B. Chitkul, M. Bradley / Bioorg. Med. Chem. Lett. 10 (2000) 2367±2369
2369
Table 3. Screening of the three polyamine conjugates with the most potent capping groups10,12
Capping acid
Norspermidine
Spermidine
Spermine
(a)
(m)
(y)
3,4-Dihydroxyhydocinnamic acid
4-Hydroxy-7-tri¯uoromethyl-3-quinoline-carboxylic acid
3-Indole acetic acid
38%
85%
97%
24%
60%
96%
63%
54%
20%
62%
95%
65%
72%
85%
93%
72%
82%
69%
97%
95%
96%
96%
97%
98%
(ii)
5-Hydroxy-3-indole acetic acid
3-Indole propanoic acid
5-Methoxy-3-indole acetic acid
3-Indole-butanoic acid
5-Bromo-3-indole acetic acid
(iii)
(vii)
(xii)
(xiii)
of these compounds that was more active than the
spermine analogue, the only example where this is the
case across the whole series.
Trends Biochem. Sci. 1991, 16, 305. Bond, C. S.; Zhang, Y. H.;
Berriman, M.; Cunningham, M. L.; Fairlamb, A. H.; Hunter,
W. N. Structure 1999, 7, 81.
6. Smith, H. K., Bradley, M. J. Combinatorial Chem. 1999, 1,
326. Faerman, C. H.; Savvides, S. N.; Strickland, C.; Ponasik,
J. A.; Ganem, B.; Krauth-Siegel, R. L.; Karplus, P. A. Bioorg.
Med. Chem. 1996, 4, 1247. Ponasik, J. A.; Strickland, C.;
Faerman, C.; Savvides, S.; Karplus, P. A.; Ganem, B. Bio-
chem. J. 1995, 311, 371.
In conclusion, a number of immobilised polyamines
were prepared which were derivatised with a range of
aromatic carboxylates. Compound 7xiii was the most
potent of the series having a Ki of 76 nM. The eective-
ness of the indole functionality ®ts with other inhibitors
reported elsewhere9 and suggests that despite the nat-
ural substrate of trypanothione reductase lacking aro-
matic residues the active site is able to accommodate
electron rich aromatics. The kinetic behaviour of all
these inhibitors was not simple competitive inhibition
but non-competitive and thus the possibility exists that
binding is taking place at an alternative active site, per-
haps that of the co-factor NADPH. It is even possible
that it is competing with the reduced product. These
possibilities, and X-ray crystallographic studies are now
under active investigation.
7. O'Sullivan, M. C.; Zhou, Q. Bioorg. Med. Chem. Lett.
1995, 5, 1957.
8. Girault, S.; Davioud-Charvet, E.; Salmon, L.; Berecibar,
A.; Debreu, M.-A.; Sergheraert, C. Bioorg Med. Chem. Lett.
1998, 8, 1175. Tromelin, A.; Moutiez, M.; Meziane-Cherif, D.;
Aumercier, M.; Sergheraert, C. Biochem. Biophys. Acta. 1995,
161.
9. Marsh, I. R.; Bradley, M. Tetrahedron 1997, 53, 17317.
Marsh, I. R.; Bradley, M. Eur. J. Biochem. 1997, 243, 690.
Marsh, I. R.; Smith, H. K.; Bradley, M. J. Chem. Soc., Chem.
Commun. 1996, 941. Page, P.; Burrage, L.; Baldock, L.; Bradley,
M. Bioorg. Med. Chem. Lett. 1998, 8, 1751.
10. Capping acids used in initial library (4, 5 and 6): (a) 3,4-
dihydro xyhydocinnamic acid, (b) 2,3-dimethoxyhydocinnamic
acid, (c) 4-hydroxy-3,5-dimethoxycinnamic acid, (d) 4-methoxy-
cinnamic acid, (e) 3-methoxycinnamic acid, (f) 4-hydroxyhydro-
cinnamic acid, (g) 2,4-dihydroxycinnamic acid, (h) 3,4-
(methylenedioxy)cinnamic acid, (i) 2,5-dihydroxyphenylacetic
acid, (j) 3-hydroxyphenylacetic acid, (k) 2-quinoxalinecarboxylic
acid, (l) 3-hydroxy-2-quinoxalinecarboxylic acid, (m) 4-hydroxy-
7-tri¯uoromethyl-3-quinoline-carboxylate, (n) 2-hydroxyphenyl-
acetic acid, (o) 2-pyrrolecarboxylic acid, (p) 2-thiophene-
carboxylic acid, (q) 2-thiopheneacetic acid, (r) 5-bromo-2-
furancarboxylic acid, (s) 2-methoxy-4-hydroxyphenylacetic
acid, (t) benzoic acid, (u) 3,4-(methylenedioxy)phenylacetic acid,
(v) 4-chlorobenzoic acid, (w) 6-chloro-3-pyridinecarboxylic
acid, (y) 3-indole acetic acid.
Acknowledgements
We thank the Thai Government for a Scholarship to BC
and the Royal Society and the BBSRC for their Support
(MB).
References and Notes
1. Fairlamb, A. H.; Cerami, A. Annu. Rev. Microbiol. 1992,
46, 695.
2. Dumas, C.; Ouellette, M.; Tovar, J.; Cunningham, M. L.;
Fairlamb, A. H.; Tamar, S.; Livier, M. O.; Papadopoulou, B.
EMBO 1997, 16, 2590.
3. Schirmer, R. H.; Muller, J. G.; Krauth-Siegel, R. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 141 and references therein.
4. Hunter, W. N.; Bailey, S.; Habash, J.; Harrop, S. J.; Helli-
well, J. R.; Aboagye-Kwarteng, T.; Smith, K.; Fairlamb, A. H.
J. Mol. Biol. 1992, 227, 322.
11. Sullivan, F. X.; Walsh, C. T. Mol. Biochem. Parasitol.
1991, 44, 145.
12. Capping acids used in optimisation library (7ii±xiv): (ii) 5-
hydroxy-3-indole acetic acid, (iii) 3-indole propanoic acid, (iv)
2-methyl-3-indole acetic acid, (v) 5-hydroxy-2-indole car-
boxylic acid, (vi) E-3-indole-acrylic acid, (vii) 5-methoxy-3-
indole acetic acid, (viii) 2-indole carboxylic acid, (ix) trypto-
phan, (x) 2-methyl-5-methoxy-3-indole acetic acid, (xi) 3-indole
carboxylic acid, (xii) 3-indole-butanoic acid, (xiii) 5-bromo-3-
indole acetic acid, (xiv) 2,3-dihydro-2-indole carboxylic acid.
5. Bradley, M.; Nadeau, K.; Walsh, C. T., Cur. Top. Cell.
Regulat., 1992, 33, 409. Walsh, C. T.; Bradley, M.; Nadeau, K.