4498
N. Ando, S. Terashima / Bioorg. Med. Chem. Lett. 17 (2007) 4495–4499
Table 1. MMP-12 inhibitory activity of ageladine A (1) and its analogs
2–10
suggestions and encouragement. We would also like to
thank Dr. Y. Kohno, Kyorin Pharmaceutical Co. Ltd,
for his helpful suggestions and discussions. The MMP-
12 inhibition assay was performed by Dr. Emme C. K.
Lin, ActivX Biosciences, to whom our thanks are also
due.
Compound
MMP-12 inhibition IC50 (lM)
1
2
3.66
>100
>100
>100
>100
10.4
3
4
5
6
References and notes
7
56.9
8
>100
>100
43.6
1. Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.;
Yamashita, J.; van Soest, R. W. M.; Fusetani, N. J. Am.
Chem. Soc. 2003, 125, 15700.
9
10
2. (a) Vaalamo, M.; Kariniemi, A. L.; Shapiro, S. D.;
Saarialho-Kere, U. J. Invest. Dermatol. 1999, 112, 499;
(b) Saarialho-Kere, U.; Kerkela, E.; Jeskanen, L.; Hasan,
T.; Pierce, R.; Starcher, B. J. Invest. Dermatol. 1999, 113,
664; (c) Suomela, S.; Kariniemi, A. L.; Snellman, E.;
Saarialho-Kere, U. Exp. Dermatol. 2001, 10, 175.
3. Matsumoto, S.; Kobayashi, T.; Katoh, M.; Saito, S.;
Ikeda, Y.; Kobori, M. Am. J. Pathol. 1998, 153, 109.
4. Curci, J. A.; Liao, S.; Huffman, M. D.; Shapiro, S. D.;
Thompson, R. W. J. Clin. Invest. 1998, 102, 1900.
5. (a) Cornelius, L. A.; Nehring, L. C.; Harding, E.;
Bolanowski, M.; Welgus, H. G.; Kobayashi, D.
J. Immunol. 1998, 161, 6845; (b) Kerkela, E.; Bohling,
T.; Herva, R.; Uria, J. A.; Saarialho-Kere, U. Bone 2001,
29, 487; (c) Kerkela, E.; Ala-Aho, R.; Jeskanen, L.;
Rechardt, O.; Grenman, R.; Shapiro, S. D. J. Invest.
Dermatol. 2000, 114, 1113.
Ageladine A (1) and its analogs 2–10 were then sub-
jected to MMP-12 inhibition assay.16 The results are
summarized in Table 1. It appeared that the debromi-
nated analogs 2–4 did not inhibit MMP-12 even at a
concentration of 100 lM. These results clearly disclosed
that two bromine atoms in the pyrrole ring are indis-
pensable for 1 to exhibit inhibitory activity. The lack
of inhibitory activity of 5 bearing 1-N-methyl group
might be explained by deformation of the conjugate sys-
tem for 1, caused by the bond rotation between the pyr-
role and the 5-azabenzimidazole rings and/or by
inhibition of the intramolecular hydrogen bond between
the 1-NH and 12-N group. While 14- and 15-N-monom-
ethylated analogs 6, 7 were found to show inhibitory
activity against MMP-12, which is obviously inferior
to that of 1, the 14,15- and 15,15-N,N-dimethylated
analogs 8, 9 exhibited no inhibitory activity even at a
concentration of 100 lM. These results and the weak
inhibitory activity observed for 10 clearly suggest that
14-NH and 15-NH2 groups might play some role in
the inhibitory activity of 1, through intermolecular
hydrogen and/or coordination bond in the catalytic
domain of MMP-12 (ageladine A numbering). In sum-
mary, these results suggest that the two bromine atoms
and the three NH groups (1-NH, 14-NH, and 15-NH2)
of 1 play important roles in its MMP-12 inhibitory
activity.
6. Meketa, M. L.; Weinreb, S. M. Org. Lett. 2006, 8, 1443.
7. Shengule, S. R.; Karuso, P. Org. Lett. 2006, 8, 4083.
8. Ando, N.; Terashima, S. Synlett 2006, 2836.
9. Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6,
74.
10. Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
J. Am. Chem. Soc. 2004, 126, 5192.
1
11. This structure was assigned by its H NMR spectra (1H
NMR (CD3OD, 400 MHz) d 0.02 (9H, s), 0.91–0.96
(2H, m), 1.51 (9H, s), 2.55–2.63 (2H, m), 2.94 (1H, dt,
J = 5.0, 12.6 Hz), 3.00–3.07 (1H, m), 3.61–3.67 (2H, m),
5.12 (1H, s), 5.46 (2H, s), 5.89 (1H, s)) as well as by
taking into account the result reported by Nicolaou
et al.10
12. Yellow powder (lit.1, yellow powder); 1H NMR (CD3OD,
400 MHz) d 7.17 (1H, s), 7.42 (1H, d, J = 6.4 Hz), 8.05
(1H, d, J = 6.4 Hz); 13C NMR (CD3OD, 400 MHz) d
102.4, 105.5, 107.8, 115.2, 125.7, 128.6, 133.0, 136.7, 147.2,
160.9; LRMS (ESI+): 356 [M+H]+; HRMS (ESI+): Calcd
for C10H8Br2N5: 355.91465, found: 355.91340. These
spectral properties were identical to those reported.
13. Although the total synthesis of 1 reported by Karuso et al.
is almost the same as that independently developed by us,
their reaction conditions for the Pictet–Spengler reaction
using Sc(OTf)3 (44% yield) and for the sequential dehy-
drogenation and deprotection using chloranil (65% yield)
were completely different from those explored by us.
Taking into account the chemical yield for each step, our
synthetic route (the Pictet–Spengler reaction: 80% yield;
the dehydrogenation: 89% yield for two steps; deprotec-
tion: 70% yield) to 1 is anticipated to be more efficient than
that of Karuso et al.7
In conclusion, we have succeeded in synthesizing agela-
dine A (1) and its analogs 2–10 by featuring the biosyn-
thetic route proposed for 1 (for 1–10) and by employing
2-(N-t-butoxycarbonylamino)imidazol-4-carbaldehyde
as the starting material (for 1–8). Contrary to our expec-
tation, it appeared that, among these analogs, 14- or 15-
N-monomethylated analogs 6, 7 and 13-deaminated
analog 10 (ageladine A numbering) only exhibited very
weak MMP-12 inhibitory activity. However, these
results clearly disclosed that the two bromine atoms
and the three NH groups were indispensable for 1 to
exhibit strong activity. Aiming at exploring novel cong-
eners of 1 that can show more prominent inhibitory
activity against MMP-12 is in progress.
14. Specific N-methylations at the N-14 not at the N-12
position were verified by the 1H NMR spectra of 16a, 16b,
1
Acknowledgments
and 18 (16a: H NMR (CD3OD, 400 MHz) d À0.25 (9H,
s), 0.59 (2H, t, J = 8.1 Hz), 1.69 (9H, s), 3.17 (2H, t,
J = 8.1 Hz), 3.57 (3H, s), 5.92 (2H, s), 7.07 (1H, s), 7.40
(1H, d, J = 5.2 Hz), 8.23 (1H, d, J = 5.2 Hz); 16b: 1H
We are grateful to Drs. T. Ishizaki and Y. Fukuda, Kyo-
rin Pharmaceutical Co. Ltd, for their many valuable