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422 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Letters
in the interaction with ligands.21 The proposed binding mode
(5) Su, B.; Diaz-Cruz, E. S.; Landini, S.; Brueggemeier, R. W. Novel
sulfonanilide analogues suppress aromatase expression and activity
in breast cancer cells independent of COX-2 inhibition. J. Med. Chem.
(Figure 1) well confirmed the difference in potency between
the meta- (1b, IC50 ) 7.3 nM) and the ortho-derivative (1a,
IC50 ) 560 nM).
2006, 49, 1413-1419.
(6) L e´ z e´ , M. P.; Le Borgne, M.; Pinson, P.; Palusczak, A.; Duflos, M.;
Le Baut, G.; Hartmann, R. W. Synthesis and biological evaluation
of 5-[(aryl)(1H-imidazol-1-yl)methyl]-1H-indoles: Potent and selec-
tive aromatase inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 1134-
1137.
In Figure 1, the putative binding mode of 3, carrying a NO2
group in para-position with respect to the methylimidazole
chain, is also reported. Docking simulations clearly pointed out
the possibility for this additional group to establish H-bond
interactions with either Ser478 or Asp309, which are equidistant
from the -NO2 oxygen (distance between heteroatoms ∼ 4.0
Å), thus accounting for the significantly increased potency (IC50
(7) Gobbi, S.; Cavalli, A.; Rampa, A.; Belluti, F.; Piazzi, L.; Palusczak,
A.; Hartmann, R. W.; Recanatini, M.; Bisi, A. Lead optimization
providing a series of flavone derivatives as potent nonsteroidal
inhibitors of the cytochrome P450 aromatase enzyme. J. Med. Chem.
2006, 49, 4777-4780.
(
8) Recanatini, M.; Bisi, A.; Cavalli, A.; Belluti, F.; Gobbi, S.; Rampa,
A.; Valenti, P.; Palzer, M.; Palusczak, A.; Hartmann, R. W. A new
class of nonsteroidal aromatase inhibitors: design and synthesis of
chromone and xanthone derivatives and inhibition of the P450
enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase. J. Med.
Chem. 2001, 44, 672-680.
)
25.9 nM) with respect to the parent compound 1a. Further-
more, to investigate the effects of the introduction of bulky
substituents on the benzophenone scaffold, docking simulations
were also performed with 1d, namely, the meta-derivative with
an additional phenyl ring in position 4′. A pose representative
of a statistically populated cluster is reported in Figure 1. This
binding mode showed that aromatase can accommodate steri-
cally hindered ligands in this region of its active site, as 1d
could establish a few further interactions, in particular, either
π-π with His475 and His480 or hydrophobic with Ala223 and
Ala226. Actually, 1d proved to be the most potent AI that we
reported so far, with an IC50 value of 5.3 nM.
(
9) Thompson, E. A., Jr.; Siiteri, P. K. Utilization of oxygen and reduced
nicotinamide adenine dinucleotide phosphate by human placental
microsomes during aromatization of androstenedione. J. Biol. Chem.
1974, 249, 5364-5372.
(
10) Hutschenreuter, T. U.; Ehmer, P. B.; Hartmann, R. W. Synthesis of
hydroxy derivatives of highly potent nonsteroidal CYP 17 inhibitors
as potential metabolites and evaluation of their activity by a non
cellular assay using recombinant human enzyme. J. Enzyme Inhib.
2004, 19, 17-32.
(
11) Lang, M.; Batzl, C.; Furet, P.; Bowman, R.; Hausler, A.; Bhatnagar,
A. S. Structure-activity relationships and binding model of novel
aromatase inhibitors. J. Steroid Biochem. Mol. Biol. 1993, 44, 421-
In conclusion, a new class of highly potent AIs was
synthesized, endowed with high selectivity with respect to
CYP17, which combine remarkable activity (in the low nano-
molar range) with higher accessibility via straightforward
synthetic procedures when compared to the conformationally
428.
(
12) Favia, A. D.; Cavalli, A.; Masetti, M.; Carotti, A.; Recanatini, M.
Three-dimensional model of the human aromatase enzyme and
density functional parameterization of the iron-containing protopor-
phyrin IX for molecular dynamics study of heme-cysteinato cyto-
chromes. Proteins 2006, 62, 1074-1087.
13) Bottegoni, G.; Cavalli, A.; Recanatini, M. A comparative study on
the application of hierarchical-agglomerative clustering approaches
to organize outputs of reiterated docking runs. J. Chem. Inf. Model.
8
constrained xanthone derivatives. Compound 1d turned out to
be our most potent AI, comparable to currently marketed drugs.
Docking simulations in combination with cluster analysis were
also carried out, providing a fairly good explanation for the
binding mode of the present series of new inhibitors at the
aromatase active site.
(
2006, 46, 852-862.
(
14) Bottegoni, G.; Rocchia, W.; Recanatini, M.; Cavalli, A. AClAP,
Autonomous hierarchical agglomerative cluster analysis based pro-
tocol to partition conformational datasets. Bioinformatics 2006, 22,
e58-e65.
Acknowledgment. This work was supported by grants from
MIUR-COFIN2004 (Rome, Italy).
(
15) Recanatini, M.; Cavalli, A.; Valenti, P. Nonsteroidal aromatase
inhibitors: recent advances. Med. Res. ReV. 2002, 22, 282-304.
16) Recanatini, M.; Cavalli, A. Comparative molecular field analysis of
nonsteroidal aromatase inhibitors: An extended model for two
different structural classes. Bioorg. Med. Chem. 1998, 6, 377-388.
(17) Cavalli, A.; Bisi, A.; Bertucci, C.; Rosini, C.; Paluszcak, A.; Gobbi,
S.; Giorgio, E.; Rampa, A.; Belluti, F.; Piazzi, L.; Valenti, P.;
Hartmann, R. W.; Recanatini, M. Enantioselective nonsteroidal
aromatase inhibitors identified through a multidisciplinary medicinal
chemistry approach. J. Med. Chem. 2005, 48, 7282-7289.
18) Graham-Lorence, S.; Amarneh, B.; White, R. E.; Peterson, J. A.;
Simpson, E. R. A three-dimensional model of aromatase cytochrome
P450. Protein Sci. 1995, 4, 1065-1080.
19) Koymans, L. M.; Moereels, H.; Van den Bossche, H. A molecular
model for the interaction between vorozole and other non-steroidal
inhibitors and human cytochrome P450 19 (P450 aromatase). J.
Steroid Biochem. Mol. Biol. 1995, 53, 191-197.
20) Cavalli, A.; Greco, G.; Novellino, E.; Recanatini, M. Linking CoMFA
and protein homology models of enzyme-inhibitor interactions: An
application to nonsteroidal aromatase inhibitors. Bioorg. Med. Chem.
(
Supporting Information Available: Full experimental proce-
dures of both synthesis and computational studies and elemental
analyses of target compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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