K. M. Smith et al.
SHORT COMMUNICATION
studies and conclusions should be subjected to further scru-
tiny with regard to the regiochemical structure of the conju-
gate. We can visualize circumstances in which the usually
3
presumed 17 -product might result from a conjugation re-
action of chlorin e , but this would be enhanced by use of
6
an excess of DCC and proceed via doubly activated com-
pounds such as 17 and 18.
Experimental Section
Synthesis of Anhydride 16: Chlorin e
EDC (32 mg, 0.17 mmol) and DMAP (9.0 mg, 0.07 mmol) were
dissolved in CH Cl (1.5 mL) and stirred for 2 h under N at room
6
(1) (100 mg, 0.17 mmol),
2
2
2
temperature. Excess ethereal diazomethane was then added to the
mixture and after 30 min stirring it was evaporated and chromato-
graphed on a silica gel thick layer plate, eluting with DCM/MeOH
(10:1). The brown product (15) was collected (62 mg, 63%) and
Figure 5. X-ray structure (absolute configuration) of the chlorin e
6
1
2
3
13 :15 -anhydride 17 -methyl ester (16); one of two independent
molecules, shown with 50% ellipsoids.
crystallized from DCM/hexane (1:3), m.p. Ͼ 260 °C. MALDI-TOF
+
calcd. for C35
5
(
H
36
N
4
+
O
5
: 592.2686 or 593.2764 [M + H] , found
–1
–1
93.2750 [M + H] . UV/Vis (DMSO): λmax nm (ε /m cm ) 411
1
97600), 507 (9500), 542 (10300), 615 (7000), 669 (33100); H NMR
CDCl , 400 MHz): δ = 9.57 (s, 1 H), 9.29 (s, 1 H), 8.49 (s, 1 H),
.92 (dd, J = 18.0, 11.6 Hz, 1 H), 6.31 (d, J = 18.3 Hz, 1 H), 6.16
(
3
7
(
(
d, J = 12.0 Hz, 1 H), 5.40 (m, 2 H), 4.53 (d, J = 9.5 Hz, 1 H), 4.38
m, 1 H), 4.16 (m, 1 H), 3.72–3.67 (m, 8 H), 3.37 (s, 3 H), 3.19 (s,
3
6
H), 2.63 (m, 1 H), 2.34 (m, 1 H), 2.01 (m, 1 H), 1.74 (d, J =
.1 Hz, 3 H), 1.69 (t, J = 7.6 Hz, 3 H), –0.40 (br, 2 H) ppm.
CCDC-1046544 (for 15), -1046545 (for 8), -1046546 (for 6),
1046547 (for 16) contain the supplementary crystallographic data
-
for the low-temperature structure determinations in this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Acknowledgments
This work was supported by the US National Institutes of Health
(
NIH) (grant number CA132861). H. C. was on leave from the De-
partment of Medicinal Chemistry, Fourth Military Medical Uni-
versity, Xi’an, Shaanxi, P. R. China.
[
[
1] T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kes-
sel, M. Korbelik, J. Moan, Q. Peng, J. Natl. Cancer Inst. 1998,
Finally, the anhydride 16 was treated with l-aspartic acid
90, 889–905.
dimethyl ester and triethylamine in the absence of a cou-
2] R. K. Pandey, G. Zheng, in: The Porphyrin Handbook, vol. 6
(Eds.: K. M. Kadish, K. M. Smith, R. Guilard), Academic
Press, Boston, 2000, p. 157–230.
2
pling agent, and gave the 15 -conjugate. Treatment with di-
azomethane gave the known tetramethyl ester of Talapor-
[
[
3] M. G. H. Vicente, Curr. Med. Chem., Anti-Cancer Agents 2001,
fin, in 75% yield from chlorin e , and the product was iden-
6
175–194.
tical in all respects with an authentic sample.
4] J. D. Spikes, J. C. Bommer, in: Chlorophylls (Ed.: H. Scheer),
CRC Press, Boston, 1996, p. 1181–1204.
We conclude that conjugation of chlorin e (1) with one
6
equivalent of a coupling agent such as DCC or EDC and a [5] L.-M. W. Song, K. K. Wang, A. R. Zinsmeister, Cancer 1998,
2
82, 421–427.
base such as DMAP should result in formation of the 15 -
1
2
[6] J. C. Bommer, B. F. Ogden, US Patent 1987, 4,693,885.
conjugate of chlorin e via the corresponding 13 :15 -an-
6
[7] S. Gomi, T. Nishizuka, O. Ushiroda, N. Uchida, H. Takahashi,
hydride; this has been shown to be categorically true for
S. Sumi, Heterocycles 1998, 48, 2231–2243.
conjugations with aspartic acid, and in the numerous conju- [8] J. A. Hargus, F. R. Fronczek, M. G. H. Vicente, K. M. Smith,
gations reported in this paper. A majority of reported con-
J. Photochem. Photobiol. A: Chem. 2007, 83, 1006–1015.
9] R. G. W. Jinadasa, X. Hu, M. G. H. Vicente, K. M. Smith, J.
Med. Chem. 2011, 54, 7464–7476.
[
[
jugations of chlorin e have either ignored the site of conju-
6
3
[14]
gation, or it has been assumed to give the 17 -conjugate
10] K. M. Smith, D. A. Goff, D. J. Simpson, J. Am. Chem. Soc.
in accord with the original patent[ and numerous subse-
6]
1985, 107, 4946–4954.
[
13]
quent publications, even including two of our own. Such [11] I. Fleming, Nature 1967, 216, 151–152.
3
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