New Jou nal o Chemis y c8nj03372b
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Q2
An ip oli e a i e ac i i y o new 2-glyco-3-ni o-1,2-
dihyd oquinolines and quinolines syn hesized unde
sol en less condi ions p omo ed by neu al alumina
V. Luque-Agudo, Jose
´M. Pad o
´n, E. Roma
´n, J. A. Se ano
and M. V. Gil*
This pape desc ibes he Q3
syn heses o new 2-glyco-3-ni o-1,2-
dihyd oquinolines and 2-glyco-3-ni oquinolines by one-po
aza-Michael–Hen y-dehyd a ion eac ions using g een
p ocedu es, such as a minimal amoun o sol en combined
wi h an he e ogeneous ca alys (neu al alumina). The eac i i y
o a ni o g oup-double bond sys em has also been
in es iga ed; hus, addi ion o indole o py ole o N- o myla ed
1,2-dihyd oquinolines has been s udied. Finally, he
an ip oli e a i e ac i i y o hese new compounds has been
e alua ed agains a panel o six human solid umo cell lines,
and compa ed o pha macological e e ence compounds,
inding ha hei ac i i y is in he low mic omola ange and ha
he ca bohyd a e moie y con igu a ion modula es GI
50
alues.
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V. Luque-Agudo
Jose
´M. Pad o
´n
E. Roma
´n
J. A. Se ano
M. V. Gil I-3146-2015 0000-0002-6236-7241
Que ies o he a en ion o he au ho s
Jou nal: NJC
Pape : c8nj03372b
Ti le: An ip oli e a i e ac i i y o new 2-glyco-3-ni o-1,2-dihyd oquinolines and quinolines syn hesized unde
sol en less condi ions p omo ed by neu al alumina
Fo you in o ma ion: You can ci e his a icle be o e you ecei e no i ica ion o he page numbe s by using he
ollowing o ma : (au ho s), New J. Chem., (yea ), DOI: 10.1039/c8nj03372b.
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Q6 The sen ence beginning ‘‘Howe e , he C-6-b omo- ...’’ has
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changed.
Q2An ip oli e a i e ac i i y o new 2-glyco-3-ni o-
1,2-dihyd oquinolines and quinolines syn hesized
unde sol en less condi ions p omo ed by neu al
alumina†
V. Luque-Agudo,
a
Jose
´M. Pad o
´n,
b
E. Roma
´n,
a
J. A. Se ano
a
and M. V. Gil *
a
This pape desc ibes he syn heses o new 2-glyco-3-ni o-1,2-dihyd oquinolines and 2-glyco-3-
ni oquinolines by one-po aza-Michael–Hen y–dehyd a ion eac ions using a minimal amoun o sol-
en and neu al alumina as he he e ogeneous ca alys . The eac i i y o he ni o g oup–double bond
sys em has also been in es iga ed; hus, he addi ion o indole o py ole o N- o myla ed 1,2-
dihyd oquinolines has been s udied. Finally, he cy o oxici y and an ip oli e a i e ac i i y o hese new
compounds ha e been e alua ed agains a panel o six human solid umo cell lines and compa ed o
pha macological e e ence compounds, inding ha hei ac i i y is in he low mic omola ange and
ha he ca bohyd a e moie y con igu a ion modula es he GI
50
alues.
In oduc ion
Quinoline 1was i s isola ed om coal a in 1834 by F. F.
Runge, and i is s ill he main sou ce o comme cial quinoline.
1
Cinchona ba k ex ac (genus Rubiaceae) has been ex ensi ely
used o comba mala ia. De ailed analysis allowed he iden i i-
ca ion o mo e han 20 alkaloids, whe e quinine 2, cinchoni-
dine 3, quinidine 4and cinchonine 5(Fig. 1) we e hose wi h
he highes biological ac i i y. In gene al e ms, quinoline 1
de i a i es exhibi diffe en biological ac i i ies,
2–5
and hei
syn heses ha e been e iewed.
6
In spi e o hei nume ous applica ions, he e a e only a ew
epo ed examples o quinoline 1de i a i es con aining acyclic
o cyclic ca bohyd a e moie ies, and none a C-2.
7–11
Rega ding he syn hesis o ni oquinolines, h ee gene al
me hods ha e usually been used o hei p epa a ion, such as
ni a ion o quinolines,
12
eac ion o 3-ni oquinolines N-oxides
wi h a limi ed numbe o eagen s,
13
and a modi ied F ied-
la
¨nde syn hesis.
14,15
Dihyd oquinolines also p esen a b oad spec um o biolo-
gical ac i i ies and a e e y impo an in medicinal and pha -
maceu ical chemis y.
16
Syn he ic me hods o chi al 1,2-
dihyd oquinolines a e e y limi ed;
17,18
hus, due o he
po en ial applica ion o hese subs ances, he syn he ic chal-
lenge o p epa ing hem using ca bohyd a es, which a e con-
side ed as a ac i e p oduc s o d ug design, as chi al
auxilia ies has been conside ed.
Al e na i e eac ion media a e being conside ed in o de o
comply wi h he cu en legisla ion on en i onmen al, sa e y
and heal h policies, such as pe o ming he eac ions in he
absence o sol en ,
19
and he combina ion o his echnique
wi h he use o he e ogeneous ca alys s, which cons i u es one
o he mos powe ul g een syn he ic ools.
In his wo k, he syn hesis o 3-ni o-1,2-dihyd oquinolines
and 3-ni oquinolines bea ing ca bohyd a e moie ies a C-2 has
been ca ied ou unde sol en less condi ions p omo ed by
neu al alumina, conside ing, addi ionally, hei possible an i-
p oli e a i e ac i i y. To he bes o ou knowledge, he e a e no
epo ed examples o his ype o compound. Due o his lack o
a ailable li e a u e, we ha e based ou syn hesis on ha
epo ed by Yao e al.
15
and adap ed i o he asymme ic
e sion using ni oole ins de i ed om ca bohyd a es as chi al
1
5
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55
1
5
10
15
20
25
30
35
40
45
50
55
Ci e his: DOI: 10.1039/c8nj03372b
Fig. 1 S uc u es o compounds 1–5.
a
IACYS-Unidad de Quı
´mica Ve de y Desa ollo Sos enible, Depa amen o de
Quı
´mica O ga
´nica e Ino ga
´nica, Facul ad de Ciencias, Uni e sidad de
Ex emadu a, 06006 Badajoz, Spain. E-mail: [email p o ec ed]
b
BioLab Ins i u o Uni e si a io de Bio-O ga
´nica An onio Gonza
´lez (IUBO-AG),
Cen o de In es igaciones Biome
´dicas de Cana ias (CIBICAN), Uni e sidad de La
Laguna, 38206 La Laguna, Tene i e, Spain
†Elec onic supplemen a y in o ma ion (ESI) a ailable. See DOI: 10.1039/
c8nj03372b
Recei ed 6 h July 2018,
Accep ed 2nd Oc obe 2018
DOI: 10.1039/c8nj03372b
sc.li/njc
This jou nal is cThe Royal Socie y o Chemis y and he Cen e Na ional de la Reche che Scien i ique 2018 New J. Chem., 2018, 00,16|1
NJC
PAPER
induce s. Ballini e al.
20
imp o ed he eac ion condi ions by
a oiding he use o DABCO and benzene. Mo eo e , since he
in luence o he s uc u e o he ca bohyd a e moie y on he
cy o oxic and an i i al ac i i y o ce ain 3-ni och omenes has
been desc ibed,
21
he in luence o he s e eochemis y o he
ca bohyd a e moie y inse ed a C-2 o he no el syn hesized
quinoline-de i a i es on hei an ip oli e a i e ac i i y has been
s udied.
Resul s and discussion
2-Glyco-3-ni o-1,2-dihyd oquinolines 9a–11c we e p epa ed by one-
po aza-Michael–Hen y-dehyd a ion eac ions be ween ca bohy-
d a e de i ed ni oalkenes 6and 7and 2-aminobenzaldehydes
8a–c, using neu al alumina as he ca alys ,
20
hea inga 601C
and adding dichlo ome hane (3.12 mol%) o homogenize he
mix u e (Scheme 1). The esul s a e summa ized in Table 1. Bo h
ni oalkenes we e used o compa e he asymme y induced by he
chi al cen e a C-3 o compounds 6and 7and o s udy whe he
ha skele on a ec s he po en ial an ip oli e a i e ac i i y o he
new compounds
Q4 (Table 2).
The assignmen o C-2 con igu a ion o 9a–c and 10a–c +
11a–c was en a i ely made, conside ing ha ni oalkenes 6
and 7adop a p e e ed con o ma ion
22
in which hei C-2 Si
and Re aces, espec i ely, a e less hinde ed o he nucleophilic
a ack o he amine g oup p esen in 8a–c, and, he e o e, mo e
a ou able (Fig. 2). P ocesses in ol ing ni oalkene 6we e
comple ely dias e eoselec i e, since only one o he wo possi-
ble dias e eoisome s was de ec ed. The obse ed dias e eos-
elec i i y could be explained aking in o accoun he s e ic
hind ance caused by he ace a e g oup a C-3 o compound 6,
no ound in 7.
Ou g oup p oposes a co ela ion be ween he alue o J
1
0
,2
and he absolu e con igu a ion assigned o C-2 in 3-ni o-1,2-
dihyd oquinolines wi h pe ace yla ed ca bohyd a e moie ies:
hus, i C-10p esen s he Scon igu a ion (D-galac o), o com-
pounds wi h C-2(S) con igu a ion, he coupling cons an s J
1’,2
will be la ge (5–10 Hz), whe eas o compounds ha ing he C-
2(R) con igu a ion, hese same cons an s will ha e a small alue
(0–2 Hz). When C-10p esen s he Rcon igu a ion (D-manno),
he alues o he coupling cons an s a e opposi e wi h espec
o hose o he p e ious case. This co ela ion has also been
obse ed, and in some cases con i med by X- ay di ac ion, in
o he 3-ni o-2H- hioch omenes and in 3-ni o-2H-ch omenes
syn hesized in ou lab.
23
3-Ni oquinolines 12a–c and 13a–c we e ob ained by ea -
men o 1,2-DHQs 9a–c o 10a–c +11a–c wi h a mix u e o
sodium dich oma e, we silica gel (50% w/w) and sodium
bisul a e
24
a oom empe a u e (Scheme 2), wi h sho eac ion
imes and in good yields (Table 3).
Deace yla ed quinolines 14a–15c we e syn hesized
(Scheme 3) o imp o e he solubili y o he new compounds
in aqueous medium, which is he closes medium o cellula
issue. The esul s a e summa ized in Table 4.
The ans-ni o g oup–double bond sys em is p ese ed in
he skele on o he 1,2-DHQs; o his eason, we s udied hei
eac i i y as accep o s in Michael addi ions. Thus, eac ions
be ween 1,2-DHQs, which we e i s ly N- o myla ed
25
o a oid
oxida ion o he co esponding quinolines, and indole 17 o
py ole 18 we e ca ied ou using basic alumina as he
ca alys ,
26
hea ing a 70 1C and adding dichlo ome hane (3.12
mol%) (Schemes 4 and 5).
1
5
10
15
20
25
30
35
40
45
50
55
1
5
10
15
20
25
30
35
40
45
50
55
Scheme 1 Reac ion be ween ni oalkenes 6and 7and aminobenzalde-
hydes 8a–c.
Table 1 Reac ion imes, yields and p oduc a ios o 9a and 10a–c +11c
p oduc s
R
2
67
(days) Yield (%) P oduc (days) Yield (%) P oduc ( a io)
H1 89 9a 1.5 88 10a +11a (1 : 1.6)
Cl 2 63 9b 1.5 92 10b +11b (1 : 1.6)
B 3 59 9c 287 10c +11c (1 : 1.1)
Table 2 Co ela ion be ween C-2 con igu a ion and alue o J
1’,2
Compound J
1
0
,2
(Hz) C-2 con igu a ion
9a 9.5 S
9b 9.5 S
9c 9.5 S
10a 0S
11a 6.0 R
10b 1.0 S
11b 5.5 R
10c 1.0 S
11c 5.0 R
Fig. 2 P e e en ial a ack o 8a–c on ni oalkene 6.
Scheme 2 Oxida ion o 9a–c and 10a–c +11a–c o quinolines 12a–c
and 13a–c.
2|New J. Chem., 2018, 00,16Thisjou nalis
cThe Royal Socie y o Chemis y and he Cen e Na ional de la Reche che Scien i ique 2018
Pape NJC

Fo p ocesses in ol ing indole 17, he wo Z/E o ame s o
he same dias e eoisome we e isola ed, excep in he case o
16c, in which only 20c was isola ed. Howe e , o hose in ol-
ing py ole 18, only E o ame s we e isola ed in pu e o m,
al hough Zones we e
Q5 also de ec ed by
1
H-NMR analysis o he
c ude eac ion. As he NOE expe imen s we e inconclusi e, he
assignmen o Z/Eisome ism was pe o med by aking in o
accoun p e ious s udies. Naga ajan e al.
27
concluded ha in
he case o N- o myl e ahyd oquinolines, he majo isome is
E, acco ding o he compa ison o chemical shi s o hei NMR
spec a signals and hose o lilolidone, an analogue p oduc .
An ip oli e a i e ac i i y
P e ious heo e ical quan i a i e s uc u e–ac i i y ela ionship
s udies applied o ans-2-(2-ni o inyl)- u an p edic ed ha
mo e han 50% o he biological ac i i y lies in he ans-ni o
g oup–double bond sys em.
28
An ip oli e a i e ac i i y esul s o
s uc u ally- ela ed compounds syn hesized by ou g oup
23,29
sup-
po his hypo hesis. Fo ha eason, he p e iously men ioned
ac i i y o compounds 9a–16c, including he s a ing ni oole ins 6
and 7, was e alua ed agains a panel o six human solid umo cell
lines: A-549 (non-small cell lung), SW1573 (non-small cell lung),
HBL-100 (b eas ), T-47D (b eas ), HeLa (ce ix) and WiD (colon).
The GI
50
alues (concen a ion o compound equi ed o inhibi
50% o umo cell g ow h) a e depic ed in Table 5. E alua ion was
accomplished by using a sligh ly modi ied e sion o he p o ocol o
he Na ional Cance Ins i u e (NCI) o he Uni ed S a es.
30,31
The
s anda d an icance d ugs e oposide, cispla in and 5- luo ou acil
we e used as e e ences o compa a i e pu poses.
As can be obse ed in Table 5, he GI
50
alues o he selec ed
compounds a e, in gene al, wo se han hose o he e e ence
pa e ns. An ip oli e a i e ac i i y oscilla es be ween mode a e
and low, bu , despi e ha , some conclusions can be in e ed:
Among he ace yla ed 3-ni o-1,2-dihyd oquinolines wi h he
D-galac o-con igu a ion moie y, 9a–c, he ac i i y dec eases in
he o de R
2
=H4Cl 4B , o all umo cell lines. Fo his se
o compounds, 9b was ound o be mo e e ec i e han 5-
luo ou acil agains T-47D and WiD cell lines, and is also
sligh ly less ac i e han he pha macological pa e ns e oposide
and cispla in.
The ac i i y o he ace yla ed 3-ni oquinolines wi h he
D-galac o-con igu a ion moie y, 12a–c, is lowe han ha o
hei p ecu so s, he 1,2-dihyd oquinolines. Howe e , he C-6-
b omo- Q6subs i u ed compound 12c has mode a e ac i i y, exhi-
bi ing alues compa able o hose o 9a o he HeLa cell line.
E en so, compound 12b emains he mos ac i e in he se ies
agains T-47D and WiD o e 5- luo ou acil.
I is no ewo hy ha upon deace yla ing he ca bohyd a e
moie y o he 3-ni oquinolines, all compounds u n ou o be
inac i e agains all cell lines, excep 14c, which exhibi s mod-
e a e ac i i y, wi h alues e y simila o hose o 5- luo ou acil
agains T-47D and WiD .
Pu e compound 10a, bea ing a D-manno-con igu a ion
moie y, has ela i ely high GI
50
alues, being inac i e agains
T-47D and WiD cell lines. Howe e , i is in e es ing ha he
ac i i y o he 10c +11c mix u e, which shows a ma kedly good
ac i i y p o ile, is mo e effec i e han 5- luo ou acil and simila
o he ac i i y exhibi ed by cispla in.
1
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1
5
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Table 3 Reac ion imes and yields o he oxida ion o 1,2-DHQs 9a–c
and 10a–c +11a–c o quinolines 12a–13c
Compound R
2
Time (h) Yield (%)
12a H 1.5 83
12b Cl 3.25 87
12c B 2.25 71
13a H 0.5 47
13b Cl 1.75 76
13c B 3 85
Scheme 3 Deace yla ion o ca bohyd a e moie ies.
Table 4 Reac ion imes and yields o deace yla ed compounds 14a–c
and 15a–c
Compound R
2
Time (h) Yield (%)
14a H1 93
14b Cl 1 95
14c B 1 66
15a H 1.5 42
15b Cl 1 53
15c B 1 67
Scheme 4 Addi ion o indole 17 o compounds 16a–c.
Scheme 5 Addi ion o py ole 18 o compounds 16a–c.
This jou nal is cThe Royal Socie y o Chemis y and he Cen e Na ional de la Reche che Scien i ique 2018 New J. Chem., 2018, 00,16|3
NJC Pape
A signi ican change o ac i i y was obse ed upon he N-
o myla ion o he 1,2-dihyd oquinolines; hus, all o hem
p esen be ween mode a e and good GI
50
alues, being o he
same o de o e en lowe in he cases o 16b and 16c o umo
cell lines HeLa, T-47D and WiD , wi h espec o 5- luo ou acil.
Fo he 3-ni o-1,2-dihyd oquinolines and hei de i a i es,
19a–b,20a–c and 21b–c, i can be concluded ha he C-6
subs i uen o he ing in luences he an ip oli e a i e ac i i y
o hese compounds, bu i is no possible o in e a clea end
in his ega d.
Expe imen al
Ma e ials and me hods
All chemicals we e pu chased om comme cial sou ces and
used di ec ly, wi hou u he pu i ica ion. P epa a i e TLC was
pe o med using silica gel (Me ck 60 GF
254
). TLC was pe -
o med on p ecoa ed Me ck Kieselgel 60 GF
254
aluminum
backed pla es; TLC spo s we e isualized by UV ligh . NMR
spec a we e eco ded on a B uke AC/PC ins umen (500 MHz
o
1
H and 125 MHz o
13
C) wi h e ame hylsilane as he
in e nal e e ence and deu e a ed chlo o o m o dime hyl sul -
oxide as he sol en . Coupling cons an s we e eco ded in Hz.
The cha ac e iza ion o NMR signals was based on homonuc-
lea double- esonance and DEPT expe imen s. High esolu ion
mass spec a we e eco ded on an Au ospec (Mic omass) spec-
ome e , a he Cen o de In es igacio
´n Tecnolo
´gica e Inno a-
cio
´n (CITIUS) om he Uni e sidad de Se illa. In a ed spec a
we e eco ded on an IR3000 The mo Elec on Co po a ion
spec opho ome e in he ange be ween 4000 and 600 cm
1
.
The e alua ion o he an ip oli e a i e ac i i y was accom-
plished ollowing he p o ocol o he NCI o he Uni ed
S a es.
30,31
Fo each compound, he cells we e exposed o se ial
decimal dilu ions in he ange o 0.001–100 mM o a pe iod o
48 h. A e exposu e, he SRB me hod was applied o de e mine
he op ical densi y o each cell a 530 nm (main) and 620 nm
(seconda y). Fo each p oduc concen a ion, he pe cen age o
g ow h (PG) acco ding o he NCI o mulae was calcula ed.
Syn he ic p ocedu es
Gene al p ocedu e o 2-glyco-3-ni o-1,2-dihyd oquinolines
9a–11c. To a he e ogeneous mix u e o ni oalkenes 6and 732
(1 g, 2.31 mmol) and he app op ia e aminobenzaldehyde 8a–c
(2.31 mmol), neu al alumina (2.31 g) and ou d ops o
dichlo ome hane ( o ini ially homogenize he mix u e) we e
added. The mix u e was s i ed a 60 1C un il eac ion comple-
ion (moni o ed by TLC, 1 : 5 hexane–die hyl e he ). The c ude
p oduc was ex ac ed wi h me hanol, il e ed and washed wi h
he same sol en un il he alumina became whi e. I necessa y,
dias e eoisome s we e pu i ied by PTLC (1 : 5 hexane–die hyl
e he ).
Gene al p ocedu e o 2-glyco-3-ni oquinolines 12a–13c.
Quinolines we e syn hesized using a p o ocol epo ed in he
li e a u e.
24
Gene al p ocedu e o he deace yla ed p oduc s 14a–15c. To
a solu ion o 12a–13c (1 mmol) in 90% me hanol (15 mL),
po assium ca bona e (0.57 g) was added. The suspension was
s i ed a oom empe a u e o 1 hou (TLC, 3 : 1, benzene–
me hanol). The c ude eac ion was acidi ied o pH B6 wi h
dilu ed HCl (i a solid appea s) o Ambe li e IR-120 (H
+
), which
was hen il e ed. Pu e p oduc s we e c ys allized om
me hanol.
Gene al p ocedu e o N- o myl-1,2-dihyd oquinolines 16a–
c. A mix u e o 9a–c (1 mmol), o mic acid (4.7 mmol) and ace ic
anhyd ide (4.8 mmol) was s i ed a oom empe a u e o 1–2
hou s (TLC, 1 : 5 hexane–die hyl e he ). A e e apo a ion, he
1
5
10
15
20
25
30
35
40
45
50
55
1
5
10
15
20
25
30
35
40
45
50
55
Table 5 An ip oli e a i e ac i i y (GI
50
) agains human solid umo cell lines and human ib oblas s
a
Compound A549 (lung) HBL-100 (b eas ) HeLa (ce ix) SW1573 (lung) T-47D (b eas ) WiD (colon) BJ-hTe ( ib oblas )
GI
50
s
D
(mM)
617 4142162 1.7 0.7 19 21834211
720 2103181 2.1 0.4 22 4245113
9a 29 47329 33 86726 71 25 53 16 4100
12a 70 28 72 26 38 77239 4100 90 18 n. .
14a 4100 4100 4100 4100 4100 4100 n. .
10a 57 43483012684100 4100 n. .
15a 4100 4100 4100 4100 4100 4100 n. .
16a 56 17 83 23 43 46310 54 15 56 16 4100
9b 25 92662494092363034100
12b 37 54100 26 69013214713 n. .
14b 4100 4100 4100 4100 4100 4100 n. .
15b 4100 4100 4100 4100 4100 4100 n. .
16b 15 21711631231841944100
9c 88 17 97 55239112 93 12 82 24 4100
12c 53 16 89 24494113 82 17 59 94100
14c 29 53233275415010 49 14100
10c +11c 3.3 0.4 8.2 2.6 3.4 0.6 2.6 0.6 2.6 0.2 4.3 0.4 4100
15c 4100 4100 4100 4100 4100 4100 n. .
16c 19 43181841532872644100
E oposide 0.7 0.2 2.3 0.9 3.0 0.9 15 2226233 1.3 0.6
5-Fluo ou acil 2.2 0.3 5.5 2.3 15 5 4.3 1.6 47 18 49 7 5.5 0.5
Cispla in 2.1 0.6 1.9 0.2 2.0 0.3 3.0 0.4 15 3266143
a
Values a e mean o wo o ou expe imen s. n. . = no es ed.
4|New J. Chem., 2018, 00,16Thisjou nalis
cThe Royal Socie y o Chemis y and he Cen e Na ional de la Reche che Scien i ique 2018
Pape NJC
esidue was dissol ed in dichlo ome hane (10 mL), washed
wi h 5% sodium bica bona e solu ion and d ied wi h magne-
sium sul a e. The ex ac was e apo a ed o yield pu e com-
pounds 16a–c.
Gene al p ocedu e o he addi ion o indole o py ole o N-
o myl-1,2-dihyd oquinolines. To a mix u e o N- o myl-1,2-
dihyd oquinolines 16a–c (1 mmol) and indole o py ole
(1 mmol), ac i a ed basic alumina (1 g) and ou d ops o
dichlo ome hane ( o ini ially homogenize he mix u e) we e
added and s i ed a 60–70 1C o wo days. The c ude eac ion
was ex ac ed wi h me hanol and il e ed. Compounds we e
pu i ied by PTLC (1 : 1 hexane–e hyl ace a e, 2 elu ions).
Conclusions
In his pape , we epo on he syn hesis o new 3-ni o-1,2-
dihyd oquinolines and de i a i es bea ing a ca bohyd a e
moie y a C-2 using g een p ocedu es, since hese p ocesses
ha e been ca ied ou in he absence o sol en and wi h a
he e ogeneous ca alys . Mo eo e , he an ip oli e a i e ac i i y
o some o he p oduc s desc ibed he ein has been s udied,
inding ha hei GI
50
alues a e o he same o de as hose o
pha macological e e ence compounds in some o he cases.
Con lic s o in e es
The e a e no con lic s o decla e.
Acknowledgemen s
This wo k was suppo ed by he Gobie no deGobie no de
Ex emadu a-Ayuda a G upos de In es igacio
´n Ca alogados
and Fondo Eu opeo de Desa ollo Regional (G an GR15022).
We also hank he Uni e sidad de Ex emadu a, Plan de
Iniciacio
´n a la In es igacio
´n, Desa ollo Tecnolo
´gico e Inno a-
cio
´n 2016 and G upo Banco San ande o p o iding a ellow-
ship o Ve o
´nica Luque-Agudo.
No es and e e ences
1 R. Heusch and B. La e kusen, Ullmann’s Encyclopedia o
Indus ial Chemis y, 2000, , DOI: 10.14356007: a09_297.
2(a) O. Bilke , V. Lindo, M. Panico, A. E. E iene, T. Pax on,
A. Dell, M. Roge s, R. E. Sinden and H. R. Mo is, Na u e,
1998, 392, 289; (b) G. Roma, M. D. B accio, G. G ossi,
F. Ma ioli and H. Ghia, Eu . J. Med. Chem., 2000,
35, 1021; (c) Y.-L. Chen, K.-C. Fang, J.-Y. Sheu, S.-L. Hsu
and C.-C. Tzeng, J. Med. Chem., 2000, 44, 2374;
(d) P. A. Wins anley, Pa asi ol. Today, 2000, 16, 146.
3(a) K.-C. Fang, Y.-L. Chen, J.-Y. Sheu, T.-C. Wang and C.-
C. Tzeng, J. Med. Chem., 2000, 43, 3809; (b) J. Che alie ,
S. A i i, A. Ey aud, A. Mahamoud, J. Ba be and J.-M. Pages,
J. Med. Chem., 2001, 44, 4023; (c) L. T. Phan, T. Jian, Z. Chen,
Y.-L. Qiu, Z. Wang, T. Beach, A. Poleme opoulos and
Y. S. O , J. Med. Chem., 2004, 47, 2965; (d) S. J. Benko ic,
S. J. Bake , M. R. K. Alley, Y.-H. Woo, Y.-K. Zhang, T. Akama,
W. Mao, J. Babo al, P. T. R. Rajagopalan, M. Wall,
L. S. Kahng, A. Ta assoli and L. Shapi o, J. Med. Chem.,
2005, 48, 7468.
4(a) K. Maje z-Maniecka, B. Oleksyn, R. Musiol, B. Podeszwa
and J. Polanski, Abs ac s o Pape s, Join Mee ing on
Medicinal Chemis y, Vienna, Aus ia, June 20–23, 2005;
In Sci. Pha m., 2005, 73 (Suppl. 1), 194; (b) L. Y. Va gas,
M. V. Cas elli, V. V. Kouzne so , J. M. U bina, S. N. Lopez,
M. So ino, R. D. En iz, J. C. Ribas and S. Zacchino, Bioo g.
Med. Chem., 2003, 11, 1531; (c) M. Shingh, M. P. Shingh and
S. Y. Ablo deppey, D ug De . Ind. Pha m., 1996, 22, 377.
5(a) L. Dassonne ille, A. Lansiaux, A. Wa ele , N. Wa ez,
C. Mahieu, S. V. Mie , L. Pie e s and C. Bailly, Eu .
J. Pha macol., 2000, 409,9;(b) L. Dassonne ille,
K. Bonjean, M.-C. De Pauw-Gille , P. Colson, C. Houssie ,
J. Quen in-Lecle q, L. Angeno and S. Y. Ablo deppey,
Bioo g. Med. Chem., 2002, 10, 1337; (c) C. Bailly, Biochem-
is y, 1999, 38, 7719; (d) C. Bailly, W. Laine, B. Baldey ou, M.-
C. De Pauw-Gille , P. Colson, C. Houssie , K. Cimanga,
S. V. Mie , A. J. Vlie inck and L. Pie e s, An i-Cance D ug
Des., 2000, 15, 191; (e) M. Chauhan, A. Rana, J. M. Alex,
A. Negi, S. Singh and R. Kuma , Bioo g. Chem., 2015, 58,1.
6 S. M. P ajapa i, K. D. Pa el, R. H. Veka iya, S. N. Panchal and
H. D. Pa el, RSC Ad ., 2014, 4, 24463, and e e ences he ein.
7 P. H. Dobbelaa and C. H. Ma zabadi, Te ahed on Le .,
2010, 51, 201.
8(a)J.S.Yada ,B.V.S.ReddyandB.Padma ani,Syn hesis, 2004,
405; (b)J.S.Yada ,B.V.S.Reddy,S.Me aj,P.Vishnumu hy,
K. Na simulu and A. C. Kunwa , Syn hesis, 2006, 2923.
9(a) C. T. Bahne , N. Hun and L. M. Ri es, J. O g. Chem.,
1960, 25, 2062; (b) S. Ou, Z. Lin, C. Duan, H. Zhang and
Z. Bai, Chem. Commun., 2006, 4392.
10 J. Godlewska, K. Badowsca-Roslonek, J. Ramza,
L. Kaczma ek, W. Peczynska-Czoch and A. Opolski, Radiol.
Oncol., 2004, 38, 137.
11 S. Naga ajan and T. M. Das, Ca bohyd . Res.,2009,344,1028.
12 (a) G. Bacha ach, A. H. Hau and L. Ca oline, Recl. T a .
Chim. Pays-Bas, 1933, 413; (b) B. A nes ad, J. M. Bakke,
I. Hegbom and E. Ranes, Ac a Chem. Scand., 1996, 50, 556;
(c) J. M. Bakke and E. Ranes, Syn hesis, 1997, 281;
(d) M. Bakke, E. Ranes, J. Riha and H. S ensen, Ac a Chem.
Scand., 1999, 53, 141.
13 (a) H. Nakagawa, T. Higuchi, K. K. Kikuchi, Y. U ano and
T. Nagano, Chem. Pha m. Bull., 1998, 46, 1656;
(b) K. S. Sha ma, S. Kuma i and R. P. Singh, Syn hesis,
1981, 316.
14 (a) K. Scho ield and R. S. Theobald, J. Chem. Soc., 1950, 395;
(b) K. Scho ield and R. S. Theobald, J. Chem. Soc., 1951,
2992; (c) D. W. Ockenden and K. Scho ield, J. Chem. Soc.,
1953, 3914; (d) H. E. Baumga en and J. L. Taylo , J. Am.
Chem. Soc., 1957, 79, 1502.
15 M. C. Yan, Z. Tu, C. Lin, S. Ko, J. Hsu and C.-F. Yao, J. O g.
Chem., 2004, 69, 1565.
16 (a) A. R. Ka i zky, S. Rachwal and B. Rachwal, Te ahed on,
1996, 52, 15031; (b) K. M. Wi he up, R. W. Ransom,
1
5
10
15
20
25
30
35
40
45
50
55
1
5
10
15
20
25
30
35
40
45
50
55
This jou nal is cThe Royal Socie y o Chemis y and he Cen e Na ional de la Reche che Scien i ique 2018 New J. Chem., 2018, 00,16|5
NJC Pape
A. C. G aham, A. M. Pi zenbe ge and S. L. Va g, J. Am.
Chem. Soc., 1995, 117, 6682; (c) R. M. Ka iba, P. J. Hough on
and A. J. Yenesew, J. Na . P od., 2002, 65, 566;
(d) S. W. Elmo e, M. J. Coghlan, D. D. Ande son,
J. K. P a , B. E. G een, A. X. Wang, M. A. S ashko,
C. W. Lin, C. M. Ty ee, J. N. Mine , P. B. Jacobson,
D. M. Wilcox and B. C. Line, J. Med. Chem., 2001,
44, 4481; (e) P. D. Leeson, R. W. Ca ling, K. W. Moo e,
A. M. Moseley, J. D. Smi h, G. S e enson, T. Chan, R. Bake
and A. C. Fos e , J. Med. Chem., 1992, 35, 1954.
17 (a) M. Takamu a, K. Funabashi, M. Kanai and M. Shibasaki,
J. Am. Chem. Soc., 2000, 122, 6327; (b) H. Li, J. Wang, H. Xie,
L. Zu, W. Jiang, E. N. Duesle and W. Wang, O g. Le ., 2007,
9, 965; (c) H. Sunden, R. Rios, I. Ib ahem, G.-L. Zhao,
L. E iksson and A. Co
´ do a, Ad . Syn h. Ca al., 2007,
349, 827; (d) X. Liu and Y. Lu, O g. Biomol. Chem., 2010,
8, 4063.
18 Y.-F. Wang, W. Wang, W. Zhang, S.-P. Luo, B.-L. Li, A.-B. Xia,
A.-G. Zhong and D.-Q. Xu, Chem. – Asian J., 2009, 4, 1834.
19 Chemis y in Al e na i e Reac ion Media, ed. D. J. Adams,
P. J. Dyson and S. J. Ta ene , Wiley, 2004.
20 R. Ballini, G. Bosica, D. Fio ini and A. Palmie i, G een
Chem., 2005, 7, 825.
21 J. M. J. T onche , S. Ze elli, N. Dola shahi and H. Tu
¨ le ,
Chem. Pha m. Bull., 1988, 36, 3725.
22 (a) J. C. Sowden and M. L. O edahl, J. O g. Chem., 1961,
26, 2153; (b) J. C. Sowden and M. L. O edahl, J. Am. Chem.
Soc., 1960, 82, 2303; (c) J. C. Sowden, A. Ki kland and
K. O. Lloyd, J. O g. Chem., 1963, 28, 3516; (d) J. A. Galbis
and J. A. Se ano, An. Quim., 1983, 79, 33.
23 V. Luque-Agudo, J. Alba a
´n-Velo, J. G. Fe na
´ndez-Bolan
˜os,
O. Lo
´pez, M. E. Ligh , J. M. Pad o
´n, I. Lagunes, E. Roma
´n,
J. A. Se ano and M. V. Gil, New J. Chem., 2017, 41, 3154.
24 J. A. Dama andi, M. A. Zol igol and B. Ka ami, Syn h.
Commun., 2001, 31(20), 3183.
25 M. L. Hill and R. A. Raphael, Te ahed on, 1990, 46, 4587.
26 R. Ballini, R. R. Clemen e, A. Palmie i and M. Pe ini, Ad .
Syn h. Ca al., 2006, 348, 191.
27 K. Naga ajan, M. D. Nai and P. M. Pillai, Te ahed on, 1967,
23, 1683.
28 H. Gonza
´lez-Dı
´az, E. Olaza
´bal, L. San ana, E. U ia e,
Y. Gonza
´lez-Dı
´az and N. Cas an
˜edo, Bioo g. Med. Chem.,
2007, 15, 962.
29 V. Luque-Agudo, A. M. Gonza
´lez-Gu ie
´ ez, I. Lagunes,
F. Lo
´pez-Galindo, J. M. Pad o
´n, E. Roma
´n, J. A. Se ano
and M. V. Gil, Bioo g. Chem., 2016, 69, 71.
30 P. Skehan, R. S o eng, D. Scudie o, A. Monks, J. McMahon,
D. Vis ica, J. T. Wa en, H. Bokesch, S. Kenney and
M. R. Boyd, J. Na l. Cance Ins ., 1990, 82, 1107.
31 P. Mi anda, J. M. Pad o
´n, J. I. Pad o
´n, J. Villa and
V. S. Ma in, ChemMedChem, 2006, 1, 323.
32 (a) J. C. Sowden and D. R. S obach, J. Am. Chem. Soc., 1960,
82, 954; (b) J. C. Sowden and R. Schaffe , J. Am. Chem. Soc.,
1950, 73, 4662.
1
5
10
15
20
25
30
35
40
45
50
55
1
5
10
15
20
25
30
35
40
45
50
55
6|New J. Chem., 2018, 00,16Thisjou nalis
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Pape NJC