Synthesis and Biological Activity of New Mixed HIV-PR Inhibitors
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
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the contrary, compound 12 is one order of magnitude more
active than its parent Phe-Pro active site inhibitor 2a, and
more than four orders of magnitude than the tripeptide 5.
The conjugate activity is thus heavily dependent upon
structure. However, true synergism appears to operate in
[3]
[4]
compound
12,
thus
indicating
that
improved
pharmacological properties can be obtained by this approach.
Table 1. IC50 Values of Free and Conjugated Compounds
Inhibitor
IC50 μMa
1a
2a
3a
4
4
0.0753
0.0019
660
[5]
5
85
[6]
[7]
6
110
11
12
13
35.2
0.0062
1.2
aThese data were obtained by measuring the initial rates of hydrolysis of the
fluorogenic substrate Abz-Thr-Ile-Nle-Phe(NO2)-Gln-Arg. Results are the average over
at least three independent experiments.
[8]
[9]
In conclusion, this first data confirm the convenience of
the fast and high yielding methodology adopted for the
preparation of a new class of mixed HIV inhibitors whose
behaviour clearly suggest a likely enhancing of the
pharmacological activity through a cooperative effect.
[10]
A larger set of derivatives is currently being synthesized
in order to gain insight in the structural effects that drive the
resulting conjugate activity. At that level extensive
pharmacokinetic analysis will be performed as well as the in
vivo behaviour on MOL T3 type linfoblastoid cells to afford
useful data also on their toxicity. Further information will be
obtained from the study of their activity in cellular tests, both
on wild type and mutants HIV viruses, in order to understand
and evaluate the PEG effect on the cellular permeability. All
these studies will be reported in a following paper focused
on the pharmacological features of these new mixed HIV-PR
inhibitors.
[11]
[12]
Dinon, F.; Campaner, P.; Berti, F.; Tossi, A.; Benedetti, F.
PCT/EP2005/052770
Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.; Zlatoidzky, P.
Versatile and stereoselective synthesis of diamino diol dipeptide
isosteres, core units of pseudopeptide HIV protease inhibitors. J.
Org. Chem., 1997, 62, 9348-9353.
[13]
Benedetti, F.; Berti, F.; Dinon, F.; Nardin, G.; Norbedo, S.
Synthesis of
a val-pro diaminodiol dipeptide isostere by
epoxyamine cyclization. Org. Lett., 2004, 6, 1017-1019.
Benedetti, F.; Berti, F.; Campaner, P.; Dinon, F.; Tossi, A.
PD2004A000151; PCT/EP2005/052770.
Shultz, M.D.; Chmielewski, J. Hydrophobicity versus activity in
crosslinked interfacial peptide inhibitors of HIV-1 protease.
Tetrahedron: Asymm., 1997, 8, 3881-3886.
[14]
[15]
ACKNOWLEDGEMENT
[16]
[17]
Davis, F.F. The origin of pegnology. Adv. Drug Deliv. Rev., 2002,
54, 457-458.
The authors would like to thank dott. A. Ostric for IC50
measurements.
Gaucher, B.; Rouquayrol, M.; Roche, D.; Greiner, J.; Aubertin, A.-
M.; Vierling, P. Prodrugs of HIV protease inhibitors-saquinavir,
indinavir and nelfinavir - derived from diglycerides or amino acids:
Synthesis, stability and anti-HIV activity. Org. Biomol. Chem.,
2004, 2, 345-357.
a) Rouquayrol, M.; Gaucher, B.; Roche, D.; Greiner, J.; Vierling, P.
Transepithelial transport of prodrugs of the HIV protease inhibitors
saquinavir, indinavir, and nelfinavir across Caco-2 cell monolayers.
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