Novel benzyl rearrangements in electrospray ionization multistage tandem mass spectra of benzyl 2',3'- didehydro-2',3'-dideoxythymidin-5'-yl H-phosphonate.

Article abstract of DOI:10.1002/jms.643

Several alkyl 2',3'-didehydro-2',3'-dideoxythymidin-5'-yl H-phosphonates were synthesized and analyzed by electrospray ionization multistage tandem mass spectrometry (ESI-MS(n)). Two kinds of novel benzyl rearrangement reactions were observed in ESI - MS(

Full text of DOI:10.1002/jms.643

JOURNAL OF MASS SPECTROMETRY
J. Mass Spectrom. 2004; 39: 730–735
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jms.643
Novel benzyl rearrangements in electrospray ionization
multistage tandem mass spectra of benzyl 2ꢀ ,3ꢀ -
didehydro-2ꢀ ,3ꢀ -dideoxythymidin-5ꢀ -yl H-phosphonate
Yi Chen,1,2 Xiaobin Sun,2 Hua Fu,2 Xiaohong Liu2 and Yufen Zhao1,2∗
1
Key Laboratory of Chemical Biology, Chemistry Department, Zhengzhou University, 450052, China
Key Laboratory for Bioorganic Phosphorus Chemistry of the Education Ministry, Department of Chemistry, School of Life Sciences and Engineering,
2
Tsinghua University, Beijing 100084, China
Received 15 October 2003; Accepted 12 March 2004
Several alkyl 2ꢀ ,3ꢀ -didehydro-2ꢀ ,3ꢀ -dideoxythymidin-5ꢀ -yl H-phosphonates were synthesized and analyzed
by electrospray ionization multistage tandem mass spectrometry (ESI − MSn). Two kinds of novel benzyl
rearrangement reactions were observed in ESI − MS2 of [M + H]+, [M + Na]+ and [M + K]+ of benzyl
2ꢀ ,3ꢀ -didehydro-2ꢀ ,3ꢀ -dideoxythymidin-5ꢀ -yl H-phosphonate. Results from tandem mass spectrometry,
high-resolution mass spectrometry and control experiments showed that the benzyl migration could
undergo a four-membered cyclic rearrangement reaction, and benzyl was essential in the process. Copyright
 2004 John Wiley & Sons, Ltd.
KEYWORDS: rearrangement reaction; benzyl; migration; electrospray ionization tandem mass spectrometry; benzyl
20,30-didehydro-20,30-dideoxythymidin-50-yl H-phosphonate
pathways were investigated and some new rearrangements
were discovered.
INTRODUCTION
Great efforts are currently being made all to discover
all kinds of new drugs in order to control AIDS. 20,30-
didehydro-20,30-dideoxythymidine (d4T) is an inhibitor of
HIV reverse transcriptase and was approved by the US
Food and Drug Administration (FDA) for the treatment
of AIDS.1–3 It was found, however, that there were some
problems with its toxic and side effects,4,5 drug resistance6
and so on. It is necessary to modify the structure of d4T
to improve its therapeutic potential. In our previous work,
its analogues such as AZT H-phosphonates,7 amino acid
thiophosphoramidates of nucleosides8 and 30,50-dithymidine
phosphoramidates9 were also analyzed by electrospray
ionization multistage tandem mass spectrometry (ESI-MSn),
and the fragmentation pathways were summarized. Since
d4T H-phosphonate derivatives can be potential candidates
as anti-HIV drugs, it is important to study their mass spectral
fragmentation pathways, which is helpful in the analysis
of other similar compounds. In this work, several d4T H-
phosphonate derivatives (compounds 1–4 in Scheme 1) were
synthesized and analyzed by ESI-MSn, their fragmentation
EXPERIMENTAL
Synthesis of alkyl 2ꢀ ,3ꢀ -didehydro-2ꢀ ,3ꢀ -
dideoxythymidin-5ꢀ -yl H-phosphonate11
A 1 mmol amount of d4T was added to 10 mmol of PCl3
°
in 10 ml of dichloromethane at ꢀ30 C under a nitrogen
atmosphere and stirred for 1 h at this temperature and for
6 h at room temperature. The solvent and excess of PCl3
were removed under reduced pressure, then the residue was
dissolved in 10 ml of dichloromethane. A 2.5 mmol amount
of alcohol (different products from different alcohols) in 5 ml
of dichloromethane was added dropwise to the solution at
°
0 C and the reaction was completed within 30 min. A 2 mmol
amount of triethylamine was added to the resulting solution,
10 min later the solvent was removed by rotary evaporation
and the product was purified by column chromatography
on silica gel using CH2Cl2 –MeOH (20 : 1) as eluent.
Mass spectrometry
ŁCorrespondence to: Yufen Zhao, Key Laboratory for Bioorganic
Phosphorus Chemistry of the Education Ministry, Department of
Chemistry, School of Life Sciences and Engineering, Tsinghua
University, Beijing 100084, China. E-mail: yinyw@tsinghua.edu.cn
Contract/grant sponsor: Chinese National Natural Science
Foundation; Contract/grant numbers: 20175026; 29632004;
39870415.
Mass spectra were acquired using a Bruker ESQUIRE-LC
ion trap mass spectrometer equipped with a gas nebulizer
probe, capable of analyzing ions up to m/z 6000. Nitrogen
was used as the drying gas at a flow-rate of 4 l minꢀ1, the
nebulizer pressure was 7 psi and the electrospray needle was
typically held at 4 kV. The heated capillary temperatures
Contract/grant sponsor: Ministry of Science and Technology.
Contract/grant sponsor: Education Ministry.
°
was 300 C. Samples dissolved in methanol were ionized
Contract/grant sponsor: Tsinghua University.
by ESI and infused continuously into the ESI chamber at a
Copyright  2004 John Wiley & Sons, Ltd.

Rearrangement of alkyl d4T-H-phosphonate in ESI-MS 731
O
N
O
N
O
N
O
N
NH
O
NH
O
NH
O
NH
O
O
P
O
P
O
P
O
H3CH2CO
O
O
O
O
O
PhH2CO P O
O
O
O
O
H
4
H
2
H
3
H
1
Scheme 1. Structures of compounds 1–4.
flow-rate of 0.6–0.7 ml hꢀ1 by a Cole-Parmer 74 900 syringe
pump. The scan range was generally from m/z 50 to 500.
Five scans were averaged for each spectrum. The selected
[M C H]C, [M C Na]C and [M C K]C ions were analyzed by
MSn. The selected ion was first isolated and then fragmented
through collisions with helium to yield tandem mass spectra.
The fragmentation amplitude values were 0.5–1.0 V and
the fragmentation time was 40 ms. High-resolution mass
spectra of benzyl 20,30-didehydro-20,30-dideoxythymidin-50-
yl H-phosphonate were recorded on a Bruker APEX II Fourier
transform ion cyclotron resonance (FT-ICR) MS instrument
equipped with 4.7 T super-conduction magnets and an
analytical electrospray source. The samples were generally
dissolved in methanol–water (1 : 1, containing 2%AcOH). All
samples were analyzed using ESI in the positive ion mode at
a concentration of ¾30 µM.
Calculations
The geometry was optimized at the B3LYP/6–31G* level
using the Gaussian 98 program. The frequency calculation
of stationary conformation was also carried out at the
B3LYP/6–31G* level, and only real frequency values were
obtained.
RESULTS AND DISCUSSION
Positive ESI mass spectra of 1–4 were determined as
shown in Fig. 1, and three adduct ions [M C H]C, [M C Na]C
and [M C K]C were observed. Their ESI-MSn fragmentation
pathways were investigated by multistage technique. For
example, multistage mass spectral fragmentation pathways
of 1 are shown in Schemes 2–5.
ESI-MSn fragmentation pathways of [M + H]+ for
compound 1
The ESI-MS2 fragmentation pattern of the protonated
molecule [M C H]C at m/z 379 of 1 can be summarized as
shown in Scheme 2, corresponding to Fig. 1(B) and (C). The
precursor ion [M C H]C at m/z 379 produced a fragment ion
at m/z 253 for loss of thymine and a pair of complementary
ions at m/z 207 and 171 were observed. There were, however,
another two ions, D and F, at m/z 217 and 297, which were
not so easily explained. In order to clarify their structures,
ESI-MS3 was performed. The two ions at m/z 91 and
127 were detected in the ESI-MS3 of the ion at m/z 217,
which might be benzyl ion and protonated thymine. High-
resolution ESI-MS (Fig. 2) indicated that the exact mass of
ion D was 217.0972, corresponding to elemental composition
C12N2O2H13, which could be the conjugate with benzyl and
thymine as shown in Scheme 3. The ion F at m/z 297 was
also identified by tandem and high-resolution (the exact mass
297.1236 corresponding to C17N2O3H17) MS techniques, and
Figure 1. Mass spectra of benzyl 20,30-didehydro-20,30-
dideoxythymidin-50-yl H-phosphonate: (A) all MS; (B) MS2 of
[M C H]C; (C) MS3 of the rearrangement ion at m/z 217;
(D) MS2 of [M C Na]C; (E) MS3 of rearrangement ion at m/z 239;
(F) MS3 of the rearrangement ion m/z 337; (G) MS2 of [M C K]C.
its possible structure is shown in Scheme 3. In view of these
experimental results, a possible mechanism was proposed
(Scheme 3). Considering Scheme 3, there were two possible
pathways. In one route the oxygen of thyminyl in A could
directly attack the benzyl to produce C, and in the other
Copyright  2004 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2004; 39: 730–735

732
Y. Chen et al.
O
NH
OH+
H2C O P O
O
P
O
H+
O
N
+
OH+
CH2O
O
H
[M-T+H]+ m/z 253
[M-208+H]+ m/z 171
[d4T-H O+H] m/z 207
2
MS2
-172
MS2
-T
MS2
-208
O
NH
OH+
O
N
H2C O P O
F (?)
MS2
O
H
-82
[M-82+H]+ m/z 297
[M+H]+ m/z 379
MS2
-162
OH+
NH
O
D (?)
[M-162 +H]+ m/z 217
+
MS3
-90
CH2
N
H
MS3
-126
m/z 127
m/z 91
Scheme 2. Proposed fragmentation pathways of [M C H]C for benzyl 20,30-didehydro-20,30-dideoxythymidin-50-yl H-phosphonate
(corresponding to Fig. 1(B) and (C)).
OH+
O
O
OH+
P
H
OH
OH
H
H
N
HN
HN
+
P
O
I
P
I
O
N
N
O
O
O
O
N
O
O
O
O
H2C
H2C
O
O
H2C
B
A
Ph
[M+H]+ m/z 379
Ph
Ph
II
I
OH+
N
OH+
N
OH+
N
N
N
PhH2C
O
O
PhH2C
O
O
N
H
PhH2C
O
O
P
D
HO
O
F
m/z 217
[M+H]+ m/z 297
H
+
C
O
P
[M+H]+ m/z 379
+
HO
O
O
O
H
HO
P
OH
neutral molecule E
H
neutral molecule G
Scheme 3. Possible formation mechanism of rearrangement ions at m/z 217 and 297 from the precursor ion [M C H]C at m/z 379 in
mass spectrum of benzyl 20,30-didehydro-20,30-dideoxythymidin-50-yl H-phosphonate.
the carbonyl of the amide of thyminyl in A could attack
the phosphorus nucleophilically to lead to pentacoordinated
phosphorane intermediate B, the subsequent four-membered
cyclic rearrangement of benzyl led to C and ordinary
fragmentation of C yielded ions D at m/z 217 and F at
m/z 297. The distance between benzyl and thyminyl in the
protonated molecule A is long, so the formation mechanism
of the ions D and F might involve a pentacoordinated
phosphorane intermediate as shown in Scheme 3. In fact,
the pentacoordinated phosphorus intermediates have been
trapped11 in previous synthetic organic chemistry, and
some stable pentacoordinated phosphoranes containing
Copyright  2004 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2004; 39: 730–735

Rearrangement of alkyl d4T-H-phosphonate in ESI-MS 733
+
+
Na or K
O
+
+
Na
OH
NH
O
O
+
+
N
H
ONa or K
P
[d4T-T+Na] m/z 121
HO
O
+
O
[T+Na] m/z 149
O
N
+
H
[T+K] m/z 165
+
NH
Na
+
O
[M-T-alkyene+Na] m/z 185
O
O
+
P O
[M-T-alkyene+K] m/z 201
O
+
2
2
MS
MS
2
M-92+Na] m/z 309
MS
2
MS
+
+
OK or Na
NH
O
N
O
+
+
ONa or K
+
+
Na or K
O
NH
2
P
H C O
2
O
O
MS
2
MS
-T
O
N
O
H C O P O
2
H
+
+
O
[d4T-H O+Na] m/z 229 or
2
[M-T+Na] m/z 275
+
H
+
[d4T-H O+K] m/z 245
+
2
[M-T+K] m/z 291
[M+Na] m/z 401
+
[M+K] m/z 417
I
II
rearrangements
2
2
-162
-64
MS
MS
+
+
ONa or K
N
?
CH O
2
N
H
+
+
I [M-64+Na] m/z 337
I’[M-64 +K] m/z 353
+
+
H [M-162 +Na] m/z 239
H’[M-162+K] m/z 255
3
3
+
MS
MS
Na
O
-HN=C=O
-126
3
3
3
+
MS
NH
MS
-92MS
Na
O
O
+
CH
CH
2
Na
Ph-CH -O
2
O
N
H
+
CH
+
2
2
ONa
N
+
N
[M-190+Na] m/z 211
+
[T+Na] m/z 149
m/z 196
m/z 91
N
O
m/z 147
Scheme 4. Proposed fragmentation pathways of [M C Na]C and [M C K]C for benzyl 20,30-didehydro-20,30-dideoxythymidin-50-yl
H-phosphonate (corresponding to Fig. 1(D)–(G)).
O
O Na+
O
-HP
NH
Na+
O
P
H
NH
O
O
O
N
CH2
O
O
O
N
- 64
O
O
CH2
I
[M+Na]+ m/z 401
[M-64+Na]+ m/z 337
Scheme 5. Possible formation mechanism of the ion at m/z 337 from the precursor ion [M C Na]C m/z 401 in the mass spectrum of
benzyl 20,30-didehydro-20,30-dideoxythymidin-50-yl H-phosphonate.
Table 1. The Mulliken charge and distance of some atoms in
compound 1
amino acid residues were synthesized and determined by
MS in our previous work.12–15 In addition, we modeled
structure of benzyl 20,30-didehydro-20,30-dideoxythymidin-
50-yl H-phosphonate with Gaussian 98,16 and the results
˚
Charge
Distance (A)
O15—P17
O15—C20
C20
P17
O15
ꢀ0.1 68 776
3.4 05 065
4.9 71 416
˚
showed that the distance (3.4 A) between P and the oxygen
1.1 28 242
˚
of carbonyl in thymine was shorter than that (4.9 A)
ꢀ0.615678
between benzyl and the same oxygen, and the charge
on P atom is positive (C1.128), but negative (ꢀ0.169) on
the carbon of benzyl (Scheme 6 and Table 1). Hence the
protonated benzyl 20,30-didehydro-20,30-dideoxythymidin-50-
yl H-phosphonate in MS might form a pentacoordinated
phosphorane intermediate as shown in Scheme 3.
ESI-MSn fragmentation pathways of [M + Na]+ and
[M + K]+ for compound 1
The ESI-MS2 fragmentation patterns of the NaC and KC
adduct ions [M C Na]C at m/z 401 and [M C K]C at m/z 417
Copyright  2004 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2004; 39: 730–735

734
Y. Chen et al.
Nano-spry. ms/ms Lo 379.1047. Bruker Dallonics Inc. APEX II. FT-ICRMS
Sample: benzyl-D4TPH
a.1.
5500000
5000000
4500000
4000000
3500000
3000000
2500000
2000000
1500000
1000000
500000
0
200
300
400
m/z
Figure 2. High-resolution MS2 of benzyl 20,30-didehydro-20,30-dideoxythymidin-50-yl H-phosphonate [M C H]C.
Table 2. MS/MS data for d4T O-alkyl-H-phosphonates
Rearrangement
ionsa
Fragment ions, m/z (relative abundance, %)
No
compound
Precursor
ions, m/z
[M ꢀ T]C [d4T ꢀ H2O]C [M ꢀ alkyene]C [M ꢀ T ꢀ alkyene]C
[T]C
—
I
II
1 Benzyl
[M C H]C 379
[M C Na]C 401
[M C K]C 417
253 (22)
275 (30)
291 (15)
207 (40)
229 (7)
245 (16)
—
—
—
—
185 (33)
201 (80)
297 (5)
149 (17) 217 (100) 211 (2)
165 (20) 239 (100) 337 (8)
255 (100) 353 (9)
2 Isopropyl
[M C H]C 331
[M C Na]C 353
[M C K]C 369
205 (81)
227 (6)
267 (50)
245 (100)
267 (1)
207 (100)
—
245 (1)
207 (31)
—
—
311 (37)
327 (50)
—
311 (74)
327 (94)
—
—
—
149 (6)
165 (7)
—
149 (1)
165 (5)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
185 (100)
201 (68)
—
185 (100)
201 (100)
—
3 Cyclohexyl [M C H]C 371
[M C Na]C 393
[M C K]C 409
283 (9)
—
4 Ethyl
[M C H]C 317
[M C Na]C 339
[M C K]C 355
191 (19)
213 (77)
229 (100)
207 (100)
229 (3)
245 (2)
—
—
185 (1)
201 (1)
149 (100)
165 (3)
a Fragment ions I come from the ions from the rearrangement reaction in Scheme 3 whereas fragment ions II arise from the
rearrangement reaction in Scheme 5.
cyclic migration of benzyl from precursor ion [M C Na]C
were also investigated, as shown in Scheme 4, corresponding
to Fig. 1(D)–(G). For example, the precursor ion [M C Na]C
occurred, as shown in Scheme 5. Hence the structure of the
at m/z 401 gave the expected product ions at m/z 309,
275, 229, 185, 149 and 121, whose structures are shown in
Scheme 4; however, ions at m/z 239 and 337 are unknown.
ESI-MS3 of the ion at m/z 239 yielded fragment ions at m/z
91 corresponding to benzyl ion and m/z 196 and 147; these
results indicated that the structure of the ion at m/z 239 could
be H, which is an analog of D, and its formation mechanism
is similar to that of D. ESI-MS3 fragmentation pathways of
ion at m/z 337 were also investigated, yielding ions at m/z
211 and 149, the latter corresponding to the sodium adduct of
thymine. The ESI-MSn results showed that a four-membered
ion at m/z 337 could be I. The fragmentation pathways of
[M C K]C for 1 and the MSn rearrangements are similar to
those of [M C Na]C
.
When benzyl was replaced with other alkyls such as
isopropyl, cyclohexyl or ethyl, the rearrangement reactions
could not be observed in ESI-MSn (Table 2) because benzyl
prefers to form a cation in mass MS, in contrast to alkyls, so
benzyl is necessary for this kind of rearrangement.
In conclusion, two kinds of rearrangement ions were
found in ESI-MSn of benzyl 20,30-didehydro-20,30-dideoxythy-
midin-50-yl H-phosphonate: the conjugate ion containing
Copyright  2004 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2004; 39: 730–735

Rearrangement of alkyl d4T-H-phosphonate in ESI-MS 735
5. Faraj A, Fowler DA, Bridges EG, Sommadossi JP. Effect of 20,30-
dideoxynucleosides on proliferation and differentiation of
human pluripotent progenitors in liquid culture and their effects
on mitochondrial DNA synthesis. Antimicrob. Agents Chemother.
1994; 38: 924.
6. Isel C, Ehresmann C, Walter P, Ehresmann B, Marquet R.
The emergence of different resistance mechanisms toward
uncleoside inhibitors is explained by the properties of the wild
type HIV-1 reverse transcriptase. J. Biol. Chem. 2001; 276: 48 725.
7. Xiao Q, Ju Y, Yang XP, Zhao YF. Electrospray ionization mass
spectrometry of AZT H-phosphonates conjugated with steroids.
Rapid Commun. Mass Spectrom. 2003; 17: 1045.
8. Miao ZW, Fu H, Chen Y, Chen J, Chemg CM, Zhao YF. Synthesis
and electrospray ionization mass spectra of amino acid thiophos-
phoramidates of nucleosides. J. Chin. Chem. 2001; 19: 1239.
9. Qin ZH, Lin CX, Chen Y, Ju Y, Zhao YF. Electrospray ionization
mass spectrometry of serine/alanine conjugated 50-UMP and
30,50-dithymidine phosphoramidates. Rapid Commun. Mass
Spectrom. 2002; 16: 1997.
C(20)
C(17)
O(15)
10. Sun XB, Kang JX, Zhao YF. One-pot synthesis of hydrogen
phosphonate derivatives of d4T and AZT. Chem. Commun 2002;
2414.
11. Fu H, Li ZL, Zhao YF, Tu GZ. Oligomerization of N,O-
bis(trimethylsilyl)-alpha-amino acids into peptides mediated by
O-phenylene phosphorochloridate. J. Am. Chem. Soc. 1999; 121:
291.
Scheme 6. The stationary conformation of 1. The geometry
was optimized at the B3LYP/6–31G* level using the Gaussian
98 program. The frequency calculation of the stationary
conformation was also carried out at the B3LYP/6–31G* level,
and only real frequency values were obtained.
12. Fu H, Tu GZ, Li ZL, Zhao YF, Zhang RQ. New and efficient
approach to the synthesis of pentacoordinate spirobicyclic
phosphoranes. J. Chem. Soc., Perkin Trans. 1 1997; 2021.
13. Fu H, Li ZL, Zhao YF, Guo DB, Xiao HZ, Wang JZ, Wu Y. Mass
spectra of pentacoordinate spirobicyclic imino(alkyl)acetoxy
phosphoranes. Rapid Commun. Mass Spectrom. 1997; 11: 1825.
14. Fu H, Zhao YF, Xiao HZ, Wang JZ. Mass spectra of aminoacyl
adenylate pentacoordinated phosphorus compounds. Rapid
Commun. Mass Spectrom. 1999; 13: 1477.
benzyl and furan rings came from the four-membered cyclic
benzyl migration; and the complex ion with benzyl and
thymine first formed a pentacoordinated phosphorane inter-
mediate and then the four-membered cyclic rearrangement
occurred. These novel rearrangements might be valuable for
structure analysis of other analogs.
15. Fu H, Xu L, Lv Q, Wang JZ, Xiao HZ, Zhao YF, Xiao HZ.
Electrospray ionization mass spectra of amino acid
phosphoramidates of adenosine. Rapid Commun. Mass Spectrom.
2000; 14: 1813.
Acknowledgements
The authors acknowledge financial support from the Chinese
National Natural Science Foundation (No. 20175026, 29632004 and
39870415), the Ministry of Science and Technology, the visiting
scholar fund of the Chinese Education Ministry and Tsinghua
University.
16. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Zakrzewski VG, Montgometry JA Jr, Strat-
mann RE, Burant JC, Dapprich S, Millam JM, Daniels AD,
Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M,
Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochter-
ski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK,
Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J,
Ortiz JV, Baboul AG, Stefanov BB, Liu G, Liashenko A,
Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T,
Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M,
Gill PMW, Johnson B, Chen W, Wong MW, Andres JL, Gon-
zalez C, Head-Gordon M, Replogle ES, Pople JA. Gaussian 98,
Revision A. 9. Gaussian: Pittsburgh, PA, 1998.
REFERENCES
1. Perry CM, Balfour JA. Didanosine: an update on its antiviral
activity, pharmacokineticproperties and therapeutic efficacy in
the management of HIV disease. Drugs 1996; 52: 928.
2. Riddler SA. Antiretroviral activity of stavudine (20,30-didehydro-
30-deoxythymidine, d4T). Antiviral Res. 1995; 27: 189.
3. Gameron JM. Lamivudine. Drugs Future 1993; 1: 319.
4. Chen CH, Vazque-Padua M, Cheng YC. Effect of anti-human
immunodeficiency virus nucleoside analogs on mitochondrial
DNA and its implication for delayed toxicity. Mol. Pharmacol.
1991; 39: 625.
Copyright  2004 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2004; 39: 730–735