5138
C.J.P. Monteiro et al. / Tetrahedron 64 (2008) 5132–5138
4.5.15. 5,10,15,20-Tetrakis(2-fluoro-5-N-piperidylsulfamoyl-
Acknowledgements
phenyl)porphyrin (6e)
Initially, 0.12 mL (1.2 mmol) of piperidine, was added 6 (108 mg;
.1 mmol) previously dissolved in dichloromethane (50 mL). Fol-
The authors thank C aˆ mara Municipal de Coimbra, Comiss a˜ o de
Coordenaç a˜ o e Desenvolvimento Regional do Centro, Bluepharma
SA, Programa Operacional da Regi a˜ o Centro, Medida 1.5 Feder, FCT
(PTDC/QUI/66015/2006) for financial support. C.J.P.M., S.M.A.P.,
A.V.C.S. and G.F.F.S. thank C aˆ mara Municipal de Coimbra for grants.
C.J.P.M. also thanks FCT for a PhD grant SFRH/BD/37652/2007.
0
lowing the procedure described above, the solid of 6e was obtained
ꢂ
þ
ꢁ
(
113 mg, 82%). Mp 228–229 C; MS (MALDI-TOF), m/z: 1274.3 M ;
1
H NMR (300 MHz, CDCl
H, Ph–H) 8.29–8.23 (m, 4H, Ph–H), 7.73–7.68 (m, 4H, Ph–H), 3.22
br s, 16H, –N(CH (CH ), 1.60 (br s, 24H, –N(CH (CH
), ꢀ2.83
s, 2H, NH); 19F NMR (282 MHz, CDCl
3
) d ppm 8.81 (s, 8H, b-H), 8.62–8.55 (m,
4
(
(
2
)
2
2
)
3
2
)
2
2 3
)
3
) d ppm ꢀ127.05 (m, 4F, o-F);
References and notes
ꢀ
1
ꢀ1
5
UV–vis (toluene)
l
max/nm (3/M cm
)
418 (4.6ꢄ10 ), 511
4
3
4
3
(
3.6ꢄ10 ), 544 (7.2ꢄ10 ), 587 (1.1ꢄ10 ), 643 (1.8ꢄ10 ). Anal. Calcd
1. Vicente, M. G. H. Curr. Med. Chem. Anticancer Agents 2001, 1, 175–194.
2. Pineiro, M.; Carvalho, A. L.; Pereira, M. M.; Gonsalves, A. M. d’A. R.; Arnaut, L. G.;
for C64
H F
62 4
N
8
O
8
S
4
: C, 60.27; H, 4.90; N, 8.79; S, 10.06. Found: C,
Formosinho, S. J. Chem.dEur. J. 1998, 4, 2299–2307.
6
0.08; H, 4.67; N, 8.54; S, 10.75.
3
4
. Sergeeva, N. N.; Senge, O. M. Tetrahedron Lett. 2006, 47, 6169–6172.
. Pineiro, M.; Pereira, M. M.; Gonsalves, A. M. d’A. R.; Arnaut, L. G.; Formosinho,
S. J. J. Photochem. Photobiol., A 2001, 138, 147–157.
4
.6. 1-Octanol/water partition coefficients
5. Chen, Y.; Li, G.; Pandey, R. K. Curr. Org. Chem. 2004, 8, 1105–1134.
6. Pineiro, M.; Gonsalves, A. M. d’A. R.; Pereira, M. M.; Formosinho, S. J.; Arnaut, L.
G. J. Phys. Chem. A 2002, 106, 3787–3795.
. Detty, M. R.; Gibson, S. L.; Wagner, S. J. J. Med. Chem. 2004, 47, 3897–3915.
8. Nyman, E. S.; Hynninen, P. H. J. Photochem. Photobiol., B 2004, 73, 1–28.
9. Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Nat. Rev. Cancer 2003, 3, 380–387.
0. Allen, C. M.; Sharman, W. M.; van Lier, J. E. J. Porphyrins Phthalocyanines 2001, 5,
The 1-octanol/water partition coefficients were measured fol-
7
3
8–40
lowing shake-flask method with minor modifications.
sulfonamide halogenated porphyrin (8ꢄ10 mmol) is dissolved in
The
ꢀ2
1
5
mL of 1-octanol previously saturated with a solution of PBS
161–169.
pH¼7.4. The same volume (5 mL) of a PBS solution, saturated with
11. Azenha, E. G.; Serra, A. C.; Pineiro, M.; Pereira, M. M.; de Melo, J. S.; Arnaut, L. G.;
Formosinho, S. J.; Gonsalves, A. M. d’A. R. Chem. Phys. 2002, 280, 177–190.
1
3
-octanol, was added to the 1-octanol phase, mixed vigorously for
min and then the phases were separated by centrifugation
12. Dabrowski, J. M.; Pereira, M. M.; Arnaut, L. G.; Monteiro, C. J. P.; Peixoto, A. F.;
Karocki, A.; Urbanska, K.; Stochel, G. Photochem. Photobiol. 2007, 83, 897–903.
13. Osterloh, J.; Vicente, M. G. H. J. Porphyrins Phthalocyanines 2002, 6, 305–324.
14. Sharman, W. M.; van Lier, J. E.; Allen, C. M. Adv. Drug. Deliv. Rev. 2004, 56, 53–76.
(
4000 rpm, 2 min). Longer contact times between the phases
were tested and shown not to influence the final results. One
aliquot of 3 mL was taken from each phase and diluted with
ethanol in order to attain the ratio ethanol/1-octanol (70:30) or
ethanol/PBS (70:30). The fluorescence of each ethanol/1-octanol
and ethanol/PBS solution was measured, and compared with
a calibration curve to obtain the concentration of the photo-
sensitizer. The solutions for the calibration curves were either
ethanol/1-octanol (70:30) or ethanol/PBS (70:30), and were both
prepared in a range of concentrations between 0.1 mM and 1 mM.
The Soret absorption band ca. 420 nm was excited, and the
fluorescence was collected in the red region, under the same in-
strumental conditions for both the solutions of the calibration
curve and the samples. The determination of log KOW for the
sulfonic acid porphyrin derivatives, 4f, 5f and 6f, was carried out
like the procedure described above, but initially the sensitizers
have been dissolved in PBS solution previously saturated with
1
5. Sasnouski, S.; Zorin, V.; Khludeyev, I.; d’Hallewin, M.; Guillemin, F.; Bezdetnaya,
L. Biochim. Biophys. Acta 2005, 1725, 394–402.
1
6. Bonneau, S.; Vever-Bizet, C.; Morli e` re, P.; Mazi e` re, J. C.; Brault, D. Biophys. J.
2002, 83, 3470–3481.
1
7. Pereira M. M.; Arnaut L. G.; Formosinho S. J.; Monteiro C. J. P. WO Patent 053707,
006.
8. Lindsey, J. S.; Hsu, H. C.; Schreimen, I. C. Tetrahedron Lett. 1986, 27, 4969–4970.
19. Wagner, R. W.; Lawrence, D. S.; Lindsey, J. S. Tetrahedron Lett.1987, 28, 3069–3070.
2
1
2
0. Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.; Marguerettaz, A. M.
J. Org. Chem. 1987, 52, 827–836.
21. Gonsalves, A. M. d’A. R.; Varejao, J. M. T. B.; Pereira, M. M. J. Heterocycl. Chem.
1991, 28, 635–640.
2
2. Johnstone, R. A. W.; Nunes, M. L. P. G.; Pereira, M. M.; Gonsalves, A. M. d’A. R.;
Serra, A. C. Heterocycles 1996, 43, 1423–1437.
3. Mahammed, A.; Goldberg, I.; Gross, Z. Org. Lett. 2001, 3, 3443–3446.
2
24. Saltsman, I.; Mahammed, A.; Goldberg, I.; Tkachenko, E.; Botoshansky, M.;
Gross, Z. J. Am. Chem. Soc. 2002, 124, 7411–7420.
5. Gonsalves, A. M. d’A. R.; Johnstone, R. A. W.; Pereira, M. M.; de Santana, A. M. P.;
Serra, A. C.; Sobral, A. J. F. N.; Stokes, P. A. Heterocycles 1996, 43, 829–838.
2
26. Monteiro, C. J. P.; Serpa, C.; Pereira, M. M.; Azenha, M. E.; Burrows, H. D.;
Arnaut, L. G.; Tapia, M. J.; Sarakha, M.; Navaratnam, S. Photochem. Photobiol.
Sci. 2005, 4, 617–624.
1
-octanol.
The partition coefficients were calculated from the ratio Coct
/
27. Sobral, A. J. F. N.; Eleouet, S.; Rousset, N.; Gonsalves, A. M. d’A. R.; Le Meur, O.;
C
PBS, where Coct and CPBS are the concentrations of the porphyrin in
Bourre, L.; Patrice, T. J. Porphyrins Phthalocyanines 2002, 6, 456–462.
the 1-octanol and in the PBS, respectively. All the measurements
were carried out at room temperature.
28. Ressurreiç a˜ o, A. S. M.; Pineiro, M.; Arnaut, L. G.; Gonsalves, A. M. d’A. R.
J. Porphyrins Phthalocyanines 2007, 11, 50–57.
2
3
9. Banfi, S.; Cavalieri, C.; Cavazzini, M.; Trebicka, A. J. Mol. Catal. A 2000, 151, 17–28.
0. Serra, A. C.; Docal, C.; Gonsalves, A. M. d’A. R. J. Mol. Catal. A 2005, 238, 192–198.
3
1. Mahammed, A.; Gross, Z. J. Am. Chem. Soc. 2005, 127, 2883–2887.
4
.7. MALDI-TOFMS
3
3
2. Mahammed, A.; Gross, Z. Angew. Chem., Int. Ed. 2006, 45, 6544–6547.
3. Agadjanian, H.; Weaver, J. J.; Mahammed, A.; Rentsendorj, A.; Bass, S.; Kim, J.;
Dmochowski, I. J.; Margalit, R.; Gray, H. B.; Gross, Z.; Medina-Kauwe, L. K.
Pharm. Res. 2006, 23, 367–377.
DCTB matrix solution was made to
a concentration of
ꢀ1
2
0 mg mL in dichloromethane. DHB matrix solution was made to
3
3
3
4. Haber, A.; Agadjanian, H.; Medina-Kauwe, L. K.; Gross, Z. J. Inorg. Biochem. 2008,
102, 446–457.
ꢀ
1
a concentration of 10 mg mL in 1:1 (v/v) EtOH/MeCN. All com-
pounds were dissolved in dicloromethane, with the exception of 6f,
which was dissolved in EtOH, at an approximate concentration of
5. Walker, D.; Chappel, S.; Brunschwig, B. S.; Winkler, J. R.; Gray, H. B.; Zaban, A.;
Gross, Z. J. Porphyrins Phthalocyanines 2006, 10, 1259–1262.
6. Lidgard, R.; Duncan, M. W. Rapid Commun. Mass Spectrom. 1995, 9, 128–132.
ꢀ1
10 mg mL . One microlitre of sample solution was vortex-mixed
37. Wyatt, M. F.; Stein, B. K.; Brenton, A. G. Anal. Chem. 2006, 78, 199–206.
3
3
4
8. Collander, R. Acta Chem. Scand. 1951, 5, 774–780.
9. Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525–616.
0. Kessel, D.; Smith, K. M.; Pandey, R. K. Photochem. Photobiol. 1993, 58, 200–203.
with 49 mL of DCTB solution; 0.5 mL of the final mixture was spotted
onto the gold-plated, deep-welled, target plate and allowed to dry.
Compound 6f was analyzed using a similar procedure, but with
DHB matrix and a stainless steel target plate. The MALDI-TOFMS
spectrometer was operated in positive ion, reflectron mode, and
spectra were accumulated in multiples of 25 laser shots, with 100
shots in total. Postacquisition processing of data was performed
utilizing Data Explorer V4.0 software supplied by Applied
Biosystems. Theoretical isotope distributions were generated at
a resolution of 15,000 fwhm.
41. Grancho, J. C. P.; Pereira, M. M.; Miguel, M. G.; Gonsalves, A. M. d’A. R.; Burrows,
H. D. Photochem. Photobiol. 2002, 75, 249–256.
4
2. Pandey, S. K.; Gryshuk, A. L.; Graham, A.; Ohkubo, K.; Fukuzumi, S.; Dobhal, M.
P.; Zheng, G.; Ou, Z.; Zhan, R.; Kadish, K. M.; Oseroff, A.; Ramaprasad, S.; Pandey,
R. K. Tetrahedron 2003, 59, 10059–10073.
43. Berg, K.; Selbo, P. K.; Weyer, A.; Dietze, A.; Prasmickaite, L.; Bonsted, A.;
Engesaeter, B. Ø.; Angell-Petersen, E.; Warloe, T.; Frandsen, N.; Høgset, A.
J. Microsc. 2005, 218, 133–147.
4
4. Burrows, H. D.; Pereira, M. M. Qu ´ı mica-S ´ı ntese e Estrutura; Escolar Editora:
Lisbon, 2006; Chapter 2, pp 19–23.