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Journal Name
Organic & Biomolecular Chemistry
DOI: 10.1039/C4OB02155J
c)S. Pastorekova, S. Parkkila, J. Pastorek and C.T. Supuran, J.
Enzyme Inhib. Med. Chem. 2004, 19, 199.
Conclusions
Herein we reported a series of 6ꢀsubstituted sulfocoumarines
obtained by intramolecular cyclization of the corresponding
methanesulfonic acid esters. We investigated compounds 4, 5,
10. a)C.T. Supuran, Bioorg. Med. Chem
.
Lett. 2010, 20, 3467; b) C.T.
Supuran, Future Med. Chem. 2011,
3, 1165; c) M. Aggarwal, C.D.
Boone, B. Kondeti and R. McKenna, J. Enzyme Inhib. Med. Chem
.
7-9 and 11 for their inhibition activities against five hCA
isoforms.
2013, 28, 267; d) A. Jain, G.M. Whitesides, R.S. Alexander and D.W.
Christianson, J. Med. Chem. 1994, 37, 2100; e) L. Baranauskiene, M.
Hilvo, J. Matuliene, D. Golovenko, E. Manakova, V. Dudutiene, V.
Michailoviene, J. Torresan, J. Jachno, S. Parkkila, A. Maresca, C.T.
Supuran, S. Grazulis and D. Matulis, J. Enzyme Inhib. Med. Chem.
2010, 25, 863.
As expected for the 6ꢀsubstituted sulfocoumarines, the
compounds showed to be ineffective in inhibiting the cytosolic
hCAs I and II, whereas showed interesting profiles against the
tumor associated hCA IX and XII with Kis in a range of 9.8ꢀ
684 nM.
For the first time we report the 6ꢀsubstituted sulfocoumarines as
effective inhibitors of the mitochondrial hCA VA isoform, with
11. F. Carta, C. Temperini, A. Innocenti, A. Scozzafava, K. Kaila and
C.T. Supuran, J. Med.Chem. 2010, 53, 5511.
compound
8 as the strongest in the series (Ki 0.06 ꢁM).
These findings are of particular importance for the future
development of new and effective inhibitors against the
mitochondrial CA isoforms having antiobesity pharmacological
applications. In particular the lack of safe and effective drugs
for the treatment of obesity and/or obesityꢀrelated pathologies
makes these compounds particularly interesting for developing
new therapeutics.
12. S.K. Nair, P.A. Ludwig and D.W. Christianson, J. Am. Chem. Soc
1994, 116, 3659.
.
13. F. Carta, M. Aggarwal, A. Maresca, A. Scozzafava, R. McKenna, E.
Masini and C.T. Supuran, J. Med. Chem. 2012, 55, 1721.
14. F. Carta, A. Akdemir, A. Scozzafava, E. Masini and C.T. Supuran, J.
Med. Chem. 2013, 56, 4691.
15. F. Carta, D. Vullo, A. Maresca, A. Scozzafava and C.T. Supuran,
Acknowledgements
Bioorg Med Chem Lett. 2012, 6, 2182.
16. A. Grandane, S. Belyakov, P. Trapencieris and R. Zalubovskis,
Tetrahedron 2012, 68, 5541.
This work was financed by two FP7 EU grants (METOXIA and
DYNANO).
.
17. H. KenꢀIchiro, A. Yamazoe, Y. Ishibashi, N. Kusaka, Y. Oono and H.
Nozaki, Bioorg. Med. Chem. 2008, 16, 5331.
Notes and references
18. R. L. Arechederra, A. Waheed, W. S. Sly, C.T. Supuran and S.D.
Minteer, Bioorg. Med. Chem. 2013, 21, 1544.
1. K. Tars, D. Vullo, A. Kazaks, J. Leitans, A. Lends, A. Grandane, R.
Zalubovskis, A. Scozzafava and C.T. Supuran, J. Med. Chem. 2013,
56, 293.
19. An Applied Photophysics stoppedflow instrument has been used for
assaying the CA catalysed CO2 hydration activity. Phenol red (at a
concentration of 0.2 mM) has been used as indicator, working at the
absorbance maximum of 557 nm, with 20 mM Hepes (pH 7.5) as
buffer, and 20 mM Na2SO4 (for maintaining constant the ionic
strength), following the initial rates of the CAꢀcatalyzed CO2
hydration reaction for a period of 10–100 s. The CO2 concentrations
ranged from 1.7 to 17 mM for the determination of the kinetic
parameters and inhibition constants. For each inhibitor at least six
traces of the initial 5–10% of the reaction have been used for
determining the initial velocity. The uncatalyzed rates were
determined in the same manner and subtracted from the total
observed rates. Stock solutions of inhibitor (0.1 mM) were prepared
in distilled–deionized water and dilutions up to 0.01 nM were done
thereafter with the assay buffer. Inhibitor and enzyme solutions were
preincubated together for 15 min—6 h at room temperature (15 min)
or 4 °C (6 h) prior to assay, in order to allow for the formation of the
E–I complex. Data from Table 1 were obtained after 6 h incubation of
enzyme and inhibitor, as for the sulfocoumarins and coumarins
reported earlier.1,7 The inhibition constants were obtained by nonꢀ
linear leastsquares methods using PRISM 3, as reported earlier,8a and
represent the mean from at least three different determinations. All
CA isofoms were recombinant ones obtained inꢀhouse as reported
earlier.1,7
2. a)A. Maresca, C. Temperini, H Vu, N.B. Pham, S.A. Poulsen, A.
Scozzafava, R.J. Quinn and C.T. Supuran, J. Am. Chem. Soc. 2009,
131, 3057; b) A. Maresca, C. Temperini, L. Pochet, B. Masereel, A.
Scozzafava and C.T. Supuran, J. Med. Chem. 2010, 53, 335.
3. F. Carta, C.T. Supuran and A. Scozzafava, Future Med Chem. 2014,
10, 1149.
4. C.T. Supuran, Nat. Rev. Drug. Discov. 2008, 7, 168.
5. a)E. Masini, F. Carta, A. Scozzafava and C.T. Supuran, Expert Opin.
Ther. Pat. 2013, 23, 705; b) C.T. Supuran and F. Carta, Expert Opin.
Ther. Pat. 2013, 23, 725; c) M. Aggarwal and R. McKenna, Expert
Opin. Ther. Pat. 2012, 22, 903; d) F. Carta and C.T. Supuran, Expert
Opin. Ther. Pat. 2013, 23, 681.
6. a)F. Carta, A. Maresca, A. Scozzafava and C.T. Supuran, Bioorg.
Med. Chem. 2012, 20, 2266; b) R.A. Davis, D. Vullo, A. Maresca,
C.T. Supuran and S.A. Poulsen, Bioorg. Med. Chem. 2013, 21, 1539.
7. a)M. Tanc, F. Carta, M. Bozdag, A. Scozzafava and C.T. Supuran,
Bioorg. Med. Chem. 2013
Zalubovskis and C.T. Supuran, Bioorg. Med. Chem. 2014
A. Grandane, M. Tanc, R. Zalubovskis and C.T. Supuran, Bioorg.
Med. Chem. 2014 , 1522
,
15,
4502; b) A. Grandane, M. Tanc, R.
,
5, 1256 c)
,
5
.
8. a)V. Alterio, A. Di Fiore, K. D’Ambrosio, C.T. Supuran and G. De
Simone, Chem. Rev. 2012, 112, 4421; b) D. Neri and C.T. Supuran,
Nat. Rev. Drug Discov. 2011, 10, 767; c) M. Aggarwal, B. Kondeti
and R. McKenna, Bioorg. Med. Chem. 2013, 21, 1526.
9. a)C.T. Supuran, J. Enzyme Inhib. Med. Chem. 2012, 27, 759; b) C.T.
Supuran, A. Scozzafava and A. Casini, Med. Res. Rev. 2003, 23, 146;
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