Inhibitors of NF-κB derived from thalidomide

Article abstract of DOI:10.1016/j.bmcl.2007.01.088

A series of compounds originally derived from thalidomide were synthesized and evaluated. The most potent compounds in this series, 5HPP-33 and compound 20, inhibited NF-κB activation in HeLa cells. Preliminary study indicated that the mechanism of inhibition of NF-κB activation is through inhibition of its translocation from the cytoplasm to the nucleus.

Full text of DOI:10.1016/j.bmcl.2007.01.088

Bioorganic & Medicinal Chemistry Letters 17 (2007) 6031–6035
Inhibitors of NF-jB derived from thalidomide
Esperanza J. Carcache de-Blanco, Bulbul Pandit, Zhigen Hu,
Jiandong Shi, Andrew Lewis and Pui-Kai Li*
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
Received 30 August 2006; revised 16 January 2007; accepted 22 January 2007
Available online 2 February 2007
Abstract—A series of compounds originally derived from thalidomide were synthesized and evaluated. The most potent compounds
in this series, 5HPP-33 and compound 20, inhibited NF-jB activation in HeLa cells. Preliminary study indicated that the mechanism
of inhibition of NF-jB activation is through inhibition of its translocation from the cytoplasm to the nucleus.
Ó 2007 Elsevier Ltd. All rights reserved.
Nuclear factor kappa B (NF-jB) is a group of transcrip-
tion factors known to regulate immune and inflammatory
responses.1 The factors are homo and heterodimers from
the Rel protein family containing five members: NF-jB1
(p50/105), NF-jB2 (p52/100), Rel A (p65), Rel B, and
c-Rel. In its inactive form, the dimers are located in the
cytoplasm and sequestered with the inhibitory proteins
IjBs. Upon activation, the IjBs are phosphorylated by
IjB kinase (IKK) and liberated from the NF-jB dimers.
These dimers will enter the nucleus, where they enhance
the transcription of genes encoding for immune and
inflammatory response.
In addition to the many classes of compounds men-
tioned above, thalidomide (Fig. 1) was also reported
to be an inhibitor of NF-jB activation.24–28 Thalido-
mide, a drug discovered in the mid-1950s in a search
for better anti-epileptic agents, was found to possess lit-
tle anti-epileptic effect, but was marketed as a safe, non-
addictive sedative-hypnotic drug with good anti-emetic
activity. The drug was used extensively for morning
sickness during pregnancy until it was found to cause
significant fetal abnormalities.29 In the mid-1960s, tha-
lidomide was found to be very useful in the treatment
of leprosy leading to resurgence in interest in the drug
and its eventual approval in 1998 by the FDA for the
acute treatment of erythema nodosum leprosum2 and
recently for multiple myeloma. Today, thalidomide is
in clinical trials for, among other things, HIV ulcers
and wasting30–33 Crohn’s disease,34 rheumatoid arthri-
tis,35,36 chronic host-versus-graft disease,37 Behcet’s vas-
culitis,38 and cancer including AIDS Kaposi’s sarcoma39
and other solid tumors.40–43 Recently, a number of novel
thalidomide analogs have been reported.44–47 These ana-
logs can be classified into two groups: the Selective
Cytokine Inhibitory Drugs (SelCIDs), which possess
phosphodiesterase Type 4 (PDE4) inhibitory activities,
and the immunomodulatory drugs (IMiDs). Currently,
two IMiDs are in clinical trials for the treatment of can-
cers. Revlimid (Fig. 1) is now in phase III clinical trials
for multiple myeloma and metastatic melanoma, while
Actimid (Fig. 1) has entered a phase I/II trial for multi-
ple myeloma and a phase II trial for prostate cancer.
Recently, constitutive activation of NF-jB has been
described in a number of tumors.2–5 The activation
resulted in upregulation of growth factors, cytokines,
cell adhesion molecules, and antiapoptotic proteins
which mediate promotion, angiogenesis, metastasis,
and chemoresistance of tumor. Thus, inhibiting the acti-
vation of NF-jB is a viable strategy for both chemother-
apy as well as chemoprevention.
Many classes of compounds have been reported to
inhibit NF-jB activation which include natural products
such as genistein,6,7 caffeic acid8,9 and curcumin;10,11
glucocorticoids12 and nonsteroidal anti-inflammatory
agents;13–16 IKK17–21, and proteasome inhibitiors.22,23
Recently, we reported the anti-angiogenic activities of
several putative metabolites of thalidomide.48 Our ongo-
ing search for potent anti-angiogenic thalidomide
Keywords: Thalidomide; NF-jB; IKK; Nuclear translocation.
Corresponding author. Tel.: +1 614 688 0253; fax: +1 614 688
8556; e-mail: li.27@osu.edu
*
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.088

6032
E. J. Carcache de-Blanco et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6031–6035
NH2 NH2
H
H
H
O
O
O
O
O
N
N
N
N
O
N
O
N
O
O
O
O
Thalidomide
Actimid
Revlimid
1
R2
R = 4 or 5 CH , Cl, CO H, CO CH ,
R1
O
N
O
3
2
2
3
4
HO
NH , NO , NHCOCH ,
2
2
3
5
N
OH, OSO NH
2
2
2
3
R , R = H, Me, Et, Pr, iPr, iBu, F,
Cl, Br
R3
Compounds 1 - 20
O
O
5HPP-33
Figure 1. Structures of thalidomide, actimid, revlimid, 5HPP-33, and its analogs.
analogs revealed a compound, 5-hydroxy-(2,6-diisopro-
pylphenyl)-1H-isoindole-1,3-dione (5HPP-33, Fig. 1),
with a paclitaxel-like anti-microtubule mode of action.49
In addition, 5HPP-33 has been reported to have tumor
necrosis factor-a inhibitory activity in vitro.50–52 In the
evaluation of 5HPP-33 described here, we determined
that 5HPP-33 inhibits the activation of NF-jB through
inhibition of its translocation to the nucleus. Twenty
5HPP-33 analogs are evaluated. 5HPP-33 and one of
its analogs are approximately 4-fold more potent than
thalidomide as inhibitors of NF-jB activation.
5HPP-33 and its analogs were assayed for their inhibi-
tory activity toward IL-1a induced NF-jB activation
in HeLa cells, with (E)-3-(tert-butylphenylsulfonyl)-2-
propenenitrile (BAY-11-7085), a potent IKK inhibi-
tor,19,20 as the positive control. Normally, NF-jB is
present in the cytoplasm as homo or heterodimer with
members of the IjB inhibitor family. Upon phosphory-
lation and degradation of IjB, the nuclear localization
sequence becomes accessible and NF-jB translocates
to the nucleus. Thus, translocation from the cytoplasm
to the nucleus is a definitive measure of NF-jB activa-
tion. A quantitative NF-jB nuclear translocation assay
was used to measure the inhibitory activities of the com-
pounds.56 In brief, HeLa cells in a 96-well plate were
stimulated with IL-1a (5 ng/ml, 25 ll/well) with or with-
out inhibitors and the cells were incubated for 30 min.
The cells were fixed and incubated with anti-p65 anti-
body and then stained with Hoechst dye. The plates
were then scanned with fluorescent imaging microscope
(Axiovert 40 CFL, Carl Zeiss Microimaging, Inc.,
Thornwood, NY). The results are shown in Figure 3.
Immunofluorescence staining of p65 in HeLa cells
(unstimulated, PBS control) shows that p65 is mainly lo-
cated in cytoplasm with minimal amount in the nucleus.
Upon stimulation with IL-1a for 30 min, significant
amount of the p65 is translocated into the nucleus.
Thalidomide,53 actimid47, and 5HPP-3354 were synthe-
sized according to the reported procedures. The synthe-
ses of compounds 1–10 and 13–20 are shown in Figure
2. The syntheses of compounds 1–3 and 5–9 involved
the coupling of various substituted phthalic anhydrides
with substituted anilines. Compounds 4 and 10 were ob-
tained by catalytic hydrogenation of compounds 3 and
9, respectively. Condensation of 4-hydroxyphthalic acid
with substituted anilines yielded compounds 13–20.
Esterification of 5 with MeOH in acidic reflux yielded
compound 6. The syntheses of compounds 11 and 12
are shown in Figure 2. In brief, compound 11 was ob-
tained by sulfamoylation55 of 5HPP-33. Acetylation of
compound 10 yielded compound 12.
(1) R=H
(2) R=4-OH
(7) R=5-Cl
(8) R=5-CH3
(9) R=5-NO2
(10) R=5-NH2
O
O
4
4
R
5
R
5
a
(3) R=4-NO2
(4) R=4-NH2
(5) R=5-COOH
(6) R=5-CO2CH3
b
+
H2N
O
N
b
c
O
O
4 or 5 substituted
phthalic anhydrides
R2
R2
R3
O
(17) R2=R3=Et
(18) R2=R3=F
(19) R2=R3=Cl
(20) R2=R3=Br
(13) R2=H, R3=iPr
a
OH
HO
COOH
(14) R2=H, R3=iBu
(15) R2=H, R3=Pr
(16) R2=R3=Me
N
+
H2N
COOH
4 - Hydroxyphthalic acid
R3
O
Figure 2. Syntheses of compounds 1–10 and 13–20. Reagents and conditions: (a) AcOH, reflux, 5–7 h, 67–95% yield; (b) H2, 10% Pd/C, acetone,
reflux, 2 h, 88–90% yield; (c) MeOH, dil H2SO4, reflux, 12 h, 84% yield.

E. J. Carcache de-Blanco et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6031–6035
6033
O
O
H2NO2SO
HO
a
N
N
O
O
Compound 11
5HPP-33
O
O
N
H
CH3
O
N
H2N
b
N
O
O
Compound 10
Compound 12
Figure 3. Syntheses of compounds 11 and 12. Reagents and conditions: (a) ClSO2NH2/2,6-di-tertbutyl-4-methyl pyridine/DMF/rt/24 h;
(b) CH3COCl/Et3N/THF/rt/1 h.
Table 1. Inhibitory activity of thalidomide, actimid, BAY-11-7085, 5HPP-33, and its analogs on IL-1 induced nuclear translocation of NF-jB in
HeLa cells
R2
R1
O
4
5
N
R3
O
Compound
R1
R2
R3
Inhibition of p50/p65 translocation IC50 (lM)
Thalidomide
Actimid
—
—
—
—
—
—
2.04
1.27
0.1
BAY-11-7085
5HPP-33
—
5-OH
H
—
—
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
H
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
Pr
0.53
>50
4.95
>50
>50
>50
>50
>50
>50
>50
29.5
>50
>50
>50
>50
>50
>50
>50
>50
>50
0.43
1
2
4-OH
4-NO2
4-NH2
5-CO2H
5-CO2CH3
5-Cl
3
4
5
6
7
8
5-CH3
5-NO2
5-NH2
5-OSO2NH2
5-NHCOCH3
5-OH
5-OH
5-OH
5-OH
5-OH
5-OH
5-OH
5-OH
9
10
11
12
13
14
15
16
17
18
19
20
H
H
Me
Et
Me
Et
F
Cl
F
Cl
Br
Br
BAY-11-7085 (an IKK inhibitor), thalidomide, 5HPP-
33, and their analogs inhibit the nuclear translocation
of p65 (Fig. 3).
pounds to reduce 50% of the nuclear minus cytoplasmic
fluorescence in the cells. The inhibitory activities of the
compounds are shown in Table 1.
In the IL-1a stimulated cells, the amount of nuclear
fluorescence is increased, while the cytoplasmic fluores-
cence markedly is decreased. The nuclear minus fluores-
cence is high. The inhibitory activities of the compounds
(IC50) are designated as the concentration of the com-
Thalidomide has been reported to be an inhibitor of
NF-jB activation.24–28 In this study, we demonstrated
that thalidomide inhibited the nuclear translocation of
NF-jB in IL-1a activated HeLa cells with an IC50 of
2.04 lM (Table 1). In addition, we also demonstrated

6034
E. J. Carcache de-Blanco et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6031–6035
Figure 4. IL-1 induced NF-jB nuclear translocation. Representative fields of p65 fluorescence are shown in HeLa cells that are unstimulated (PBS
control), IL-1 stimulated, and IL-1 stimulated in the presence of BAY-11-7085, thalidomide, actimid, 5HPP-33, and compounds 2 and 20 (please
refer Table 1 for the structures of compounds 2 and 20).
for the first time that actimid, a thalidomide analog cur-
rently in clinical trial for multiple myeloma,57,58 also
inhibited NF-jB activation with a slightly higher poten-
cy than thalidomide (IC50—1.27 lM, Table 1). 5HPP-
33, a thalidomide analog reported to have tumor necro-
sis factor-a (TNF-a) inhibitory activity, in vitro is four
times more potent than thalidomide as an inhibitor of
NF-jB activation (IC50—0.53 lM, Table 1). Thus, we
conducted a detailed structure–activity relationship
study of 5HPP-33 in regard to its ability to inhibit
NF-jB activation. Twenty 5HPP-33 analogs (com-
pounds 1–20) were synthesized with modifications on
2,6-diisopropyl phenyl ring or on the phthalimide ring
(Table 1). The 2,6-diisopropyl groups in 5HPP-33 are
necessary but not essential for activity. Replacing one
of the isopropyl groups with a H (compounds 13–15)
or substituting the 2,6-diisopropyl groups with Me, Et,
F or Cl (compounds 16–19) resulted in elimination of
inhibitory activity. However, 2,6-dibromo analog of
5HPP-33 (compound 20) is as active as 5HPP-33
(IC50—0.43 lM, Table 1).
activity. Preliminary studies indicated that the active
analogs inhibit NF-jB activation through inhibition of
its translocation from the cytoplasm to the nucleus.
We are currently investigating the molecular target(s)
of the inhibition.
References and notes
1. Ghosh, S.; May, M. J.; Kopp, E. B. Annu. Rev. Immunol.
1998, 16, 225.
2. Bottero, V.; Busuttil, V.; Loubat, A.; Magne, N.; Fischel,
J. L.; Milano, G.; Peyron, J. F. Cancer Res. 2001, 61, 7785.
3. Gilmore, T.; Gapuzan, M. E.; Kalaitzidis, D.; Starczy-
nowski, D. Cancer Lett. 2002, 181, 1.
4. Yang, J.; Richmond, A. Cancer Res. 2001, 61, 4901.
5. Romieu-Mourez, R.; Landesman-Bollag, E.; Seldin, D.
C.; Traish, A. M.; Mercurio, F.; Sonenshein, G. E. Cancer
Res. 2001, 61, 3810.
6. Li, Y.; Ellis, K. L.; Ali, S.; El-Rayes, B. F.; Nedeljkovic-
Kurepa, A.; Kucuk, O.; Philip, P. A.; Sarkar, F. H.
Pancreas 2004, 28, e90.
7. Gong, L.; Li, Y.; Nedeljkovic-Kurepa, A.; Sarkar, F. H.
Oncogene 2003, 22, 4702.
The 5-OH group in 5HPP-33 is essential for activity.
Substituting the 5-OH group with H (compound 1),
COOH (compound 5), CO2CH3 (compound 6), Cl
(compound 7), CH3 (compound 8), NO2 (compound
9), OSO2NH2 (compound 11), and NHCOCH3 (com-
pound 12) all resulted in the elimination of inhibitory
activity. The inhibitory activity is decreased by 500-fold
when the 5-OH is substituted with a 5-NH2 group (com-
pound 10). Transferring the OH group of 5HPP-33 from
the 5 to the 4 position (compound 2) resulted in 10-fold
reduction in inhibitory activity. Substituting the 4-OH in
compound 2 with NO2 or NH2 all resulted in the elimi-
nation of the inhibitory activity of NF-jB (Fig. 4).
8. Natarajan, K.; Singh, S.; Burke, T. R., Jr.; Grunberger,
D.; Aggarwal, B. B. Proc. Natl. Acad Sci. U.S.A. 1996, 93,
9090.
9. Watabe, M.; Hishikawa, K.; Takayanagi, A.; Shimizu, N.;
Nakaki, T. J. Biol. Chem. 2004, 279, 6017.
10. Li, L.; Aggarwal, B. B.; Shishodia, S.; Abbruzzese, J.;
Kurzrock, R. Cancer 2004, 101, 2351.
11. Aggarwal, S.; Takada, Y.; Singh, S.; Myers, J. N.;
Aggarwal, B. B. Int. J. Cancer 2004, 111, 679.
12. Brown, K.; Gerstberger, S.; Carlson, L.; Franzoso, G.;
Siebenlist, U. Science 1995, 267, 1485.
13. Yin, M. J.; Yamamoto, Y.; Gaynor, R. B. Nature 1998,
396, 77.
14. Yamamoto, Y.; Yin, M. J.; Lin, K. M.; Gaynor, R. B.
J. Biol. Chem. 1999, 274, 27307.
In conclusion, we have discovered a series of compounds
derived from thalidomide with potent NF-jB inhibitory
15. Wahl, C.; Liptay, S.; Adler, G.; Schmid, R. M. J. Clin.
Invest. 1998, 101, 1163.

E. J. Carcache de-Blanco et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6031–6035
6035
16. Weber, C. K.; Liptay, S.; Wirth, T.; Adler, G.; Schmid, R.
M. Gastroenterology 2000, 119, 1209.
17. Olsen, L. S.; Hjarnaa, P. J.; Latini, S.; Holm, P. K.;
Larsson, R.; Bramm, E.; Binderup, L.; Madsen, M. W.
Int. J. Cancer 2004, 111, 198.
37. Koc, S.; Leisenring, W.; Flowers, M. E.; Anasetti, C.;
Deeg, H. J.; Nash, R. A.; Sanders, J. E.; Witherspoon, R.
P.; Appelbaum, F. R.; Storb, R.; Martin, P. J. Blood 2000,
96, 3995.
38. Yazici, H.; Fresko, I.; Hamuryudan, V.; Mat, C.; Meliko-
glu, M.; Ozyazgan, Y.; Tuzun, Y.; Yurdakul, S. Adv. Exp.
Med. Biol. 1999, 455, 135.
39. Little, R. F.; Wyvill, K. M.; Pluda, J. M.; Welles, L.;
Marshall, V.; Figg, W. D.; Newcomb, F. M.; Tosato, G.;
Feigal, E.; Steinberg, S. M.; Whitby, D.; Goedert, J. J.;
Yarchoan, R. J. Clin. Oncol. 2000, 18, 2593.
40. Patt, Y. Z.; Hassan, M. M.; Lozano, R. D.; Ellis, L. M.;
Peterson, J. A.; Waugh, K. A. Am. J. Clin. Oncol. 2000,
23, 319.
41. Eisen, T.; Boshoff, C.; Mak, I.; Sapunar, F.; Vaughan, M.
M.; Pyle, L.; Johnston, S. R.; Ahern, R.; Smith, I. E.;
Gore, M. E. Br. J. Cancer 2000, 82, 812.
18. Hovstadius, P.; Larsson, R.; Jonsson, E.; Skov, T.; Kiss-
meyer, A. M.; Krasilnikoff, K.; Bergh, J.; Karlsson, M. O.;
Lonnebo, A.; Ahlgren, J. Clin. Cancer Res. 2002, 8, 2843.
19. Mabuchi, S.; Ohmichi, M.; Nishio, Y.; Hayasaka, T.;
Kimura, A.; Ohta, T.; Kawagoe, J.; Takahashi, K.; Yada-
Hashimoto, N.; Seino-Noda, H.; Sakata, M.; Motoyama,
T.; Kurachi, H.; Testa, J. R.; Tasaka, K.; Murata, Y. Clin.
Cancer Res. 2004, 10, 7645.
20. Mabuchi, S.; Ohmichi, M.; Nishio, Y.; Hayasaka, T.;
Kimura, A.; Ohta, T.; Saito, M.; Kawagoe, J.; Takahashi,
K.; Yada-Hashimoto, N.; Sakata, M.; Motoyama, T.;
Kurachi, H.; Tasaka, K.; Murata, Y. J. Biol. Chem. 2004,
279, 23477.
42. Fine, H. A.; Figg, W. D.; Jaeckle, K.; Wen, P. Y.; Kyritsis,
A. P.; Loeffler, J. S.; Levin, V. A.; Black, P. M.; Kaplan,
R.; Pluda, J. M.; Yung, W. K. J. Clin. Oncol. 2000, 18,
708.
21. Pierce, J. W.; Schoenleber, R.; Jesmok, G.; Best, J.;
Moore, S. A.; Collins, T.; Gerritsen, M. E. J. Biol. Chem.
1997, 272, 21096.
22. Adams, J.; Palombella, V. J.; Elliott, P. J. Invest. New
Drugs 2000, 18, 109.
23. Hideshima, T.; Chauhan, D.; Richardson, P.; Mitsiades,
C.; Mitsiades, N.; Hayashi, T.; Munshi, N.; Dang, L.;
Castro, A.; Palombella, V.; Adams, J.; Anderson, K. C.
J. Biol. Chem. 2002, 277, 16639.
43. Stebbing, J.; Benson, C.; Eisen, T.; Pyle, L.; Smalley, K.;
Bridle, H.; Mak, I.; Sapunar, F.; Ahern, R.; Gore, M. E.
Br. J. Cancer 2001, 85, 953.
44. Corral, L. G.; Muller, G. W.; Moreira, A. L.; Chen,
Y.; Wu, M.; Stirling, D.; Kaplan, G. Mol. Med. 1996,
2, 506.
24. Keifer, J. A.; Guttridge, D. C.; Ashburner, B. P.; Baldwin,
A. S., Jr. J. Biol. Chem. 2001, 276, 22382.
25. Yagyu, T.; Kobayashi, H.; Matsuzaki, H.; Wakahara, K.;
Kondo, T.; Kurita, N.; Sekino, H.; Inagaki, K.; Suzuki,
M.; Kanayama, N.; Terao, T. J. Clin. Endocrinol. Metab.
2005, 90, 3017.
45. Muller, G. W.; Corral, L. G.; Shire, M. G.; Wang, H.;
Moreira, A.; Kaplan, G.; Stirling, D. I. J. Med. Chem.
1996, 39, 3238.
46. Corral, L. G.; Haslett, P. A.; Muller, G. W.; Chen, R.;
Wong, L. M.; Ocampo, C. J.; Patterson, R. T.; Stirling, D.
I.; Kaplan, G. J. Immunol. 1999, 163, 380.
26. Majumdar, S.; Lamothe, B.; Aggarwal, B. B. J. Immunol.
2002, 168, 2644.
27. Moreira, A. L.; Corral, L. G.; Ye, W.; Johnson, B.;
Stirling, D.; Muller, G. W.; Freedman, V. H.; Kaplan, G.
AIDS Res. Hum. Retroviruses 1997, 13, 857.
47. Muller, G. W.; Chen, R.; Huang, S. Y.; Corral, L.
G.; Wong, L. M.; Patterson, R. T.; Chen, Y.; Kaplan,
G.; Stirling, D. I. Bioorg. Med. Chem. Lett. 1999, 9,
1625.
48. Marks, M. G.; Shi, J.; Fry, M. O.; Xiao, Z.; Trzyna, M.;
Pokala, V.; Ihnat, M. A.; Li, P. K. Biol. Pharm. Bull. 2002,
25, 597.
28. Moreira, A. L.; Friedlander, D. R.; Shif, B.; Kaplan, G.;
Zagzag, D. J. Neurooncol. 1999, 43, 109.
29. Lenz, W.; Knapp, K. Arch. Environ. Health 1962, 5, 100.
30. Gorin, I.; Vilette, B.; Gehanno, P.; Escande, J. P. Lancet
1990, 335, 1343.
49. Li, P. K.; Pandit, B.; Sackett, D. L.; Hu, Z.; Zink, J.; Zhi,
J.; Freeman, D.; Robey, R. W.; Werbovetz, K.; Lewis, A.;
Li, C. Mol. Cancer Ther. 2006, 5, 450.
31. Reyes-Teran, G.; Sierra-Madero, J. G.; Martinez del
Cerro, V.; Arroyo-Figueroa, H.; Pasquetti, A.; Calva, J.
J.; Ruiz-Palacios, G. M. Aids 1996, 10, 1501.
50. Hashimoto, Y. Curr. Med. Chem. 1998, 5, 163.
51. Miyachi, H.; Azuma, A.; Hashimoto, Y. Yakugaku Zasshi
1997, 117, 91.
32. Marriott, J. B.; Cookson, S.; Carlin, E.; Youle, M.;
Hawkins, D. A.; Nelson, M.; Pearson, M.; Vaughan, A.
N.; Gazzard, B.; Dalgleish, A. G. AIDS Res. Hum.
Retroviruses 1997, 13, 1625.
52. Hashimoto, Y. Bioorg. Med. Chem. 2002, 10, 461.
53. Shah, J. H.; Swartz, G. M.; Papathanassiu, A. E.; Treston,
A. M.; Fogler, W. E.; Madsen, J. W.; Green, S. J. J. Med.
Chem. 1999, 42, 3014.
33. Jacobson, J. M.; Spritzler, J.; Fox, L.; Fahey, J. L.;
Jackson, J. B.; Chernoff, M.; Wohl, D. A.; Wu, A. W.;
Hooton, T. M.; Sha, B. E.; Shikuma, C. M.; MacPhail, L.
A.; Simpson, D. M.; Trapnell, C. B.; Basgoz, N. J. Infect.
Dis. 1999, 180, 61.
34. Ehrenpreis, E. D.; Kane, S. V.; Cohen, L. B.; Cohen, R.
D.; Hanauer, S. B. Gastroenterology 1999, 117, 1271.
35. Raza, A. Microsc. Res. Tech. 2000, 50, 229.
36. Keesal, N.; Wasserman, M. J.; Bookman, A.; Lapp, V.;
Weber, D. A.; Keystone, E. C. J. Rheumatol. 1999, 26,
2344.
54. Shibata, Y.; Sasaki, K.; Hashimoto, Y.; Iwasaki, S. Chem.
Pharm. Bull. (Tokyo) 1996, 44, 156.
55. Li, P. K.; Chu, G. H.; Guo, J. P.; Peters, A.; Selcer, K. W.
Steroids 1998, 63, 425.
56. Ding, G. J.; Fischer, P. A.; Boltz, R. C.; Schmidt, J. A.;
Colaianne, J. J.; Gough, A.; Rubin, R. A.; Miller, D. K.
J. Biol. Chem. 1998, 273, 28897.
57. Teo, S. K. Aaps. J. 2005, 7, E14.
58. Schey, S. A.; Fields, P.; Bartlett, J. B.; Clarke, I. A.;
Ashan, G.; Knight, R. D.; Streetly, M.; Dalgleish, A. G.
J. Clin. Oncol. 2004, 22, 3269.