4316
S. C. Jonnalagadda et al. / Tetrahedron Letters 50 (2009) 4314–4317
oxyglyceryl carboranes as targeted molecules for LDL receptor and
liposomal encapsulation. Some of these molecules were evaluated
for cytotoxicity in two brain tumor cell lines, and were found to be
O
O
O
(i)
NEt3, DMAP
82%
17
non-cytotoxic even at high concentration (50 lM), thus fulfilling
CHO
the basic requirement for utility as BNCT agents. The present work
should be of interest to organic, inorganic, and medicinal chemists
due to the flexibility of the multicomponent coupling reactions in
providing wide array of carboranyl structural entities.
H
H
H
16
(ii) RNC,
HO
2
Acknowledgments
We thank the Departments of Chemistry and Biochemistry,
Rowan University, and University of Minnesota Duluth for the
resources and funding. Partial support for this work was provided
by research grants from the National Institutes of Health
(CA129993) (VRM) and Whiteside Institute for Clinical Research
(VRM).
H
H
N
R
O
H
H
O
O
O
18a, R = Bn, 70%
18b
i
= CH
= BH
O
, R = Pr, 68%
Scheme 2. Preparation of cholesterol carborane conjugates.
References and notes
1. (a) Zhu, Y.; Yan, K. C.; Maguire, J. A.; Hosmane, N. S. Curr. Chem. Biol. 2007, 1,
141; (b) Armstrong, A. F.; Valliant, J. F. Dalton Trans. 2007, 4240; (c) Wu, G.;
Barth, R. F.; Yang, W.; Lee, R. J.; Tjarks, W.; Backer, M. V.; Backer Joseph, M.
Anticancer Agents Med. Chem. 2006, 6, 167; (d) Barth, R. F.; Coderre, J. A.;
Vicente, M.; Graca, H.; Blue, T. E. Clin. Cancer Res. 2005, 11, 3987; (e) Soloway, A.
H.; Tjarks, W.; Barnum, B. A.; Rong, F. G.; Barth, R. F.; Codogni, I. M.; Wilson, J. G.
Chem. Rev. 1998, 98, 1515.
2. Banfi, L.; Riva, R. Org. React. 2005, 65. and references cited therein.
3. (a) Peacock, G.; Sidwell, R.; Pan, G.; Oie, S.; Lu, D. R. J. Pharm. Sci. 2004, 93, 13;
(b) Alanazi, F.; Li, H.; Halpern, D. S.; Oie, S.; Lu, D. R. Int. J. Pharm. 2003, 255, 189;
(c) Ji, B.; Peacock, G.; Lu, D. R. Bioorg. Med. Chem. Lett. 2002, 12, 2455; (d)
Maletínska, L.; Blakely, E. A.; Bjornstad, K. A.; Deen, D. F.; Knoff, L. J.; Forte, T. M.
Cancer Res. 2000, 60, 2300.
4. For select few references: (a) Lee, J. D.; Ueno, M.; Miyajima, Y.; Nakamura, H.
Org. Lett. 2007, 9, 323; (b) Li, T.; Hamdi, J.; Hawthorne, M. F. Bioconjugate Chem.
2006, 17, 15–20; (c) Feakes, D. A.; Spinier, J. K.; Harris, F. R. Tetrahedron 1999,
55, 11177; (d) Lum, D. F.; McQuaid, K. R.; Gilbertson, V. L.; Hughes-Fulford, M.
Int. J. Cancer 1999, 83, 162.
5. (a) Antimisiaris, S. G.; Kallinteri, P.; Fatouros, D. G. Pharm. Manuf. Handbook
2008, 443; (b) Torchilin, V. Exp. Opin. Drug Delivery 2008, 5, 1003.
6. (a) Zhu, Y.; Nong, L. C.; Zhao, L. C.; Widjaja, E.; Hwei, C. Si.; Wang, C.; Tan, J.; Van
Meurs, M.; Hosmane, N. S.; Maguire, J. A. Organometallics 2009, 28, 60; (b)
Meshcheryakov, V. I.; Zheng, C.; Kudinov, A. R.; Maguire, J. A.; Hosmane, N. S.
Organometallics 2008, 27, 5033; (c) Zhu, Y.; Koh, C.; Peng, A. T.; Emi, A.;
Monalisa, W.; Loo, K.-J. L.; Hosmane Narayan, S.; Maguire, J. A. Inorg. Chem.
2008, 47, 5756; (d) Dash, B. P.; Satapathy, R.; Maguire, J. A.; Hosmane, N. S. Org.
Lett. 2008, 10, 2247; (e) Valliant, J. F.; Guenther, K. J.; King, A. S.; Morel, P.;
Schaffer, P.; Sogbein, O. O.; Stephenson, K. A. Coord. Chem. Rev. 2002, 232, 173.
7. Reddy, V. J.; Roforth, M. M.; Tan, C.; Reddy, M. V. R. Inorg. Chem. 2007, 47, 381.
8. Dozzo, P.; Kasar, R. A.; Kahl, S. B. Inorg. Chem. 2005, 44, 8053.
Similarly, the long-chain alkyl carborane conjugates 20a–b
were envisioned as the potential substrates for liposomal encapsu-
lation. Thus the reaction of bishexadecyl-substituted alcohol 19
with succinic anhydride provided the monosuccinate ester which
upon reaction with carborane aldehyde 2 and benzyl or isopropyl
isonitrile provided the lipophilic carboranes 20a11 and 20b, respec-
tively (Scheme 3).
After synthesizing various carboranyl acyloxy amides, we car-
ried out the cytotoxicity studies of the representative molecules
4–15. Since the BNCT modality works better on localized cancers
(such as brain tumors) than systemic treatment, we chose two hu-
man brain cancer cell lines A-172 and U-87 for the current studies.
Cells were treated with compounds at a high concentration
(50 lM), dissolved in DMSO for 18 h. Cell viability was determined
using a colorimetric MTS assay. All the compounds tested were
found to be non-toxic12 to both the cancer cell lines thus fulfilling
the primary criteria as potential BNCT agents. Future studies would
include advanced biological studies especially involving LDL and
liposomal encapsulation studies to determine the efficacy of these
molecules as potential BNCT agents.
3. Conclusions
9. Preparation of N-benzyl-a-carboranyl-a-benzoyloxy-acetamide 4: To a stirred
In conclusion, we have synthesized several
acyloxy-amides as valuable intermediates for potential BNCT
applications. We have also prepared cholesterol and bishexadecyl-
a-carboranyl-a-
suspension of o-carborane aldehyde (0.34 g, 2.0 mmol), and benzoic acid
(0.25 g, 2.1 mmol) in 2.0 mL water was added benzyl isonitrile (0.3 mL,
2.4 mmol), and it was stirred overnight. Upon completion (TLC), the reaction
mixture was worked up with ethyl acetate and satd NaHCO3. The combined
organic layers were dried (MgSO4), concentrated in vacuo, and triturated with
hexane and ether to obtain 0.65 g (80% yield) of 4 as a white solid. Mp 192–
194 °C (C18H25B10O3N requires: C, 52.54; H, 6.12; N, 3.40. Found: C, 52.96; H,
6.22; N, 3.31); 1H NMR (500 MHz, CDCl3): 7.34–7.33 (m, 3H), 7.20–7.25 (m,
5H), 7.08–7.10 (m, 2H), 6.15 (t, J = 5.5 Hz, 1H), 5.60 (s, 1H), 4.25 (dd, J = 6.0,
15.0 Hz, 1H), 4.16 (dd, J = 5.5. 14.5 Hz, 1H), 4.15 (br s, 1H), 3.72 (s, 2H), 1.74–
2.90 (m, 10H); 13C NMR (125 MHz, CDCl3): 168.5, 164.5, 136.6, 132.6, 129.4,
129.3, 129.2, 128.3, 128.2, 128.0, 71.8, 71.3, 59.2, 43.8, 41.3; ESI-MS: 401
[(MÀBH)+, 100%].
O
O
O
NEt3, DMAP
85%
O
(i)
17
CHO
O
OH
10. Preparation of cholesteryl carborane conjugate 18a: Procedure similar to that of 4
(70% yield). Mp 98–100 °C (C42H69B10O5N requires: C, 64.99; H, 8.96; N, 1.80.
Found: C, 64.74; H, 8.99; N, 1.84); 1H NMR (400 MHz, CDCl3): 1H NMR
(500 MHz, CDCl3): d 7.44 (t, J = 7.3 Hz, 1H), 7.23–7.34 (m, 5H), 5.64 (s, 1H), 5.41
(dd, J = 2.5, 6.0 Hz, 1H), 4.28–4.54 (m, 4H), 2.61–2.74 (m, 4H), 2.19–2.31 (m,
3H), 1.96–2.04 (m, 3H), 1.74–2.90 (m, 10H), 1.66–1.90 (m, 4H), 1.03–1.62 (m,
18H), 1.00 (s, 3H), 0.92 (d, J = 8.0 Hz, 3H), 0.87 (d, J = 2.0 Hz, 3H), 0.85 (d,
J = 2.0 Hz, 3H), 0.68 (s, 3H); 13C NMR (100 MHz, CDCl3): d 172.9, 169.9, 164.7,
139.5, 137.2, 128.9, 128.1, 128.0, 123.2, 77.4, 75.6, 72.0, 71.0, 59.1, 57.0, 56.4,
50.4, 43.8, 42.6, 40.0, 39.8, 38.2, 37.1, 36.8, 36.4, 36.0, 32.2, 32.1, 29.6, 28.5,
28.2, 27.9, 24.5, 24.0, 23.0, 22.8, 21.3, 19.5, 19.0, 12.1; ESI-MS: 799 [(M+Na)+,
100%].
(ii) RNC,
19
2
O
O
O
H
N
O
R
O
20a
20b
, R = Bn, 71%
, R = Pr, 73%
O
O
i
= CH
= BH
11. Preparation of long alkyl chain carborane conjugate 20a: Procedure similar to
that of 4 (71% yield). Low-melting waxy solid (C51H97B10O7N requires: C, 64.85;
H, 10.35; N, 1.48. Found: C, 64.72; H, 10.44; N, 1.55); 1H NMR (500 MHz,
CDCl3): 1H NMR (500 MHz, CDCl3): d 7.33 (t, J = 7.0 Hz, 1H), 7.18–7.28 (m, 5H),
Scheme 3. Preparation of lipophilic carborane conjugates.