Synthesis and biological evaluation of C-12′ substituted vinflunine derivatives

Article abstract of DOI:10.1016/j.bmcl.2008.07.025

A series of novel C-12′ substituted vinflunine derivatives have been synthesized. Several compounds in this series possess comparable in vitro cytotoxic potency against A549 cell lines.

Full text of DOI:10.1016/j.bmcl.2008.07.025

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4602–4605
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of C-120 substituted vinflunine derivatives
*
Lei Xin Sheng , Yu Xiang Da, Yin Long, Liu Zhen Hong, Tang Peng Cho
Shanghai Hengrui Pharmaceuticals Co., Ltd., 279 Wenjing Road, Shanghai 200245, China
a r t i c l e i n f o
a b s t r a c t
A series of novel C-120 substituted vinflunine derivatives have been synthesized. Several compounds in
this series possess comparable in vitro cytotoxic potency against A549 cell lines.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 5 May 2008
Revised 4 July 2008
Accepted 9 July 2008
Available online 12 July 2008
Keywords:
Vinflunine derivatives
Synthesized
In vitro
A549 cell lines
Compounds interfering with microtubule function form an
important class of anticancer agents, they are widely used in com-
bination chemotherapy regimens for treating solid tumors as well
as leukemias.1 One of the best-known classes of these agents is the
Vinca alkaloids, which inhibit cell proliferation by their effects on
the mitotic spindle microtubules.2 Four drugs are currently avail-
able: Vinblastine,3 Vincristine,4 Vindesine,5 and Vinorelbine6 (Fig.
1). Vinflunine, a novel semi-synthetic fluoride containing Vinca
alkaloid, is now in clinical development, with marked antitumor
activities, reduced neurotoxicity and less P-glycoprotein-mediated
drug resistance.7
Despite enormous efforts in the fields of both chemistry and
biology since Vinblastine was isolated in 1958, it is still necessary
to discover new Vinca alkaloid derivatives with higher cytotoxic
potency, less side effect, and a broader spectrum of anticancer effi-
cacies. Numerous studies indicate that the minor difference in the
structure among these Vinca alkaloids could often result in signif-
icant difference in their potency and clinical toxicity.5b,8 While pre-
vious structure-activity relationship (SAR) studies were focused on
the indoline moiety in the Vinca alkaloids,5b,8,9 very little was re-
ported on modification of the indole moiety.10
in the synthesis and biological evaluation of the novel vinflunine
derivatives at C-120 position on the indole ring.
Our synthesis of the C-120 substituted derivatives of vinflunine
is outlined in Schemes 1 and 2. Vinflunine 1 was formylated at the
C-12prime position on the indole ring by treating vinflunine with
HMTA in the presence of TFA. Subsequent reductive amination of
the C-120-formyl led to compounds 3–8. Treatment of intermediate
2 with various Grignard’s reagents, followed by Dess–Martin oxi-
dation12 of the resulting alcohols to the corresponding ketones,
generated compounds 9–11. Cyano vinflunine 12 was obtained
by condensing the aldehyde intermediate 2 with hydroxylamine
hydrochloride in the presence of triethylamine, followed by dehy-
dration in situ using phthalic acid anhydride under reflux.13
As shown in Scheme 2, vinflunine was allowed to react with NIS
in the mixture of TFA and dichloromethane at ꢀ15 °C for 1 h, pro-
viding smoothly the important C-120 iodinated intermediate 13 in
94% yield. Iodide 13 was coupled with various aryl boronic acids,
catalyzed by Pd(OAc)2/dppf system, in the presence of Cs2CO3 to
give compounds 14–23.14 Negishi coupling reaction of 13 cata-
lyzed by Pd(OAc)2/PPh3 system with organozinc species, prepared
from the corresponding Grignard’s reagents and anhydrous zinc
chloride, gave rise to compounds 24–27. Compound 28 was ob-
tained by coupling 13 with ETMS under Sonogashira conditions,13c
followed by removing the silyl protective group with TBAF. The
alkyloxycarbonyl derivatives 29–32 were furnished using
Pd(OAc)2/dppf/Et3N in carbon monoxide atmosphere in the pres-
ence of the corresponding alcohols.15
Recently, Vinblastine-binding study indicated that the vindoline
moieties, particularly the C-120 site on the upper aromatic moiety,
were involved in the interaction with tubulin heterodimers.11
Therefore, modification on the upper aromatic moiety of Vinca
alkaloids might be a probe to aid in elucidating or demonstrating
the binding information in detail. Herein, we report our progress
Iodide 13 reacted with sodium azide using CuI as catalyst and L-
proline as ligand in the presence of NaOH16 to furnish the corre-
sponding azide 33, which was hydrogenated to give amine 34. Di-
rect alkylation of amine 34 led to compounds 35–37. Hydroxyl
group of the intermediate 13 was protected with silyl group, and
* Corresponding author. Tel.: +86 21 54759101; fax: +86 21 54759072.
E-mail address: tangpc@shhrp.com (P.C. Tang).
Present address: School of Pharmacy, Fudan University, Shanghai, China.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.025

X. S. Lei et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4602–4605
4603
N
N
H
O
N
H
O
8'
1'
7'
N
OH
N
OAc
OH
OMe
O
N
12'
9'
H
O
N
2'
N
H
H
Vinorelbine
O
O
3
R
O
O
F
7'
H
1
OH
F
R
2
9'
5'
N
R
O
12'
N
3'
N
R1=CH3, R2=OMe, R3=Ac Vinblastine
R1=CHO, R2=OMe, R3=Ac Vincristine
H
H
O
O
OAc
O
N
R1=CH3, R2=NH2, R3= H
Vindesine
H
OH
OMe
O
Vinflunine
1
Figure 1. Structures of the clinically effective compounds.
O
F
F
F
7'
F
F
F
9'
R
H
N
5'
N
12'
N
N
H
b, c, d
a
N
N
3'
N
H
N
N
H
H
H
H
O
O
O
O
O
O
O
O
OAc
OH
OMe
O
N
OAc
OH
OMe
OAc
OH
OMe
N
N
H
O
H
H
O
O
Vinflunine 1
2
3-12
Scheme 1. Reagents and conditions: (a) hexamethylenetetramine, TFA, 75 °C, 1 h; (b) i—amines, CH2Cl2, rt, 20 h; ii—NaBH3CN, rt, 3 hr; (c) i—RMgCl, THF, rt, 1 h; ii—Dess–
Martin reagent, CH2Cl2, rt, 20 h; (d) i—HONH2ꢁHCl/Et3N, CH3CN, reflux, 1.5 h; ii—phthalic acid anhydride, reflux, overnight.
then coupled with aromatic or aliphatic amines, followed by
deprotection reaction to give the desired compounds 38–39. Com-
pound 34 could be further acylated to compounds 40–44. Amine
34 was reacted with 4-nitrophenyl chloroformate in the presence
of triethylamine, and then treated with different organic amines
to give compounds 45–48. Compounds 49 and 50 were prepared
conveniently from compound 34 by being treated with alkyl isothi-
ocyanate. All the synthesized compounds are well characterized by
spectroscopic methods such as ESI-MS, 1H NMR, 13C NMR, HMQC,
HMBC, and COSY, and the spectrums of the novel compounds were
assigned by comparing to that of vinflunine.17
39), suggesting that the vinflunine derivatives substituted at C-
120 position are required to maintain good cell-permeability and
suitable size for a promising activity. Those above results also indi-
cate that the indole moiety of vinflunine remains the limited space
to modify without loss of the desired activity.
Encouraged by the knowledge, the compounds bearing different
protics but permeable substituents at C-120 position were assessed
by the same assay, and the biological result was summarized in Ta-
ble 2. The ketones (compounds 9, 10, and 11) and the esters (com-
pounds 29, 30, and 31) show weak activities compared with
vinflunine, and a notable exception was compound 32 with a good
The vinflunine derivatives (3–50) were tested in vitro for their
anti-proliferative activity as compared with vinflunine. The cyto-
toxicity assay was carried out by a sulforhodamine B (SRB) method
using A549 human lung carcinoma cell lines.18 Evaluation directly
at the cell level is aimed at screening the drug-like candidates from
the synthesized compounds.
Data for selected compounds are presented in Tables 1–3. As
shown in Table 1, the basic substituents at the C-120 position,
which may improve the solubility, have an evident effect on the
activity. Trying to introduce various amino groups at the benzyl
position (see compounds 3, 4, and 7) gives rise to a marginal cyto-
toxic activity, and attaching a bulky group or a hydrophilic group
on the terminal of the substituents results in complete loss of cyto-
toxicity (see compounds 5, 6, and 8). Compound 34 exhibits a
IC50 of 0.28
exhibit potent activities with IC50 of 0.20–0.42
pounds 40 and 41 with IC50 of 41.0 and 1.81 M, respectively, while
the corresponding urinyl or thiourinyl compounds lead to poor
activities (compounds 45, 46, 47, 48, 49, and 50). It appeared that
hydrophilic substituents at C-120 position might improve the cyto-
toxicity to a limited extension.
As shown in Table 3, the series of compounds bearing hydro-
phobic substituents with different sizes at C-120 position gives an
interesting result. In general, the compounds bearing a aryl or het-
eroaryl group (see compounds 14, 15, 16, 17, 18, 19, 20, 21, 22,
and 23) have a less potent activity than vinflunine, and the substit-
uents on the aryl ring have a slight modified effect on the activity
(see compounds 15 and 21). However, the compounds containing
the small hydrophobic group such as alkyl, cyano, or azide) possess
good to excellent activities (see compounds 12, 24, 25, 26, 28, and
l
M. However, the amides (compounds 42, 43, and 44)
l
M except com-
l
rather weak activity against A549 cell with IC50 of 37.8lM, but
introduction of alkyl or phenyl group on the amino group leads
to an improved activity (see compounds 35, 37, and 38), and the
alkyl group seems to be superior to the phenyl group. Furthermore,
the increased alkyl substituents to the amino group resulted in
33) with IC50 of 0.92–0.037
leads to decreasing activity. The most potent compound exhibits a
IC50 up to 0.037 M, which is twofold as potent as vinflunine (see
compounds 24 and 28).
lM, and increasing the substituent size
l
good activity with IC50 of 0.22–0.64 lM (see compounds 36 and

4604
X. S. Lei et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4602–4605
F
F
F
7'
F
I
F
F
R
5'
N
N
12'
N
N
H
O
f,g,h,i,j,
e
N
N
H
O
3'
N
H
O
N
N
H
H
H
O
k,l,m,n,o,p
OAc
OH
OMe
O
O
O
N
OAc
OH
OMe
OAc
OH
OMe
O
N
O
N
H
H
H
O
O
O
Vinflunine 1
13
14-50
Scheme 2. Reagents and conditions: (e) NIS, CH2Cl2/dioxane, ꢀ15 °C, 1 h; (f) ArB(OH)2, Pd(OAc)2/dppf, Cs2CO3, dioxane, 60 °C,24 h; (g) Grignard’s reagents/ZnCl2, Pd(OAc)2/
PPh3, THF, rt, 1–3 h; (h) i—ethynyltrimethylsilane, CuI, Pd(PPh3)2Cl2, DIPEA, toluene, 60 °C, 18 h; ii—Bu4NF.3H2O, THF, rt, 1 h; (i) alcohols, CO, Et3N, Pd(OAc)2/PPh3; rt,
overnight; (j) NaN3, CuI/L-Proline(cat.), NaOH, DMSO; (k) H2, 10% Pd/C, 1 atm, rt, overnight; (l) aldehydes, NaBH3CN; (m) i—TESOTf, DIPEA, CH2Cl2, rt, 2 h; ii—amines,
Pd2(dba)3/Cy2P(20,40,60-tri-i-propyl-1,10biphenyl) (cat.), toluene, 80 °C, 2 h; iii—Bu4NF.3H2O, THF; (n) acyl chlorides, Et3N, DMPA(cat.), THF, rt, 1–4 h; (o) i—4-nitrophenyl
chloroformate, Et3N, DMAP (cat.), THF, rt, 1 h; ii—amines, THF, 1 h; (p) RNCS, EtOH, 70 °C, 2 h.
Table 1
Table 3
In vitro cytotoxicity of vinflunine derivatives against A549
In vitro cytotoxicity of vinflunine derivatives against A549
Compound
R
Yield %
IC50
(
lM)
Compound
R
Yield %
IC50 (lM)
Vinflunine
3
4
5
6
7
8
34
35
36
37
38
39
H
0.08
3.52
3.93
Vinflunine
12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
H
Cyano
Ph
0.08
0.29
2.16
0.56
1.17
1.01
1.02
2.50
2.56
0.29
2.28
3.00
0.037
0.92
0.12
1.88
0.05
0.16
(4-Methoxy-phenylamino)-methyl
Morpholin-4-ylmethyl
(2-Morpholin-4-yl-ethylamino)-methyl
(3-Morpholin-4-yl-propylamino)-methyl
Butylaminomethyl
(2-Hydroxy-ethylamino)-methyl
NH2
MeNH
62
25
52
53
17
40
74
25
33
56
11
8
47
73
60
53
20
57
46
80
39
39
32
44
31
31
22
68, 25
68
>100
>100
1.74
95.5
37.8
6.91
0.22
0.51
1.86
0.64
4-Me-Ph
4-Cl-Ph
2-Cl-Ph
2,4-di-F-Ph
4-NC-Ph
4-F-Ph
2-CF3-Ph
Furan-3-yl
Thiophen-3-yl
Me
Me2N
Allylamino
PhNH
Pyrrolidin-1-yl
Et
Cyclopropyl
n-Bu
Ethynyl
N3
Table 2
In vitro cytotoxicity of vinflunine derivatives against A549
33
Compound
R
Yield %
IC50 (lM)
Vinflunine
9
10
11
29
30
31
32
40
41
42
43
44
45
46
47
48
H
Acetyl
Propionyl
Cyclopropanecarbonyl
MeOCO
EtOCO
i-PrOCO
BnOCO
AcNH
CF3CONH
Cl2CHCONH
MsNH
MeOCONH
NH2CONH
MeNHCONH
Me2NHCONH
Morpholine-4-carboxamido
EtNHCSNH
Cyclopropylthioureido
0.08
4.72
17.4
4.45
8.73
1.03
3.26
0.28
41.0
1.81
0.20
0.32
0.42
>100
35.1
>100
>100
5.68
27.5
57, 41
47, 79
14, 41
52
76
64
15
59
50
68
26
41
23
49
46
51
60
67
Acknowledgments
The authors gratefully acknowledge the work of Mr. LV Ai Feng
for providing vinflunine and Mr. YUAN Kai Hong for his responsi-
bility for the biological evaluation of the compounds, both from
Hengrui Medicine Co., Ltd., Lianyungang, China.
References and notes
1. (a) Attard, G.; Greystoke, A.; Kaye, S.; De Bono, J. Pathologie Biologie 2006, 54,
72; (b) Hotta, K.; Ueoka, H. Crit. Rev. Oncol. Hematol. 2005, 55, 45; (c) Checchi, P.
M.; Nettles, J. H.; Zhou, J.; Snyder, J. P.; Joshi, H. C. Trends Pharmacol. Sci. 2003,
24, 361.
2. (a) Lobert, S.; Vuleric, B.; Correia, J. Biochemistry 1996, 35, 6806; (b) Aapro, M.
S.; Harper, P.; Johnson, S. A.; Vermorken, J. B. Crit. Rev. Oncol. Hematol. 2001, 40,
251.
49
50
3. Nobel, R. L.; Beer, C. T.; Cutts, J. H. Biochem. Pharmacol. 1958, 1, 347.
4. Svoboda, G. H. Lloydia 1961, 24, 173.
5. (a) Cersosimo, R. J.; Bromer, R.; Licciardello, J. T. W.; Ki Hong, W.
Pharmacotherapy 1983, 3, 259; (b) Barnett, C. T.; Gullinan, G. J.; Gerzon, K.;
Hoying, R. C.; Jones, W. E.; Newlon, W. M.; Poore, G. A.; Robison, R. L.; Sweeney,
M. J.; Todd, G. C.; Dyke, R. W.; Nelson, R. L. J. Med. Chem. 1978, 21, 88.
6. (a) Langlois, N.; Gueritte, F.; Langlois, Y.; Potier, P. J. Am. Chem. Soc. 1976, 98,
7017; (b) Mangeney, P.; Andriamialisoa, R. Z.; Lallemand, J. Y.; Langlois, N.;
Langlois, Y.; Potier, P. Tetrahedron 1979, 35, 2175.
7. (a) Fahy, J.; Duflos, A.; Ribert, J. P.; Jacquesy, J. C.; Berrier, C.; Jouannetaud, M. P.;
Zunino, F. J. Am. Chem. Soc. 1997, 119, 8576; (b) Kruczynski, A.; Hill, B. T. Crit.
Rev. Oncol. Hematol. 2001, 40, 159.
8. (a) Conrad, R. A.; Cullinan, G. J.; Gerzon, K.; Poore, G. A. J. Med. Chem. 1979, 22,
391; (b) Miller, J. C.; Gutowski, G. E.; Poore, G. A.; Boder, G. B. J. Med. Chem.
1977, 20, 409.
9. (a) Langlois, N.; Gueritte, F.; Langlois, Y.; Potier, P. J. Am. Chem. Soc. 1976, 98,
7017; (b) Mangeney, P.; Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y.; Potier,
P. J. Org. Chem. 1979, 44, 3765; (c) Potier, P. J. Natural Product. 1980, 43, 72; (d)
Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J. Org. Chem. 1991, 56, 513; (e)
In conclusion, we have prepared a series of new C-120 substi-
tuted derivatives of vinflunine, and performed biological assay of
those compounds. Among them, several compounds were discov-
ered to exhibit promising cytotoxicity against A549 cell lines in
contrast to that of vinflunine. From the SAR analysis, it appeared
evident that the modification on the upper aromatic moiety of
vinflunine has an important effect on the cytotoxicity, and that
the small hydrophobic group was required to possess the cyto-
toxicity against A549 cell lines. Studies aiming at further explor-
ing the characteristic features of biological activity for some
compounds, including the interaction with tubulin, are in
progress.

X. S. Lei et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4602–4605
13. Wang, E. C.; Lin, G. L. Tetrahedron Lett. 1998, 39, 4047.
4605
Magnus, P.; Mendoza, J. S.; Stamford, A.; Ladlow, M.; Willis, P. J. Am. Chem. Soc.
1992, 114, 10232; (f) Danieli, B.; Lesma, G.; Palmisano, G.; Passarella, D. J. Org.
Chem. 1994, 59, 5810; (g) Szabo, L.; Szentirmay, E.; Baitz-Gacs, E.; Kalaus, G.;
Szantay, C. Tetrahedron Lett. 1997, 38, 115; (h) Danieli, B.; Lesma, G.; Martineli,
M.; Passarella, D.; Silvani, A. J. Org. Chem. 1998, 63, 8586; (i) Lafitte, C.;
Jouannetaud, M. P.; Jacquesy, J. C.; Fahy, J.; Duflos, A. Tetrahedron Lett. 1998, 39,
8281; (j) Kuehne, M. E.; Qin, Y.; Huot, A. E. J. Org. Chem. 2001, 66, 5317; (k) Eles,
J.; Kalaus, G.; Greiner, I.; Kajtar-Peredy, M.; Szabo, P.; Szabo, L.; Szantay, C.
Tetrahedron 2002, 58, 8921; (l) Jacquesy, J. C.; Berrier, C.; Jouannetaud, M. P.;
Zunino, F.; Fahy, J.; Duflos, A.; Ribet, J. P. J. Fluorine Chem. 2002, 114, 139; (m)
Fahy, J.; Boullay, V. T.; Bigg, D. C. H. Bioorg. Med. Chem. Lett. 2002, 12, 505; (n)
Kuehne, M. E.; Bornmann, W. G.; Marko, I.; Qin, Y.; LeBoulluec, K. L.; Frasier, D.
A.; Xu, F.; Mulamba, T.; Ensinger, C. L.; Borman, L. S.; Huot, A. E.; Exon, C.;
Bizzarro, F. T.; Cheung, J. B.; Bane, S. L. Org. Biomol. Chem. 2003, 1, 2120.
10. (a) Szabo, L.; Szantay, C.; Baitz, E. G.; Mak, M. Tetrahedron Lett. 1995, 36, 5265;
(b) Trouet, A. B.; Hannart, J. A.; Rao, K. S. B. US4639456, 1987.; Trouet, A. B.;
Hannart, J. A.; Rao, K. S. B. Chem. Abstr. 1987, 107, 40181; (c) Scott, I. L.; Ralph, J.
M.; Voss, M. E. WO2005055943, 2005.; Scott, I. L.; Ralph, J. M.; Voss, M. E. Chem.
Abstr. 2005, 143, 60126; (d) Scott, I. L.; Ralph, J. M.; Voss, M. E. WO2005055939,
2005.; Scott, I. L.; Ralph, J. M.; Voss, M. E. Chem. Abstr. 2005, 142, 28005.
11. Gigant, B.; Wang, C.; Ravelli, R. B. G.; Roussi, F.; Steinmetz, M. O.; Curmi, P. A.;
Sobel, A.; Knossow, M. Nature 2005, 435, 519.
14. (a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400; (b) Young, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; (c) Chinchilla, R.; Najera,
C. Chem. Rev. 2007, 107, 874. and references therein.
15. Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318.
16. Zhu, W.; Ma, D. Chem. Commun. 2004, 7, 888.
17. Assignment of 1H and 13C NMR of Vinflunine, see: Ribet, J. P.; Zalavari, P.; Fahy,
J.; Duflos, A.; Beltran, T. Magn. Reson. Chem. 2001, 39, 43. Spectroscopic data for
1
24: ESI:[M+1] = 831. H NMR (CDCl3,400 MHz) d 9.75 (brs, 1H, N-160), 8.29 (s,
1H, O-3), 7.44 (s, 1H, C-110), 7.02 (d, 1H, J = 8.4Hz, C-130), 6.98 (d, 1H, J =8.4 Hz,
H-140), 6.39 (s, 1H, H-14), 6.08 (s, 1H, H-17), 5.83 (dd, 1H, J1 = 10.4 Hz, J2
=
4.0 Hz, C-7), 5.41 (s, 1H, C-4), 5.27 (d, 1H, J = 10.4 Hz, C-6), 4.49 (d, 1H, J =
12.6 Hz, C-70(endo)), 4.31 (d, 1H, J = 12.6 Hz,C-70(exo)), 3.81 (s, 3H, H-25), 3.78
(s, 3H,C-24), 3.71 (s, 1H, C-2), 3.69 (s, 3H, C-230), 3.40–3.27 (m, 3H), 3.27–3.20
(m, 1H), 3.08 (dd, 1H, J1 = 13.2 Hz, J2 = 12.4 Hz), 2.97 (dd, 1H, J1 = 14.4 Hz, J2
14.0 Hz), 2.80–2.70 (m, 1H), 2.70–2.65 (m, 1H), 2.71 (s, 3H, C-22), 2.56 (dd, 1H,
1 = 14.8 Hz, J2 = 6.0 Hz), 2.51(s, 3H, C-19), 2.44(s, 3H, C-240), 2.38-2.32(m, 1H),
=
J
2.24(d, 1H, J =14.4 Hz), 2.14–2.09 (m, 1H), 2.09 (s, 3H, C-27), 1.87–1.80 (m, 2H),
1.70–1.68 (m, 1H), 1.68–1.61 (m, 1H), 1.61 (dd, 3H, J1 = 18.8 Hz, J2 = 18.8 Hz, C-
210), 1.22–1.20 (m, 1H), 1.17–1.08 (brs, 1H), 0.70 (dd, 3H, J1 = 7.6 Hz, J2 = 7.2 Hz,
C-21).
18. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D. J. Natl.
Cancer Inst. 1990, 82, 1107.
12. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.