dime �dissocia es�p io �AC�
inclusion.
AC�can�adop �bo h�( ype�I�and�II)�
o ien a ions�in o� he�monome �ca i y
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