Chapter 26
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Fluorinated Inhibitors of Matrix Metalloproteinases Fiorenza Viani, Luca Bruché, Gabriele Candiani, Florent Huguenot, Monika Jagodzinska, Raffaella Maffezzoni, Nathalie Moussier, Monica Sani, Roberta Sinisi, and Matteo Zanda* C.N.R.-Instituto di Chimica del Riconoscimento Molecolare, and Dipartimento di Chimica, Materiali ed Ingegneria Chimica "G. Natta" del Politecnico di Milano, via Mancinelli 7,I-20131 Milano, Italy
The synthesis of potent inhibitors of matrix metalloproteinases (MMPs) bearing trifluoromethyl or difluoromethyl groups in purely aliphatic positions, and the effect of the incorporation of the fluoroalkyl functions on the inhibitory potency is presented.
Incorporation of fluorine into organic molecules is an effective strategy for improving and modifying the biological activity (1). In particular, the trifluoromethyl (Tfm) group occupies a prominent position in medicinal chemistry as a substituent of peculiar properties. It is in fact highly hydrophobic, electron-rich, sterically demanding, moreover it can provide high in vivo stability, and features a good mimicry with several naturally occurring residues such as methyl, isopropyl, isobutyl, phenyl, etc. (2). Matrix metalloproteinases (MMPs) are zinc (II)-dependent proteolytic enzymes involved in the degradation of the extracellular matrix (3). More than 25 human MMPs have been identified so far. Loss in the regulation of their activity can result in the pathological destruction of connective tissue, a process 420
© 2007 American Chemical Society
In Current Fluoroorganic Chemistry; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
421 associated with a number of severe diseases, such as cancer and arthritis. The inhibition of various M M P s has been envisaged as a strategy for the therapeutic intervention against such pathologies. To date, however, a number of drawbacks have hampered the successful exploitation of M M P s as pharmacological targets. In particular, the toxicity demonstrated by many M M P s ' inhibitors in clinical trials has been ascribed to nonspecific inhibition. Recently (4) we described the synthesis of the Tfm-malic hydroxamate 1 (Fig. 1). Unfortunately, the effect of the replacement of the a - C H group of the highly potent parent molecule A (5) with a C F on the inhibition of M M P - 3 and -9 was detrimental, and a drop of about 5 orders of magnitude of inhibitory potency was observed.
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3
3
P1 1
R = (CH ) Ph R = tert-Bu R = Me 2
3
2
3
A
pr
1
P2
R = CH ; 3
1
P3* R = CF
3
Figure 1. Low potency Tfm-malic hydroxamate inhibitor of MMP-2 and -9.
Two concurrent reasons for the reduced activity of the fluorinated inhibitors were postulated: (a) reduced coordinating strength of the neighbouring hydroxamate group by the electron-withdrawing Tfm, and (b) the need of the fluorinated molecule to adopt within the binding site a conformation which does not coincide with its minimum-energy conformation in solution. In order to probe the importance of the first effect (reduced coordinating strength), and assess the compatibility of a Tfm group in a-position to the hydroxamic function, we decided to investigate the effect of a Tfm group positioned as R substituent in structures 2 (Fig. 2), analogs of molecules B (Fig. 2) which were recently reported by Becker et al. as potent inhibitors of M M P - 2 , M M P - 9 and M M P - 1 3 (
