Synthesis of lipophilic sila derivatives of N-acetylcysteineamide, a cell permeating thiol

Article abstract of DOI:10.1002/aoc.1572

N-acetyl-L-cysteine (L-NAC) is a potent antioxidant that can reduce levels of reactive oxygen species. N-acetyl-cysteine-amide, the amide form of L-NAC, has recently been reported to be more lipophilic and permeable through cell membranes than NAC, and to be able to traverse the blood-brain barrier. In this communication we report the synthesis and characterization of highly lipophilic sila-amide derivatives of L-NAC thatmay showenhanced cell penetration and bioavailability. Copyright

Full text of DOI:10.1002/aoc.1572

Full Paper
Received: 30 July 2009
Revised: 1 September 2009
Accepted: 16 September 2009
Published online in Wiley Interscience: 6 November 2009
(www.interscience.com) DOI 10.1002/aoc.1572
Synthesis of lipophilic sila derivatives
of N-acetylcysteineamide, a cell permeating
thiol
Uzma I. Zakaia, Galina Bikzhanovaa, Daryl Stavenessa, Stephen Gatelyb
and Robert Westa∗
N-acetyl-L-cysteine (L-NAC) is a potent antioxidant that can reduce levels of reactive oxygen species. N-acetyl-cysteine-amide,
the amide form of L-NAC, has recently been reported to be more lipophilic and permeable through cell membranes than NAC,
and to be able to traverse the blood–brain barrier. In this communication we report the synthesis and characterization of highly
c
lipophilic sila-amide derivatives of L-NAC that may show enhanced cell penetration and bioavailability. Copyright ꢀ 2009 John
Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: antioxidant; N-acetyl-L-cysteine; lipophilic; blood–brain barrier; sila drugs
Introduction
regulating the activation of key transcription factors such as NF-kβ
and HIF-1α.[29]
Sila-amidation of certain pharmacological agents has shown
to increase potency and selectivity.[33,34] Silicon substitution onto
the L-NAC molecule should lead to more lipophilic compounds
of type 6,[34–36] better able to penetrate across the gut wall and
cell membranes.[36] This may result in improved pharmacological
properties,[37,38] including bioavailability, metabolism and/or
pharmacokinetics. Towards this goal, we report the synthesis and
characterization of silicon derivatives 6a–c. These compounds can
be prepared from N-acetyl-L-cysteine (2) as shown in Scheme 3.
Protection of the thiol group was obtained by conversion of 2
into thiazolidine 7 using Montmorilline K 10 clay in an acetone/2,2-
dimethoxypropane solvent mixture.[39,40] Although conversion of
7 into an acyl chloride derivative fails, direct amidation to 8 can
be achieved by first forming a mixed anhydride which can be
reacted with the respective sila amine to give amido derivatives
of type 8a–c. A final deprotection step using HCl in methanolic
solution[41] affords the desired compounds 6a–c.
N-acetyl L-cysteine[1,2] (L-NAC, 2) the acetylated form of the simple
amino acid L-cysteine (1), is a more efficiently bio-absorbed and
used form of L-cysteine,[3] while its stereoisomer, D-NAC (3) usually
does not display activity under similar conditions (Scheme 1).[4]
L-NAC is a powerful antioxidant,[2,5] a premier antitoxin,[6] an
immune support substance,[7,8] and a precursor to glutathione
(4),[9] an antioxidant critical in protecting against oxidative stress.
L-NAC is able to decrease reactive oxygen species (ROS) levels
through two separate mechanisms.[1] It can directly reduce
compounds with its sulfhydryl group,[1,10] and it can also boost
cellular levels of glutathione through conversion into metabolites
that can stimulate glutathione synthesis.[1,11,12]
These antioxidants are intrinsically connected to the regulation
of the cellular physiological redox state,[1,3,13] disruption of which
can lead to oxidative injury via processes such as inflammation,[14]
and mutagenesis.[15] L-NAC can also enhance hypoxia-induced
apoptosis in human cancer cell lines. Hence, it is not surprising
thatL-NACdisplaysanticarcinogenicandantimutagenicproperties
and has been proposed for cancer treatment.[13,16–18]
However, the administration of L-NAC is usually employed
only to target tissues outside of the central nervous system.
N-acetylcysteine amide (NACA, AD4, 5) is a more lipophilic
derivative[19] which is a better radical scavenger[20,21] and is able
to cross the blood–brain barrier (Scheme 2).[22–24] AD4 has been
showntoincreasecellularlevelsofglutathione[23] andtoattenuate
oxidative stress[20,21,23] related to disorders such Alzheimer’s
disease, Parkinson’s disease and multiple sclerosis.[24–27]
ROS also play an important role in the pathogenesis of
airwayinflammationandhyperresponsiveness.[28–30] Studieshave
demonstrated that antioxidants such as L-NAC are able to reduce
airway inflammation and hyperreativity in animal models of
allergic disease.[31,32] AD4 is able to attenuate this response by
Experimental
General Methods
Manipulation of air and moisture sensitive compounds was per-
formed in a nitrogen atmosphere glove box or using standard
∗
Correspondence to: Robert West, Organosilicon Research Center, University of
Wisconsin-Madison, 1101 University Ave, Madison, WI 53706, USA.
E-mail: west@chem.wisc.edu
a
Organosilicon Research Center, University of Wisconsin-Madison, 1101
University Avenue, Madison, WI 53706, USA
b
Silamed Inc., 9977 N. 90th Street, Suite 110, Scottsdale, AZ 85258, USA
c
Appl. Organometal. Chem. 2010, 24, 189–192
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

U. I. Zakai et al.
Scheme 1. L-cysteine (1), N-acetyl L-cysteine (2), N-acetyl D-cysteine (3) and glutathione (4).
removed under reduced pressure and the reaction worked up with
dichloromethane–brine. The dichloromethane solution was then
dried with MgSO4, filtered and evaporated to give the respective
derivatives of type 6.
Synthesis of (R)-2-acetamido-3-mercapto-N-(3-(trimethylsilyl)
propyl)propanamide (6a)
Scheme 2. AD4 (5) and silicon derivatives (6).
The title compound was prepared using 7 (1.03 g, 5 mmol)
to give (R)-4-(trimethylsilyl)propyl)propanamide-3-acetyl-2,2-
dimethylthiazolidine (8a, 1.2 g, 59% yield) as a pale yellow oil
(85% pure) by 1H NMR spectroscopy, which was used for the next
step without further purification.
high-vacuum line techniques. Hexane and CH2Cl2 were distilled
from CaH2. All other solvents and reagents were used as received.
N-acetyl-L-cysteine, ethyl chloroformate and triethylamine were
received from Sigma–Aldrich. 3-Aminopropyltrimethylsilane,
aminomethyltrimethylsilane, chloromethyldimethylphenylsilane
and 3-chloropropyltrimethylsilane were purchased from Gelest.
Aminomethyldimethylphenylsilane was synthesized as previously
reported.[33]
1H NMR spectra were obtained on a Varian Unity 500
spectrometer, 13C {H} NMR spectra were obtained on a Varian
Unity500spectrometeroperatingat125 MHz,29Si{H}NMRspectra
were obtained on a Varian Unity 500 spectrometer operating at
99 MHz. ESI mass spectra were determined on a VG AutoSpec M
mass spectrometer. Chemisar Laboratories Inc. of Ontario, Canada
performed elemental analysis. Melting points were determined on
Mel-Temp Laboratory Device.
From 8a (0.8 g, 2 mmol) 6a (0.5 g, 67% yield) was obtained as
pale yellow oil (85% pure) by 1H NMR spectroscopy. Recrystalliza-
tion from dichloromethane–hexane mixture at −20 ◦C gave pure
product (0.4 g, 57% yield) as a white solid; m.p. = 97–100 ◦C. 1H
NMR (CDCl3, 500 MHz) δ −0.02 (s, 9 H, TMS), 0.49 (m, 2 H, CH2), 1.50
(ddd, J = 14.8, 12.2, 7.3 Hz, 2 H, CH2), 1.62 (dd, J = 9.7 Hz; 8.0 Hz,
1 H, SH), 2.04 (s, 3 H, NAc), 2.75 (ddd, J = 13.7, 9.7, 7.1 Hz, 1 H,
CHH), 2.93 (ddd, J = 13.0, 7.9, 4.9 Hz, 1 H, CHH), 3.23 (m, 1 H, CHH),
3.27 (m, 1 H, CHH), 4.60 (dt, J = 7.5, 7.5, 5.0 Hz, 1 H, CH), 6.84 (dd,
1
J = 16.0, 6.2 Hz, 2 H, 2 NH). 13C { H} NMR (CDCl3, 125 MHz) δ −1.8
(3 C, TMS), 13.8, 23.1, 24.0, 26.7, 42.8, 54.5, 169.7 (CO), 170.3 (CO).
1
29Si { H} NMR (CDCl3, 99 MHz) δ 0.58 (s, TMS). MS (electrospray
ionization, MeOH) m/z (M + Na)+ calcd for C11H24N2O2SSiNa,
299.1225; found, 299.1214. Anal. calcd for C11H24N2O2SSi: C, 47.79;
H, 8.75; N, 10.13. Found: C, 48.00; H, 9.16; N, 9.83.
(R)-4-carboxy-3-acetyl-2,2-dimethylthiazolidine (7)[39,40]
A suspension of N-acetyl-S-cysteine (1.0 g, 6 mmol) and mont-
morillonite K10 (0.2 g, 20 wt%) in 40 ml of anhydrous ace-
tone–2,2-dimethoxypropane (1 : 3) mixture was stirred at room
temperature for 3 h. The reaction mixture was then filtered,
and solvent was evaporated to give (R)-4-carboxy-3-acetyl-2,2-
dimethylthiazolidine (1.12 g, 95% yield) as white solid (90% pure)
which was later purified by recrystallization from acetone–hexane
Synthesis of (R)-2-acetamido-3-mercapto-N-[3-(trimethylsilyl)
methyl]propanamide (6b)
From
7
(3.09 g, 15 mmol) (R)-[4-(trimethylsilyl)methyl]
propanamide-3-acetyl-2,2-dimethylthiazolidine (8b, 3.64 g, 83%
yield) was attained as a pale yellow oil (85% pure) by 1H NMR
spectroscopy, which was used in the next step without further
purification.
1
(1.03 g, 84% yield). H NMR (acetone-d6, 500 MHz) δ 1.48 (s, 3 H,
Me), 1.50 (s, 3 H, Me), 1.95 (s, 3 H, NAc), 2.86 (dd, J = 13.3, 7.1, 1 H,
CHH), 3.00 (dd, J = 13.3, 5.1, 1 H, CHH), 4.67 (ddd, J = 8.0, 7.1, 5.1,
1 H, CH), 12.80 (br. s, 1 H, OH).
Using8b(3.7 g,13 mmol)6b(1.97 g,61%yield)wasaffordedasa
paleyellowoil,85%pureby1HNMRspectroscopy.Recrystallization
from dichloromethane–hexane mixture at −20 ◦C gave pure
product (1.6 g, 51% yield) as a white solid; m.p. = 103–106 ◦C. 1H
NMR (CDCl3, 500 MHz) δ 0.07 (s, 9 H, TMS), 1.61 (td, J = 14.1 Hz,
7.1 Hz, 7.1 Hz, 1 H, SH), 2.03 (s, 3 H, NAc), 2.66–2.94 (m, 4 H, 2CH2),
4.62 (dt, J = 7.6, 7.6, 5.1, 1 H, CH), 6.82 (br. s, 1 H, NH), 6.99
General Synthesis of 6a–c
A solution of 7 (1 equiv) and triethylamine (1 equiv) in
dichloromethane (4 ml for 1 mmol 7) was cooled to −5 ◦C and a
solution of ethyl chloroformate (1 equiv) in dichloromethane (1 ml
for1 mmol7)wasaddeddropwise.After15 minofstirringat−5 ◦C,
therespectivesilaamine(1equiv)wasslowlyaddedtothereaction
mixture. Stirring was continued for 25 min at −5 ◦C and 15 h at
room temperature. The reaction mixture was then diluted with
dichloromethane (6 ml for 1 mmol 7) and washed thoroughly with
portions of 5% hydrochloric acid, sodium bicarbonate and water
(6 ml for 1 mmol 7). The dichloromethane solution was then dried
over magnesium sulfate and evaporated to give intermediates of
type 8.
1
(d, J = 8.0 Hz, 1 H, NH). 13C { H} NMR (CDCl3, 125 MHz) δ −2.7
(3 C, TMS), 23.1, 26.7, 29.9, 54.6, 169.8 (CO), 170.3 (CO). 29Si { H}
1
NMR (CDCl3, 99 MHz) δ 0.19 (s, TMS). MS (electrospray ionization,
MeOH) m/z (M + Na)+ calcd for C9H20N2O2SSiNa, 271.0912; found,
271.0902. Anal. calcd for C9H20N2O2SSi: C, 43.51; H, 8.11; N, 11.28.
Found: C, 43.40; H, 8.37; N, 11.34.
Synthesis of (R)-2-acetamido-3-mercapto-N-[3-(dimethylphenylsilyl)
methyl]propanamide (6c)
A solution of 8 in 2 M HCl methanolic solution (15 ml for 1 mmol
7) was stirred at room temperature for 24 h. The methanol was
Starting with 7 (1.23 g, 6 mmol) gave (R)-[4-(dimethylphenylsilyl)
methyl]propanamide-3-acetyl-2,2-dimethylthiazolidine (8c, 1.2 g,
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 189–192

Synthesis of lipophilic sila derivatives of N-acetylcysteineamide
Scheme 3. Synthesis of sila-amide derivatives of L-NAC.
57% yield) as a pale yellow oil (90% pure) by 1H NMR spectroscopy,
which was used for the next step without further purification.
Subsequently 8c (1.2 g, 3 mmol) was converted to 6c (0.63 g,
67% yield) as a pale yellow oil (90% pure) by 1H NMR
spectroscopy. Recrystallization from dichloromethane–hexane
mixture at −20 ◦C gave pure product (0.56 g, 60% yield) as a
white solid; m.p. = 93–96 ◦C. 1H NMR (CDCl3, 500 MHz) δ 0.37 (s,
6 H, SiMe2), 1.48 (v. t, J = 8.8 Hz, 1 H, SH), 1.95 (s, 3 H, NAc), 2.64
(ddd, J = 13.7, 9.8, 7.4 Hz, 1 H, CHH), 2.82–2.93 (m, 2 H, 2 CHH),
3.07 (dd, J = 15.4, 6.1 Hz, 1 H, CHH), 4.53 (dd, J = 12.2, 7.4 Hz,
1 H, CH), 6.59 (br. s, 1 H, NH), 6.80 (d, J = 7.6 Hz, 1 H, NH), 7.38
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1
(d, J = 6.9 Hz, 3 H, Ph), 7.52 (m, 2 H, Ph). 13C { H} NMR (CDCl3,
125 MHz) δ −4.1 (2 C, SiMe), 23.0, 26.6, 29.0, 54.5, 128.0, 129.6,
1
133.7, 136.1, 169.7 (CO), 170.2 (CO). 29Si { H} NMR (CDCl3, 99 MHz)
δ −5.01 (s, SiMe2). MS (electrospray ionization, MeOH) m/z (M +
Na)+ calcd for C14H22N2O2SSiNa, 333.1069; Found, 333.1082. Anal.
calcd for C14H22N2O2SSi: C, 54.16; H, 7.14; N, 9.02. Found: C, 54.21;
H, 7.56; N, 8.85.
Conclusions
The synthesis of novel lipophilic, silicon-containing derivatives
of AD4 can be performed by protection of N-acetyl-L-cysteine
and subsequent amidation and deprotection. The resulting
compounds are more lipophilic than 5 and hence should be useful
towardsoptimizingpharmacologicalpropertiesofthisantioxidant
derivative.
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Supporting information
Supporting information may be found in the online version of this
article.
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