Ci a ion: del Co e, X.; López-
F ancés, A.; Villa e-Bei ia, I.;
Sainz-Ramos, M.; Ma ínez de
Ma igo a, E.; Palacios, F.; Alonso, C.;
de los San os, J.M.; Ped az, J.L.;
Vica io, J. Mul icomponen Syn hesis
o Unsa u a ed γ-Lac am De i a i es.
Applica ions as An ip oli e a i e
Agen s h ough he Bioisos e ism
App oach: Ca bonyl s. Phospho yl
G oup. Pha maceu icals 2022,15, 511.
h ps://doi.o g/10.3390/
ph15050511
Academic Edi o : Simone Luca ini
Recei ed: 29 Ma ch 2022
Accep ed: 20 Ap il 2022
Published: 22 Ap il 2022
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Licensee MDPI, Basel, Swi ze land.
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pha maceu icals
A icle
Mul icomponen Syn hesis o Unsa u a ed γ-Lac am
De i a i es. Applica ions as An ip oli e a i e Agen s h ough
he Bioisos e ism App oach: Ca bonyl s. Phospho yl G oup
Xabie del Co e 1, Ad ián López-F ancés1, Ilia Villa e-Bei ia 2,3,4 , My iam Sainz-Ramos 2,3,4 ,
Edo a Ma ínez de Ma igo a 1, F ancisco Palacios 1, Concepción Alonso 1, Jesús M. de los San os 1,
JoséLuis Ped az 2,3,4,* and Ja ie Vica io 1,*
1Depa men o O ganic Chemis y I, Facul y o Pha macy, Uni e si y o he Basque Coun y,
UPV/EHU Paseo de la Uni e sidad 7, 01006 Vi o ia-Gas eiz, Spain; xabie [email p o ec ed] (X.d.C.);
[email p o ec ed] (A.L.-F.); [email p o ec ed] (E.M.d.M.);
[email p o ec ed] (F.P.); [email p o ec ed] (C.A.); [email p o ec ed] (J.M.d.l.S.)
2NanoBioCel G oup, Uni e si y o he Basque Coun y (UPV/EHU), 01006 Vi o ia-Gas eiz, Spain;
[email p o ec ed] (I.V.-B.); [email p o ec ed] (M.S.-R.)
3Biomedical Resea ch Ne wo king Cen e in Bioenginee ing, Bioma e ials and Nanomedicine (CIBER-BBN),
Facul y o Pha macy, Uni e si y o he Basque Coun y (UPV/EHU), 01006 Vi o ia-Gas eiz, Spain
4
Bioa aba, NanoBioCel Resea ch G oup, Facul y o Pha macy, Uni e si y o he Basque Coun y (UPV/EHU),
01006 Vi o ia-Gas eiz, Spain
*Co espondence: [email p o ec ed] (J.L.P.); ja ie [email p o ec ed] (J.V.)
Abs ac :
We epo e icien syn he ic me hodologies o he p epa a ion o 3-amino and 3-hyd oxy
3-py olin-2-ones (unsa u a ed
γ
-lac ams) h ough a mul icomponen eac ion o amines, aldehydes
and ace ylene o py u a e de i a i es. The densely subs i u ed
γ
-lac am subs a es show
in i o
cy o oxici y, inhibi ing he g ow h o he ca cinoma human umo cell lines RKO (human colon
epi helial ca cinoma), SKOV3 (human o a ian ca cinoma) and A549 (ca cinomic human al eola
basal epi helial cell). In iew o he possibili ies o he di e si y o he subs i uen s ha o e a
mul icomponen , syn he ic me hodology, an ex ensi e s uc u e–ac i i y p o ile is p esen ed. In addi-
ion, he bioisos e ic eplacemen o he la es e g oup by a e ahed al phosphona e o phosphine
oxide moie y in
γ
-lac am subs a es leads o inc eased g ow h inhibi ion ac i i y. Cell mo phology
analysis and low cy ome y assays indica e ha he main pa hway by which ou compounds induce
cy o oxici y is based on he ac i a ion o he in acellula apop o ic mechanism.
Keywo ds: γ
-lac ams; mul icomponen syn hesis; an ip oli e a i e ac i i y; bioisos e ism; phosphona es;
phosphine oxides
1. In oduc ion
Due o a ise in li e expec ancy and/o decline in he e ili y a e, i ually e e y
coun y in he wo ld is expe iencing g ow h in he numbe and p opo ion o olde pe sons
in he popula ion. Acco ding o da a om he Uni ed Na ions [
1
], in 2019, 9% o people in
he wo ld we e o e aged age 65. By 2050, i is expec ed ha 16% o he wo ld’s popula ion
will be aged o e 65, and one in ou pe sons li ing in Eu ope and No he n Ame ica will
be aged 65 o o e . Mo eo e , he numbe o pe sons aged 80 yea s o o e is p ojec ed o
iple, om 143 million in 2019 o 426 million in 2050. These longe i y gains a e one o he
g ea es accomplishmen s o humankind bu , a he same ime, one o he mos o midable
challenges o he u u e wi h implica ions o nea ly all socioeconomic sec o s [
2
] and
an especially high impac in all heal h ca e sys ems wo ldwide. Du ing he las cen u y,
he causes o mo ali y changed om in ec ious and pa asi ic o ch onic and degene a i e
diseases, and acco dingly, cance has become one o he wo ld’s g ea es heal h p oblems [
3
].
The sys emic ea men o cance o en in ol es he adminis a ion o chemo he apeu ic
Pha maceu icals 2022,15, 511. h ps://doi.o g/10.3390/ph15050511 h ps://www.mdpi.com/jou nal/pha maceu icals
Pha maceu icals 2022,15, 511 2 o 19
agen s, which possess he abili y o a el h oughou he body and des oy malignan
cells [
4
]. The de elopmen o an ineoplasic d ugs has unde gone exponen ial g ow h
in he las decades, bu he e is s ill a se ious need o sea ch o newe , sa e and mo e
po en cy o oxic d ugs, especially due o he known abili y o cance cells o de elop
esis ance o adi ional he apies [
5
,
6
]. He e, d ug disco e y plays a c ucial ole h ough,
i s , he iden i ica ion o d ug candida es; second, he syn hesis and cha ac e iza ion o
a ge molecules; and inally, he e alua ion o hei he apeu ic e icacy p io o d ug
de elopmen and subsequen clinical ials.
Among he innume able po en ial chemo he apeu ic agen s, he
γ
-lac am ing
(Figu e 1)
is a key s uc u al sca old used in medicinal chemis y ha is ound in he s uc u es o
many na u al and syn he ic bioac i e compounds [
7
]. In pa icula , 3-py olin-2-ones
(Figu e 1) a e unsa u a ed
γ
-lac am de i a i es ha p esen a conjuga ed ing sys em
which possesses la en eac i i y o u he modi ica ions [
8
–
11
]. Mo eo e , he s uc u es
o hese unsa u a ed
γ
-lac am de i a i es a e essen ial pa s o he skele ons o nume ous
ele an bioac i e molecules ha show a la ge a ie y o biological ac i i ies [
12
–
14
], such
as he cy o oxic polyke ides Mycelio he mophins E, C and D [
15
], cy o oxic Pukeleumid E
p esen in Lyngbya majuscule algae [
16
], he HIV-in eg ase inhibi o O e omicyn [
17
,
18
] and
he an ibio ic Py ocidine A [19].
Pha maceu icals 2022, 15, x FOR PEER REVIEW 2 o 20
heal h p oblems [3]. The sys emic ea men o cance o en in ol es he adminis a ion
o chemo he apeu ic agen s, which possess he abili y o a el h oughou he body and
des oy malignan cells [4]. The de elopmen o an ineoplasic d ugs has unde gone expo-
nen ial g ow h in he las decades, bu he e is s ill a se ious need o sea ch o newe ,
sa e and mo e po en cy o oxic d ugs, especially due o he known abili y o cance cells
o de elop esis ance o adi ional he apies [5,6]. He e, d ug disco e y plays a c ucial
ole h ough, i s , he iden i ica ion o d ug candida es; second, he syn hesis and cha -
ac e iza ion o a ge molecules; and inally, he e alua ion o hei he apeu ic e icacy
p io o d ug de elopmen and subsequen clinical ials.
Among he innume able po en ial chemo he apeu ic agen s, he γ-lac am ing (Fig-
u e 1) is a key s uc u al sca old used in medicinal chemis y ha is ound in he s uc-
u es o many na u al and syn he ic bioac i e compounds [7]. In pa icula , 3-py olin-2-
ones (Figu e 1) a e unsa u a ed γ-lac am de i a i es ha p esen a conjuga ed ing sys em
which possesses la en eac i i y o u he modi ica ions [8–11]. Mo eo e , he s uc u es
o hese unsa u a ed γ-lac am de i a i es a e essen ial pa s o he skele ons o nume ous
ele an bioac i e molecules ha show a la ge a ie y o biological ac i i ies [12–14], such
as he cy o oxic polyke ides Mycelio he mophins E, C and D [15], cy o oxic Pukeleumid
E p esen in Lyngbya majuscule algae [16], he HIV-in eg ase inhibi o O e omicyn [17,18]
and he an ibio ic Py ocidine A [19].
Figu e 1. Rele an γ-lac am-con aining s uc u es.
In e es ingly, some unsa u a ed γ-lac am subs a es ha e been iden i ied as
p53−MDM2 [20] and STAT3 [21] inhibi o s ha ha e s ong an ip oli e a i e ac i i y. In
addi ion, se e al 2-py olidone de i a i es ha e been desc ibed as an i umo agen s [22–
29].
As a pa o ou ongoing esea ch on he mul icomponen syn hesis o γ-lac am de-
i a i es, in 2006, we epo ed ha a h ee-componen eac ion o amines, aldehydes and
py u a e de i a i es in he p esence o a B øns ed acid ca alys leads o he o ma ion o
3-amino 3-py olin-2-ones [30]. Mo e ecen ly, we de eloped an enan ioselec i e e sion
o his eac ion [31] and ex ended his mul icomponen p o ocol o he syn hesis o phos-
pho us- and luo ine-con aining iso e onic acid-based γ-lac ams [32]. In addi ion, we
we e able o demons a e ha hese subs a es can be p epa ed h ough a simila mul i-
componen eac ion using ace ylene ca boxyla es ins ead o py u a e de i a i es [33].
These mul icomponen p o ocols a e conside ed essen ial ools in di e si y-o ien ed syn-
hesis [34,35] due o he high deg ee o molecula di e si y achie ed and, acco dingly,
Figu e 1. Rele an γ-lac am-con aining s uc u es.
In e es ingly, some unsa u a ed
γ
-lac am subs a es ha e been iden i ied as p53
−
MDM2 [
20
]
and STAT3 [
21
] inhibi o s ha ha e s ong an ip oli e a i e ac i i y. In addi ion, se e al 2-
py olidone de i a i es ha e been desc ibed as an i umo agen s [22–29].
As a pa o ou ongoing esea ch on he mul icomponen syn hesis o
γ
-lac am de i a-
i es, in 2006, we epo ed ha a h ee-componen eac ion o amines, aldehydes and py u-
a e de i a i es in he p esence o a B øns ed acid ca alys leads o he o ma ion o 3-amino
3-py olin-2-ones [
30
]. Mo e ecen ly, we de eloped an enan ioselec i e e sion o his
eac ion [
31
] and ex ended his mul icomponen p o ocol o he syn hesis o phospho us-
and luo ine-con aining iso e onic acid-based
γ
-lac ams [
32
]. In addi ion, we we e able
o demons a e ha hese subs a es can be p epa ed h ough a simila mul icomponen
eac ion using ace ylene ca boxyla es ins ead o py u a e de i a i es [
33
]. These mul icom-
ponen p o ocols a e conside ed essen ial ools in di e si y-o ien ed syn hesis [
34
,
35
] due
o he high deg ee o molecula di e si y achie ed and, acco dingly, hey ha e become a
p e e en ial me hodology in he ield o medicinal chemis y [
36
,
37
]. 3-Amino 3-py olin-
2-ones can be seen as cyclic
α
-dehyd o
α
-amino acids, and such skele ons a e known o
be p esen in many bioac i e molecules, such as an imic obials wi h an i-bio ilm ac i i y,
Pha maceu icals 2022,15, 511 3 o 19
caspase-3 inhibi o s, analgesics, and an ipy e ics [
38
–
42
]. They also ep esen he basic
s uc u e o di hiopy olone an ibio ics [
43
]. In addi ion, 3-hyd oxy 3-py olin-2-ones ha e
been desc ibed as HIV in eg ase inhibi o s [
44
,
45
], an ibac e ials [
46
–
48
], noo opics [
49
]
and an i i als [50]. Addi ionally hey show an icance ac i i y [26,27].
In his con ex , e y ecen ly, we conduc ed a s udy on he an ip oli e a i e ac i i y o
3-amino 3-py olin-2-ones, showing e idence o he abili y o hese subs a es o ac i a e
he in acellula apop o ic mechanism [
29
]. Taking in o conside a ion he po en ial o i e-
membe ed he e ocycles con aining he 3-py olin-2-one skele on o ac as an icance agen s,
we belie e ha his epo on he syn hesis o unsa u a ed 3-hyd oxy and 3-amino
γ
-lac am
de i a i es ob ained by mul icomponen me hodologies and s udy o hei applica ions as
an ip oli e a i e agen s will be o g ea alue o his ield.
2. Resul s and Discussion
2.1. Chemis y
The mul icomponen p o ocol o he syn hesis o 3-amino 3-py olin-2-ones
4
implies
he eac ion o a oma ic amines
1
, aldehydes
2
and ace ylene ca boxyla e de i a i es
3
in
he p esence o a ca aly ic amoun o BINOL-de i ed phospho ic acid o se e al hou s in
e luxing oluene [
32
]. The p esence o MgSO
4
is necessa y in o de o emo e he wa e
gene a ed in he p ocess. The mechanism o he eac ion comp ises he ini ial o ma ion
o imine and enamine species
5
and
6
h ough he eac ion o wo equi alen s o amine
subs a e
1
wi h aldehydes
2
and ace ylene dica boxyla e de i a i es
3
. Nex , an acid-
p omo ed Mannich eac ion leads o he o ma ion o in e media e
7
, which spon aneously
e ol es h ough in amolecula cycliza ion be ween he amine and he es e g oups o yield
γ-lac am subs a es 4(Scheme 1).
Pha maceu icals 2022, 15, x FOR PEER REVIEW 3 o 20
hey ha e become a p e e en ial me hodology in he ield o medicinal chemis y [36,37].
3-Amino 3-py olin-2-ones can be seen as cyclic α-dehyd o α-amino acids, and such skel-
e ons a e known o be p esen in many bioac i e molecules, such as an imic obials wi h
an i-bio ilm ac i i y, caspase-3 inhibi o s, analgesics, and an ipy e ics [38–42]. They also
ep esen he basic s uc u e o di hiopy olone an ibio ics [43]. In addi ion, 3-hyd oxy 3-
py olin-2-ones ha e been desc ibed as HIV in eg ase inhibi o s [44,45], an ibac e ials [46–
48], noo opics [49] and an i i als [50]. Addi ionally hey show an icance ac i i y [26,27].
In his con ex , e y ecen ly, we conduc ed a s udy on he an ip oli e a i e ac i i y
o 3-amino 3-py olin-2-ones, showing e idence o he abili y o hese subs a es o ac i-
a e he in acellula apop o ic mechanism [29]. Taking in o conside a ion he po en ial o
i e-membe ed he e ocycles con aining he 3-py olin-2-one skele on o ac as an icance
agen s, we belie e ha his epo on he syn hesis o unsa u a ed 3-hyd oxy and 3-amino
γ-lac am de i a i es ob ained by mul icomponen me hodologies and s udy o hei ap-
plica ions as an ip oli e a i e agen s will be o g ea alue o his ield.
2. Resul s and Discussion
2.1. Chemis y
The mul icomponen p o ocol o he syn hesis o 3-amino 3-py olin-2-ones 4 im-
plies he eac ion o a oma ic amines 1, aldehydes 2 and ace ylene ca boxyla e de i a i es
3 in he p esence o a ca aly ic amoun o BINOL-de i ed phospho ic acid o se e al
hou s in e luxing oluene [32]. The p esence o MgSO4 is necessa y in o de o emo e
he wa e gene a ed in he p ocess. The mechanism o he eac ion comp ises he ini ial
o ma ion o imine and enamine species 5 and 6 h ough he eac ion o wo equi alen s
o amine subs a e 1 wi h aldehydes 2 and ace ylene dica boxyla e de i a i es 3. Nex , an
acid-p omo ed Mannich eac ion leads o he o ma ion o in e media e 7, which spon a-
neously e ol es h ough in amolecula cycliza ion be ween he amine and he es e
g oups o yield γ-lac am subs a es 4 (Scheme 1).
Scheme 1. Mul icomponen syn hesis o 3-amino 3-py olin-2-ones 4.
Following his app oach, 13 densely unc ionalized subs a es we e syn hesized in
o de o illus a e he syn he ic po en ial o he eac ion. Fi s , he eac ion was applied o
he use o di e en amines 1 using benzaldehyde (2a, R2 = Ph) and die hyl ace ylenedica -
boxyla e (3a, R3 = E ). The eac ion wi h weakly ac i a ed p- oluidine (1a, R1 = p-CH3C6H4)
as an amine subs a e p o ided a e y good yield o γ-lac am de i a i e 4a a e 48 h.
(Figu e 2, 4a). Howe e , he use o an elec on- ich aniline o alipha ic amines, such as p-
anisidine (1b, R1 = p-CH3OC6H4) o benzylamine (1c, R1 = Bn), led o a sligh dec ease in
yield (Figu e 2, 4b,c). Rema kably, when elec on-de icien amines we e used as sub-
s a es, he o ma ion o imine and enamine in e media es was ini ially obse ed bu , in
his case, he eac ion ailed o p o ide he γ-lac am subs a es. I should be no ed ha , in
Scheme 1. Mul icomponen syn hesis o 3-amino 3-py olin-2-ones 4.
Following his app oach, 13 densely unc ionalized subs a es we e syn hesized in
o de o illus a e he syn he ic po en ial o he eac ion. Fi s , he eac ion was applied o
he use o di e en amines
1
using benzaldehyde (
2a
, R
2
= Ph) and die hyl ace ylenedica -
boxyla e (
3a
, R
3
= E ). The eac ion wi h weakly ac i a ed p- oluidine (
1a
, R
1
=p-CH
3
C
6
H
4
)
as an amine subs a e p o ided a e y good yield o
γ
-lac am de i a i e
4a
a e 48 h.
(Figu e 2,4a)
. Howe e , he use o an elec on- ich aniline o alipha ic amines, such as
p-anisidine (
1b
, R
1
=p-CH
3
OC
6
H
4
) o benzylamine (
1c
, R
1
= Bn), led o a sligh dec ease in
yield (Figu e 2,
4b
,
c
). Rema kably, when elec on-de icien amines we e used as subs a es,
he o ma ion o imine and enamine in e media es was ini ially obse ed bu , in his case,
he eac ion ailed o p o ide he
γ
-lac am subs a es. I should be no ed ha , in iew
o he mechanism p oposed o he ans o ma ion (Scheme 1), he elec onic cha ac e
o he amine subs a e migh be a c ucial ac o in he eac i i y o he key s ep o he
mul icomponen p ocess. Acco dingly, while he use o elec on- ich amines may bene i
he nucleophilic cha ac e o enamine species
6
, his would esul in a dec ease in he
elec ophilic cha ac e o imine species
5
. On he o he hand, he use o deac i a ed amines
Pha maceu icals 2022,15, 511 4 o 19
would esul in he ac i a ion o imine elec ophile
5
and he colla e al deac i a ion o
enamine nucleophile
6
. In addi ion, he sligh ly lowe yield ob ained using p-anisidine
compa ed o p- oluidine can be also a ibu ed o he o ma ion o side p oduc s
8a
,
b
,
gene a ed by a subsequen nucleophilic addi ion o an addi ional molecule o amine o he
ca boxyla e g oup o lac am
4b
. Amides
8a
,
b
we e isola ed in 3% and 13% yield om he
c ude eac ion (Figu e 2).
Pha maceu icals 2022, 15, x FOR PEER REVIEW 4 o 20
iew o he mechanism p oposed o he ans o ma ion (Scheme 1), he elec onic cha -
ac e o he amine subs a e migh be a c ucial ac o in he eac i i y o he key s ep o he
mul icomponen p ocess. Acco dingly, while he use o elec on- ich amines may bene i
he nucleophilic cha ac e o enamine species 6, his would esul in a dec ease in he elec-
ophilic cha ac e o imine species 5. On he o he hand, he use o deac i a ed amines
would esul in he ac i a ion o imine elec ophile 5 and he colla e al deac i a ion o
enamine nucleophile 6. In addi ion, he sligh ly lowe yield ob ained using p-anisidine
compa ed o p- oluidine can be also a ibu ed o he o ma ion o side p oduc s 8a,b, gen-
e a ed by a subsequen nucleophilic addi ion o an addi ional molecule o amine o he
ca boxyla e g oup o lac am 4b. Amides 8a,b we e isola ed in 3% and 13% yield om he
c ude eac ion (Figu e 2).
Figu e 2. 3-Amino 3-py olin-2-ones 4, 8 and 9 ob ained.
The use o o he ace ylenedica boxyla es 3b,c (R3 = iP o Me) as elec ophile sub-
s a es in he mul icomponen eac ion wi h p- oluidine (1a, R1 = p-CH3C6H4) and benzal-
dehyde 2a (R2 = Ph) led o he o ma ion o γ-lac ams 4d,e in mode a e o good yields
(Figu e 2). The bulkie di-iso-p opyl ace ylenedica boxyla e 3b (R3 = iP ) equi ed a longe
eac ion ime (72 h), which may ha e also acili a ed he o ma ion o he amide side p od-
uc 8a as a esul o he g ea e coexis ence o p- oluidine (1a, R1 = p-CH3C6H4) and γ-lac am
4d. In he case o dime hyl ace ylenedica boxyla e 3c (R3 = Me), amide 8a o med in equal
p opo ion as wi h he use o die hyl ace ylenedica boxyla e 3a, e en hough he eac ion
p oceeded o ull con e sion wi h a sho e eac ion ime (24 h).
Nex , he scope o he eac ion was ex ended o he use o di e en aldehydes by
u ilizing dime hyl ace ylenedica boxyla e 3c (R3 = Me) as he elec ophile and p- oluidine
(1a, R1 = p-CH3C6H4) and benzylamine (1c, R1 = Bn) as amine subs a es. The use o elec-
on-de icien p- i luo ome hyl benzaldehyde (2b, R2 = p-CF3C6H4) in he mul icomponen
eac ion p o ided a mo e elec ophilic imine species 5, a o ing he eac i i y o he Man-
nich in e media e p ocess. Indeed, when p- oluidine (1a, R1 = p-CH3C6H4) was used as he
eac ion pa ne , a e y good yield o lac am 4 was ob ained wi h no p esence o he
amide side p oduc , as expec ed due o he less nucleophilic cha ac e o he amine
Figu e 2. 3-Amino 3-py olin-2-ones 4,8and 9ob ained.
The use o o he ace ylenedica boxyla es
3b
,
c
(R
3
=
i
P o Me) as elec ophile subs a es
in he mul icomponen eac ion wi h p- oluidine (
1a
, R
1
=p-CH
3
C
6
H
4
) and benzaldehyde
2a
(R
2
= Ph) led o he o ma ion o
γ
-lac ams
4d
,
e
in mode a e o good yields (Figu e 2).
The bulkie di-iso-p opyl ace ylenedica boxyla e
3b
(R
3
=
i
P ) equi ed a longe eac ion
ime (72 h), which may ha e also acili a ed he o ma ion o he amide side p oduc
8a
as a esul o he g ea e coexis ence o p- oluidine (
1a
, R
1
=p-CH
3
C
6
H
4
) and
γ
-lac am
4d
.
In he case o dime hyl ace ylenedica boxyla e
3c
(R
3
= Me), amide
8a
o med in equal
p opo ion as wi h he use o die hyl ace ylenedica boxyla e
3a,
e en hough he eac ion
p oceeded o ull con e sion wi h a sho e eac ion ime (24 h).
Nex , he scope o he eac ion was ex ended o he use o di e en aldehydes by
u ilizing dime hyl ace ylenedica boxyla e 3c (R3= Me) as he elec ophile and p- oluidine
(
1a
, R
1
=p-CH
3
C
6
H
4
) and benzylamine (
1c
, R
1
= Bn) as amine subs a es. The use o
elec on-de icien p- i luo ome hyl benzaldehyde (
2b
, R
2
=p-CF
3
C
6
H
4
) in he mul icom-
ponen eac ion p o ided a mo e elec ophilic imine species
5
, a o ing he eac i i y o
he Mannich in e media e p ocess. Indeed, when p- oluidine (
1a
, R
1
=p-CH
3
C
6
H
4
) was
used as he eac ion pa ne , a e y good yield o lac am
4
was ob ained wi h no p esence
o he amide side p oduc , as expec ed due o he less nucleophilic cha ac e o he amine
(Scheme 1). Howe e , al hough he eac ion wi h benzylamine (
1c
, R
1
= Bn) led o he
o ma ion o a mo e nucleophilic enamine in e media e
6
o he Mannich eac ion, o
his pa icula case, a low yield o
γ
-lac am
4g
was ob ained, possibly due o he lowe
elec ophilic cha ac e ound o N-benzylimine in e media e 5(Scheme 1).
Pha maceu icals 2022,15, 511 5 o 19
On he con a y, i was expec ed ha he in e media e Mannich eac ion would be
dis a o ed by he use o an aldehyde holding a s ong elec on-dona ing subs i uen , which
would gene a e, in his case, a less elec ophilic imine species
5
. Acco dingly, he use o
p-hyd oxybenzaldehyde (
2c
, R
2
=p-HOC
6
H
4
) and p- oluidine (
1a
, R
1
=p-CH
3
C
6
H
4
) in he
mul icomponen eac ion led o he o ma ion o a modes yield o
γ
-lac am
4h
, possibly
due o he poo e elec ophilic cha ac e expec ed o N-a ylimine in e media e
5
(Scheme 1).
Ne e heless, he same eac ion using benzylamine (
1c
, R
1
= Bn) p oduced a good yield o
γ
-lac am de i a i e
4i
, whe e an inc ease in he nucleophilic cha ac e o he enamine in e -
media e seems o d i e he Mannich eac ion and o e come he dec eased elec ophilici y
expec ed o he N-benzylimine species
5
(Scheme 1). In acco dance wi h he obse ed eac-
i i y o he mul icomponen eac ion, m-anisaldehyde (
2d
,
R2=m-MeOC6H4)
p o ided
simila esul s as benzaldehyde (
2a
, R
2
= Ph), wi h a e y good yield o p- oluidine-de i ed
γ
-lac am
4j
and a sligh ly lowe yield o benzylamine-de i ed
γ
-lac am
4k
(Figu e 2). Fi-
nally, he scope o he eac ion was comple ed using a disubs i u ed benzaldehyde. In
his case, by ollowing he same mul icomponen p o ocol wi h dime hyl ace ylenedica -
boxyla e
3c
(R
3
= Me) and anillin (
2e
, R
2
= 3-MeO-4-HO-C
6
H
3
),
γ
-lac ams
4l
–
m
we e
ob ained wi h mode a e o good yields (Figu e 2). In addi ion, he benzyl g oup a he
enamine moie y in
4c
was selec i ely emo ed by hyd ogenolysis h ough ea men wi h
E OH unde an H
2
a mosphe e a 80 psi in he p esence o 10% mol o palladium on
ca bon, leading o he p oduc ion o lac am de i a i e
9
wi h a quan i a i e yield (Figu e 2).
Rema kably, unde hose condi ions, only one o he benzyl g oups was emo ed, and he
ca bon–ca bon double bond emained in ac .
Due o hei chemical simili ude o na u al phospha e me aboli es, phosphona e
de i a i es show mul iple biological ac i i ies, and o his eason, hey ha e nume ous
applica ions in medicine and ag ochemis y [
51
–
56
]. Thus, in o de o u he b oaden
he scope o he B øns ed acid-ca alyzed mul icomponen eac ion, we ied o ex end
he syn he ic p o ocol o he use o ac i a ed-ace ylene-bea ing phospho a ed g oups
(subs i u ion o a ca boxyla e by a phosphona e g oup). Howe e , he eac ion using
me hyl 3-(die hoxyphosphinyl)-2-p opynoa e (MeO
2
C-C
≡
C-P(O)(OE )
2
) ins ead o dialkyl
ace ylenedica boxyla es ga e complex mix u es. Ne e heless, he use o phospho us-
subs i u ed py u a es as su oga es o ace ylenedica boxyla es p o ed o be an excellen
choice. To ou deligh , he B øns ed-acid-ca alyzed mul icomponen eac ion o amines
1
, aldehydes
2
and phospho a ed py u a es
10
in e luxing MTBE led o he o ma ion o
an excellen yield o phospho us-subs i u ed
γ
-lac am de i a i es
12
a e 48 h. (Figu e 3).
Simila o he mul icomponen eac ion using ace ylene ca boxyla es (Scheme 1, ide
sup a), he enamine in e media e
6
was gene a ed in his case h ough an amine-ca bonyl
condensa ion eac ion be ween py u a e de i a i e
10
and amine
1
using MgSO
4
o emo e
he wa e eleased. Nex , 3-amino 3-py olin-2-ones
11
we e o med in an iden ical Mannich
eac ion. Due o he high s e ic hind ance expec ed in he highly unc ionalized he e ocycle,
enamine de i a i es
11
a e no isolable, and 3-hyd oxy 3-py olin-2-ones
12
we e ob ained
in his case a e spon aneous hyd olysis o he enamine moie y (Figu e 3).
Fi s , he eac ion was applied o di e en amine subs a es
1
using benzaldehyde
2a
(R
2
= Ph) and die hylphospho yl subs i u ed py u a e
10a
(R
3
= OE ), p o iding good
o excellen yields o
γ
-lac am de i a i es
12a
–
c
(Figu e 3). The scope o he eac ion was
ex ended o he use o di e en aldehydes using die hylphospho yl-subs i u ed py u a e
10a
(R
1
= OE ) and p- oluidine (
1a
, R
1
=p-CH
3
C
6
H
4
) as he eac ion pa ne s and p o iding
good o excellen yields o
γ
-lac am de i a i es
12d
–
h
(Figu e 3). In addi ion, he mul i-
componen eac ion was applied o di e se phospho us-subs i u ed py u a es o p oduce
se e al di e en phosphona e and phosphine oxide-subs i u ed lac ams 12i–p(Figu e 3).
Pha maceu icals 2022,15, 511 6 o 19
Pha maceu icals 2022, 15, x FOR PEER REVIEW 6 o 20
Figu e 3. 3-Hyd oxy 3-py olin-2-ones 12 ob ained.
Nex , in o de o ex end he s uc u al di e si y ob ained in his s udy, some addi ional
3-hyd oxy 3-py olin-2-ones 13 we e p epa ed om alkyloxyca bonyl-subs i u ed 3-amino
3-py olin-2-ones 4 p e iously ob ained om he mul icomponen eac ion using ace y-
lenedica boxyla es. Upon ea men o γ-lac ams 4 unde acidic condi ions, selec i e hyd ol-
ysis o he enamine moie y was obse ed, leading o he o ma ion o enol-con aining lac am
subs a es 13a–g. The eac ion was applied success ully o e hyl es e -subs i u ed γ-lac am
subs a es 13a–c de i ed om p- oluidine (1a, R1 = p-CH3C6H4), p-anisidine (1b, R1 = p-
CH3OC6H4) o benzylamine (1c, R1 = Bn) and could be also ex ended o me hyl es e s de i ed
om a a ie y o aldehydes o he p epa a ion o γ-lac ams 13d–g (Figu e 4).
Figu e 4. 3-Hyd oxy 3-py olin-2-ones 13 ob ained.
Figu e 3. 3-Hyd oxy 3-py olin-2-ones 12 ob ained.
Nex , in o de o ex end he s uc u al di e si y ob ained in his s udy, some addi-
ional 3-hyd oxy 3-py olin-2-ones
13
we e p epa ed om alkyloxyca bonyl-subs i u ed
3-amino 3-py olin-2-ones
4
p e iously ob ained om he mul icomponen eac ion using
ace ylenedica boxyla es. Upon ea men o
γ
-lac ams
4
unde acidic condi ions, selec i e
hyd olysis o he enamine moie y was obse ed, leading o he o ma ion o enol-con aining
lac am subs a es
13a–g
. The eac ion was applied success ully o e hyl es e -subs i u ed
γ
-lac am subs a es
13a
–
c
de i ed om p- oluidine (
1a
, R
1
=p-CH
3
C
6
H
4
), p-anisidine (
1b
,
R
1
=p-CH
3
OC
6
H
4
) o benzylamine (
1c
, R
1
= Bn) and could be also ex ended o me hyl
es e s de i ed om a a ie y o aldehydes o he p epa a ion o
γ
-lac ams
13d
–
g
(Figu e 4).
Pha maceu icals 2022, 15, x FOR PEER REVIEW 6 o 20
Figu e 3. 3-Hyd oxy 3-py olin-2-ones 12 ob ained.
Nex , in o de o ex end he s uc u al di e si y ob ained in his s udy, some addi ional
3-hyd oxy 3-py olin-2-ones 13 we e p epa ed om alkyloxyca bonyl-subs i u ed 3-amino
3-py olin-2-ones 4 p e iously ob ained om he mul icomponen eac ion using ace y-
lenedica boxyla es. Upon ea men o γ-lac ams 4 unde acidic condi ions, selec i e hyd ol-
ysis o he enamine moie y was obse ed, leading o he o ma ion o enol-con aining lac am
subs a es 13a–g. The eac ion was applied success ully o e hyl es e -subs i u ed γ-lac am
subs a es 13a–c de i ed om p- oluidine (1a, R1 = p-CH3C6H4), p-anisidine (1b, R1 = p-
CH3OC6H4) o benzylamine (1c, R1 = Bn) and could be also ex ended o me hyl es e s de i ed
om a a ie y o aldehydes o he p epa a ion o γ-lac ams 13d–g (Figu e 4).
Figu e 4. 3-Hyd oxy 3-py olin-2-ones 13 ob ained.
Figu e 4. 3-Hyd oxy 3-py olin-2-ones 13 ob ained.
Pha maceu icals 2022,15, 511 7 o 19
Wi h his collec ion o highly unc ionalized
γ
-lac am de i a i es in ou hands, we
s udied hei biological ac i i y. The an ip oli e a i e ac i i y o he subs a es agains
se e al cance cell lines was in es iga ed.
2.2. Biological Resul s
The
in i o
cy o oxici y o he
γ
-lac am de i a i es was e alua ed by es ing hei
an ip oli e a i e ac i i y agains se e al human cance cell lines. The cell coun ing ki
(CCK-8) assay was used o he e alua ion o g ow h inhibi ion. Mo eo e , nonmalignan
MRC5 lung ib oblas s we e es ed o s udy he selec i e oxici y [
57
], and chemo he apeu ic
doxo ubicin was used as a e e ence.
In he i s s udy, we es ed he cy o oxici y o 3-amino 3-py olin-2-ones
4
,
8
and
9
ob ained om SKOV3 (human o a ian ca cinoma) and A549 (ca cinomic human al eola
basal epi helial cell) cell lines. The cell p oli e a ion inhibi o y ac i i y o he
γ
-lac ams is
shown as IC50 alues (Table 1).
Table 1. An ip oli e a i e ac i i y o 3-amino γ-lac am de i a i es 4,8and 9.
En y Cmpd. IC50 (µM)
A549 (Lung) SKOV3 (O a ian) MRC5
14a 11.70 ±1.02 >50 >50
24b 14.26 ±1.80 >50 >50
34c 2.42 ±0.15 >50 >50
44d 3.34 ±0.29 48.45 ±2.90 >50
54e 1.67 ±0.49 >50 >50
64 42.58 ±2.55 30.27 ±1.03 >50
74g 7.64 ±0.17 >50 >50
84h 1.98 ±0.18 10.37 ±1.41 10.01 ±1.79
94i 10.71 ±1.35 21.91 ±1.53 17.37 ±1.68
10 4j 13.03 ±1.48 43.93 ±1.66 30.93 ±6.16
11 4k 11.39 ±1.49 >50 >50
12 4l 0.11 ±0.016 1.23 ±0.31 12.64 ±2.09
13 4m 6.02 ±1.01 >50 >50
14 8a 2.97 ±0.29 6.95 ±0.59 >50
15 8b 32.38 ±1.58 16.62 ±0.19 21.42 ±2.7
16 912.45 ±0.71 >50 >50
17 Doxo ubicin <0.1 0.13 ±0.098 >50
Acco dingly,
γ
-lac am de i a i e
4a
, de i ed om p- oluidine (
1a
), benzaldehyde (
2a
)
and die hyl ace ylenedica boxyla e (
3a
) showed a modes IC
50
alue o
11.70 ±1.02 µM
agains he A549 cell line (Table 1, En y 1). Analogous
γ
-lac ams
4b
,
c
, de i ed om
p-anisidine o benzylamine p esen ed IC
50
alues o 14.26
±
1.80 and 2.42
±
0.15
µ
M
(Table 1, En ies 2–3). Rema kably, subs a es
4a
–
c
did no show signi ican cy o oxici y
agains SKOV3, while hey displayed e y good selec i i y agains nonmalignan cells
wi h IC
50
alues highe han 50
µ
M (Table 1, En ies 1–3). Swi ching he e hyl es e wi h
an iso-p opyles e g oup a he 5-membe ed ing esul ed in an imp o ed le el o oxici y
owa ds he A549 and SKOV3 cell lines wi h IC
50
alues o 3.34
±
0.29 and
48.45 ±2.90 µM
,
espec i ely, in subs a e
4d
while main aining good selec i i y wi h espec o he MRC5
cell line (Table 1, En y 4). Rema kably, he p esence o a me hyl es e subs i uen in
4e
p o ided a no able imp o emen in he inhibi ion o cell g ow h in he A549 cell line wi h a
e y good IC
50
alue o 1.67
±
0.49
µ
M and e y good selec i i y agains he SKOV3 and
MRC5 cell lines (Table 1, En y 5).
Wi h he iew ha he bes oxici y le el was ob ained o me hyl es e de i a i e
4e
,
we nex ex ended he s uc u e–ac i i y ela ionship s udy o an in es iga ion o in luence
o he subs i uen a posi ion 5 o he
γ
-lac am ing using
4e
as he model. Al hough he
e ec o he in oduc ion o luo ine a oms in o he s uc u e o o ganic compounds is a he
di icul o p edic , i e y o en leads o inc eased ac i i y [
58
–
61
]. The key p ope ies
Pha maceu icals 2022,15, 511 8 o 19
ha make luo ine-con aining compounds a ac i e in chemical biology include he small
a omic adius and high elec onega i i y o he luo ine a om and he low pola izabili y o
he C–F bond. In addi ion, he ac ha he only na u al iso ope o
19
F a om has a nuclea
spin o
1
2
makes i ideal o moni o ing s udies by NMR. Fo his eason, we nex es ed
he
in i o
cy o oxici y o i luo ome hyl-con aining
γ
-lac ams
4
,
g
. The in oduc ion
o a pa a- i luo ophenyl subs i uen a he 5-membe ed ing did no esul in imp o ed
ac i i y, and IC
50
alues o 42.58
±
2.55 and 7.64
±
0.17
µ
M we e ob ained in A549 cell
line o compounds
4
,
g
, espec i ely. Howe e , compound
4
did show some oxici y
agains he SKOV3 cell line wi h a mode a e IC
50
alue o 30.27
±
1.03
µ
M. Rema kably,
bo h compounds exhibi ed e y high selec i i y owa ds malignan cells wi h IC
50
alues
highe han 50 µM in he MRC5 cell line. (Table 1, En ies 6–7).
The an ioxidan p ope ies o phenols a e known o be associa ed wi h he an i umo
ac i i ies o a ple ho a o compounds bea ing his moie y [
62
]. Acco dingly, he an ip oli -
e a i e ac i i y o phenol-subs i u ed
γ
-lac ams
4h
,
i
, was es ed. Indeed, an excellen IC
50
alue o 1.98
±
0.18
µ
M was ound o he A549 cell line o p- oluidine-de i ed
γ
-lac am
4h
. Al hough compound
4h
also showed some oxici y agains nonmalignan cells, i s
selec i i y was ound o be 5 imes highe compa ed wi h A549 cells. Likewise, in his
case, he oxici y owa ds o a ian ca cinoma was compa able o ha obse ed in he MRC5
cell line (Table 1, En y 8). In addi ion, benzylamine-de i ed
γ
-lac am
4i
p esen ed IC
50
alues o 10.71
±
1.35 and 21.91
±
1.53
µ
M in he A549 and SKOV3 cell lines, espec i ely,
al hough a simila le el o oxici y was ound o nonmalignan cells (Table 1, En y 9).
The me hoxy g oup is a s ong elec on-dona ing subs i uen in a oma ic ings ha is
known o be a widesp ead mo i in d ugs and na u al p oduc s. The in oduc ion o his
moie y o po en ial an icance agen s e y o en leads o inc eased selec i e ac i i y [
63
,
64
],
which is a ibu ed in pa o i s weak o medium an imi o ic ac i i y. Consequen ly, he
cy o oxici y o m-me hoxyphenyl-subs i u ed
γ
-lac ams
4j
,
k
was nex explo ed. Fo he
pa icula case o p- oluidine-de i ed
γ
-lac am
4j
, some cy o oxici y was obse ed agains
he A549 and SKOV3 cell lines wi h IC
50
alues o 13.03
±
1.48 and 43.93
±
1.66
µ
M,
espec i ely, al hough no much selec i i y was ob ained compa ed wi h nonmalignan
cells (Table 1, En y 10). Mo eo e , swi ching p- oluidine wi h a benzylamine g oup in
4k
did no ha e a posi i e e ec on he cy o oxici y agains he A549 cell line wi h an
IC
50
alue o 11.39
±
1.49
µ
M. Howe e , compound
4k
was ound o be e y selec i e
in A549 cells compa ed wi h he SKOV3 o MRC5 cell lines (Table 1, En y 11). To ou
su p ise, he combina ion o phenol and me hoxy moie ies in
γ
-lac ams
4l
,
m
p o ided
excellen IC
50
alues o 0.11
±
0.016 and 6.02
±
1.01
µ
M in he A549 cell line o p- oluidine-
and benzylamine-de i ed subs a es, espec i ely, wi h a high le el o selec i i y owa ds
nonmalignan cells. No iceably, p- oluidine de i a i e
4l
deli e ed a e y good IC
50
alue
o 1.23 ±0.31 µM agains SKOV3 cells (Table 1, En ies 12–13).
In addi ion, he e ec o he eplacemen o he me hyl es e wi h an amide g oup had
dispa a e e ec s on he an ip oli e a i e ac i i y o
γ
-lac am subs a es. While a e y good
IC50 alue o 2.97 ±0.29 µM was ob ained o he A549 cell line o p- oluidine de i a i e
8a
, a modes IC
50
alue o 32.38
±
1.58
µ
M was obse ed o p-anisidine de i ed subs a e
8b
. Fu he , compounds
8a
,
b
also showed oxici y in he SKOV3 cell line wi h IC
50
alues
o 6.95
±
0.59 and 16.62
±
0.19
µ
M, espec i ely. In addi ion, compound
8a
was ound
o be e y selec i e owa ds malignan cells, al hough subs a e
8b
p esen ed signi ican
oxici y in he MRC5 cell line (Table 1, En ies 14–15). Likewise, N-debenzyla ed subs a e
9ga e sligh ly wo se alues compa ed wi h i s p ecu so , γ-lac am 4c (Table 1, En y 3 s.
En y 16).
In o de o u he ex end ou s uc u e–ac i i y s udy, we nex es ed he an ip o-
li e a i e ac i i y o he 3-hyd oxy
γ
-lac am de i a i es
13
ob ained om he hyd olysis
o hei pa en enamine de i a i es (see Figu e 4). The eplacemen o enamine wi h an
enol moie y in e hyl es e subs i u ed s uc u es
4a
–
c
esul ed in simila o sligh e lowe
cy o oxic ac i i y agains he A549 cell line in compounds
13a
–
c
(Table 2, En ies 1–3 s.
Table 1, En ies 1–3), showing IC
50
alues o 15.73
±
1.27, 13.05
±
0.56 and
4.50 ±0.18 µM
,
Pha maceu icals 2022,15, 511 9 o 19
espec i ely. Mo eo e , compounds
13a
–
c
did no p esen signi ican oxici y in he SKOV3
o MRC5 cell lines. Simila ly, me hyl-es e -subs i u ed 3-hyd oxy
γ
-lac am
13d
holding
ap- i luo ome hyl subs i uen a he chi al ca bon o he lac am ing p esen ed lowe
oxici y agains he A549 cell line compa ed wi h he pa en enamine subs a e
4g
, wi h
an IC
50
alue o 19.13
±
3.00
µ
M and no oxici y owa ds he SKOV3 and MRC5 cell lines
(Table 2, En y 4 s. Table 1, En y 7). The same lowe ing o an ip oli e a i e ac i i y
was obse ed in m-anisyl de i a i es
13e
,
and anillin de i a i e
13g
ela i e o hei
enamine p ecu so s
4j
–
l
, wi h IC
50
alues o 17.64
±
3.76, 15.96
±
1.97 and 13.30
±
2.19
µ
M,
espec i ely (Table 2, En ies 5–7 s. Table 1, En ies 10–12). Compounds
13d
,
e
showed no
oxici y in he SKOV3 and MRC5 cell lines.
Table 2. An ip oli e a i e ac i i y o 3-hyd oxy γ-lac am de i a i es 13.
En y Cmpd. IC50 (µM)
A549 (Lung) SKOV3 (O a ian) MRC5
113a 15.73 ±1.27 >50 >50
213b 13.05 ±0.56 >50 >50
313c 4.50 ±0.18 >50 >50
413d 19.13 ±3.00 >50 >50
513e 17.64 ±3.76 >50 >50
613 15.96 ±1.97 >50 >50
713g 13.30 ±2.19 10.36 ±0.35 >50
17 Doxo ubicin <0.1 0.13 ±0.098 >50
Bioisos e ism ep esen s an app oach ha is widely used o he a ional modi ica ion
o lead compounds in o sa e and mo e clinically e ec i e agen s [
65
]. Acco dingly, i
is well known ha he subs i u ion o a ca boxyla e wi h a phosphona e g oup in ac i e
subs a es may esul in new o inc eased ac i i y [
51
–
56
]. Fo his eason, we nex s udied
he an ip oli e a i e ac i i y o phospho us-subs i u ed
γ
-lac am de i a i es
12
agains
he A549 and SKOV3 cell lines (Table 3). Indeed, he eplacemen o he e hyl ca boxyla e
g oup wi h a die hyl phosphona e subs i uen in p- oluidine- and p-anisidine-de i ed
lac ams
13a
,
b
, esul ed in an inc ease in he cy o oxic ac i i y owa ds he A549 cell line in
12a
,
b
wi h IC
50
alues o 3.11
±
0.31 and 4.56
±
0,44
µ
M, espec i ely, and a high le el o
selec i i y compa ed wi h he SKOV3 and MCR5 cell lines (Table 3, En ies 1–2 s. Table 2,
En ies 1–2). Howe e , phospho a ed
γ
-lac am
12c
de i ed om o- luo oaniline p esen ed
dec eased ac i i y in he A549 cell line wi h an IC50 alue o 16.03 ±1.49 µM.
Wi h hese esul s in hand, we nex s udied he e ec o he subs i u ion a he chi al
ca bon o he i e membe ed ing 3-hyd oxy 3-py olin-2-ones
12d
–
h
using he mos
ac i e subs a e
12a
, de i ed om p- oluidine and die hyl phosphona e, as a model. The
in oduc ion o a s ong elec on-wi hd awing p-ni ophenyl g oup a he s e eogenic
ca bon o he
γ
-lac am ing had a e y nega i e e ec on he cy o oxici y, and IC
50
alues
highe han 50
µ
M we e ound o compound
12d
in bo h he A549 and SKOV3 cell lines
(Table 3, En y 4).
In spi e o he bene i s expec ed om he in oduc ion o a luo ine a om in o he
he e ocyclic s uc u e [
58
–
61
], p- luo ophenyl-subs i u ed lac am
12e
p o ided a sligh ly
wo se IC
50
alue o 6.6
±
0.58
µ
M in he A549 cell line ela i e o he pa en compound
12a
(Table 3, En y 5 s. En y 1). The in oduc ion o o he he e oa oma ic, es e o alipha ic
subs i uen s also had a nega i e e ec on he oxici y o subs a es
12
. Acco dingly, a
d op in an ip oli e a i e ac i i y owa ds he A549 cell line was obse ed o 2- hienyl,
e hoxyca bonyl and iso-p opyl subs i u ed
γ
-lac ams
12
–
h
wi h IC
50
alues o 23.29
±
2.4,
8.27
±
0.91 and 24.20
±
0.81
µ
M, espec i ely. Howe e , compounds
12
–
h
p esen ed high
selec i i y compa ed wi h he SKOV3 cell line and nonmalignan cells (Table 3, En ies 6–8).
Pha maceu icals 2022,15, 511 16 o 19
inhibi ing he g ow h o human umo cells RKO (human colon epi helial ca cinoma),
SKOV3 (human o a ian ca cinoma) and A549 (ca cinomic human al eola basal epi helial
cell), and p oducing low ac i i y owa d MRC5 nonmalignan lung ib oblas s. QSAR
s udies indica e ha he cy o oxici y is enhanced, in gene al, by he p esence o a oma ic
g oups bea ing lipophilic me hyl subs i uen s o luo ine a oms. Mo eo e , he p esence o
an es e g oup a C-4 o he 5-membe ed he e ocycle p o ided lowe IC
50
alues han hose
p e iously epo ed o unsubs i u ed
γ
-lac am de i a i es. Be e an ip oli e a i e ac i i y
was ob ained o small me hyl es e s compa ed wi h e hyl o iso-p opyl es e s, which
sugges s a c ucial in e ac ion o he es e g oup, which can be complica ed i a bulky g oup
is p esen . In addi ion, while inc eased cy o oxici y was obse ed o 3-amino subs i u ed
γ
-
lac ams compa ed wi h he 3-hyd oxy subs i u ed de i a i es, he an ip oli e a i e ac i i y
o such enol de i a i es was enhanced when he la es e g oup was isos e ically eplaced
by a e ahed al phosphona e o phosphine oxide moie y. Me hyl es e -subs i u ed
γ
-
lac am
4e
, de i ed om p- oluidine, p esen ed an excellen IC
50
alue o 1.67
µ
M agains
he A549 cell line wi h excellen selec i i y owa ds he SKOV3 and RKO cell lines and
nonmalignan cells. I s amide de i a i e
8a
showed good oxici y agains lung, o a ian
and colon cance cells wi h IC
50
alues o 2.97, 6.95 and 18.67
µ
M, espec i ely, as well as
e y high selec i i y owa ds malignan cell lines compa ed wi h noncance ous MRC5. The
combina ion o phenol and me hoxy moie ies p o ided excellen IC
50
alues o 0.11 and
1.23
µ
M in he A549 and SKOV3 cell lines o p- oluidine-de i ed 3-amino
γ
-lac am
4l
wi h a 10 o 100 imes highe selec i i y le el owa ds nonmalignan cells. The bes le el
o cy o oxici y o 3-hyd oxy
γ
-lac ams was ound o compound
4l
wi h an IC
50
alue o
4.00
µ
m in he A549 cell line. Likewise, he bioisos e ism app oach was shown o be an
excellen ool in his s udy, leading o inc eased cy o oxici y o phospho us-subs i u ed
γ
-lac ams wi h espec o he pa en ca boxyla e-subs i u ed de i a i es wi h IC
50
alues
o 1.46 and 21.97
µ
M in he A549 and SKOV3 cell lines in phosphine oxide subs i u ed
γ
-lac am
12o
. These esul s may suppo he ele ance o he isos e ical subs i u ion o
ca boxylic g oups wi h e ahed al phospho us de i a i es in iew o hei abili y o block
enzymes in ol ed in he hyd olysis o pep ides. In gene al e ms, he
γ
-lac am de i a i es
desc ibed in his s udy we e shown o be highly ac i e owa ds he A549 cell line, while
he SKOV3 and RKO cell lines we e ound o be mo e esis an . Impo an ly, mos o he
subs a es showed high selec i i y in cance cells compa ed wi h nonmalignan cells. In
addi ion, he cell mo phology analysis and low cy ome y assays indica e ha he main
pa hway by which
γ
-lac am de i a i es induce cy o oxici y owa ds cance cells is based
on he ac i a ion o in acellula apop o ic mechanisms.
Supplemen a y Ma e ials:
The ollowing suppo ing in o ma ion can be downloaded a h ps:
//www.mdpi.com/a icle/10.3390/ph15050511/s1: expe imen al p ocedu es and cha ac e iza ion
da a o compounds
4
,
8
,
9
,
12
and
13
;
1
H NMR,
13
C NMR,
31
P NMR and
19
F NMR spec a o
compounds
4
,
8
,
9
,
12
and
13
; HPLC ch oma og ams o compounds
4
,
8
,
9
,
12
and
13
; Flow cy ome ic
assays on A-549 cells a e addi ion o compounds
4l
and
12a
;
e
; Table S1 an ip oli e a i e ac i i y in
RKO cell line and Table S2 calcula ion o Lipinski’s ule o i e and p edic ion o ADME p ope ies.
Au ho Con ibu ions:
Concep ualiza ion, A.L.-F., X.d.C., E.M.d.M., J.M.d.l.S., C.A., F.P. and J.V.;
me hodology, A.L.-F., X.d.C., I.V.-B. and M.S.-R.; so wa e, A.L.-F., X.d.C., I.V.-B. and M.S.-R.; alida-
ion, E.M.d.M. and J.V.; o mal analysis, A.L.-F. and X.d.C.; in es iga ion, A.L.-F., X.d.C., I.V.-B. and
M.S.-R.; esou ces, E.M.d.M., J.L.P., J.M.d.l.S., C.A., F.P. and J.V.; da a cu a ion, A.L.-F. and X.d.C.;
w i ing—o iginal d a p epa a ion, J.V.; w i ing— e iew and edi ing, A.L.-F., X.d.C., I.V.-B., M.S.-R.,
J.M.d.l.S., C.A., E.M.d.M., F.P. and J.V.; isualiza ion, E.M.d.M., J.L.P., F.P. and J.V.; supe ision,
E.M.d.M. and J.V.; p ojec adminis a ion, E.M.d.M. and J.V.; unding acquisi ion, E.M.d.M., J.M.d.l.S.,
C.A., J.L.P., F.P. and J.V. All au ho s ha e ead and ag eed o he published e sion o he manusc ip .
Funding:
Financial suppo by Minis e io de Economía, Indus ia y Compe i idad (MINECO)
(RTI2018-101818-B-I00) and Gobie no Vasco (GV, IT 992-16) is g a e ully acknowledged. X.d.C. and
A.L.-F. hank he Basque Coun y Go e nmen o a p edoc o al g an . I.V.-B. hanks he Uni e si y
o he Basque Coun y (UPV/EHU) o a pos doc o al ellowship (ESPDOC19/47). M.S.-R. hanks
he Uni e si y o he Basque Coun y (UPV/EHU) o a p e-doc o al ellowship (PIF17/79).
Pha maceu icals 2022,15, 511 17 o 19
Ins i u ional Re iew Boa d S a emen : No applicable.
In o med Consen S a emen : No applicable.
Da a A ailabili y S a emen : Da a is con ained wi hin he a icle and Supplemen a y Files.
Acknowledgmen s:
The au ho s a e hank ul o he echnical and human suppo p o ided by
SGIke (UPV/EHU/ERDF, EU).
Con lic s o In e es : The au ho s decla e no con lic o in e es .
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