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L YS OSOMOTROP IC SURFAKTANT S

L YS OSOMOTROP IC SURFAKTANT S. Stanis l aw WITEK Wroc l aw University of Technology E-mail: stanislaw.witek@pwr.wroc.pl. LYSOSOMOTROPIC COMPOUNDS.

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L YS OSOMOTROP IC SURFAKTANT S

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  1. LYSOSOMOTROPIC SURFAKTANTS Stanislaw WITEK Wroclaw University of Technology E-mail: stanislaw.witek@pwr.wroc.pl

  2. LYSOSOMOTROPIC COMPOUNDS The term "lysosomotropic compounds" was introduced by deDuve et al. The unprotonated form of these drugs, which are mostly weak bases, easily penetrates cell membranes and the protonated form accumulates in acidic cell compartments (vacuoles, lysosomes or endosomes) At pH above the pKa value of the drugs, their unprotonated forms prevail; hence at higher external pH values the drugs cross the plasma membrane more easily and their concentration in vacuoles is higher. C.deDuve, T.deBarsy, B.Poole, A.Trouet, P.Tulkens, F.vanHoof, Biochem.Pharmacol., 1974, 23, 2495

  3. LYSOSOMOTROPIC COMPOUNDS When they exceed the critical micellar concentration in the vacuoles, lysosomotropic drugs of amphiphilic character, act as surfactants and destroy the tonoplast. This results in the vacuolar hydrolytic enzymes causing cell autolysis. At the same time exhanging of intralysosomal pH is observed (even to about 1.7 unit higher).

  4. LYSOSOMOTROPIC COMPOUNDS • inhibition of multidrug resistance process, i.e.the processes of pumping drugs (eg. cytostatics) out of the cell. • enhancing of cytostatics and antibiotics activity • concentration of lysosomotropic drugs (cytostatics) in cancer cells in which interlysosomal pH is ca. 0.5 unit lower than in normal cells

  5. LYSOSOMOTROPIC COMPOUNDS • Lysosomotropic compounds have different chemical structure, but usually they are nitrogen containing compounds which is responsible for their properties as week bases. To the group of lysosomotropic compounds belong such as ammonium chloride, L-leucine-L-leucine methyl ester, N-dodecyl imidazol, some cardiological drugs, verapamil and chloroquine

  6. LYSOSOMOTROPIC COMPOUNDS NH4ClCH3NH2

  7. LYSOSOMOTROPIC COMPOUNDS Sulmazol (Ar- L 115 BS) cardiological drug HX-CH 44 BS ß-blocker

  8. LYSOSOMOTROPIC COMPOUNDS SX-AB 1316 SE Anticoagulant

  9. LYSOSOMOTROPIC COMPOUNDS AF-CX 1325 XX Antiepileptic drug

  10. AMMONIUM SALTS - FUNGICIDES

  11. RESEARCH PROGRAMME • „soft” lysosomotropic compounds; • biological activity; • hemolysis of erythrocytes; • Inhibition of ATPases activity • oddziaływanie na sieć pdr drożdży.

  12. COMPOUNDS STRUCTURES

  13. COMPOUNDS STRUCTURES PP – n MR – n PI – n IM - n

  14. COMPOUNDS STRUCTURES

  15. EQUILIBRIUM + H+ + R1R2N – R3 R1R2 – N – R3 - H+ H [R1R2N – R3] [H+] K = -------------------------------- [R1R2N+(H) – R3]

  16. BIOLOGICAL ACTIVITY

  17. BIOLOGICAL ACTIVITY Minimal inhibitory concentrationjace (MIC) of α-aminoacid esters

  18. HEMOLYTIC ACTIVITY Concentration of laurate caused 50% (A) and 100% (B) hemolysis hematocrite = 1, pH7.4 , temp. 370C

  19. HEMOLYTIC ACTIVITY Concentration of laurate caused 50% (A) and 100% (B) hemolysis hematocrite = 1, pH 7.4 , temp. 370 C.

  20. HEMOLYTIC ACTIVITY Polarisation coeficient P versus laurates concentration.

  21. ATPases ACTIVITY INHIBITION Inhibition in vitroplasma membrane H+-ATPase of yeastS.cerevisiae

  22. ATPases ACTIVITY INHIBITION

  23. ESTABLIHED ORDERS Inhibition of yeast growth: PY = DM = DE > PP >> MR > MO >> PI Hemolitic activity of laurates: PY = DM = DE > PP >> MR > MO >> PI Erytrocytes membrane fluidity: PY > DM > DE > PP > MR > PI Inhibition of plasma membrane H+ATPase: PY = DM = DE > PP >> MR > MO >> PI

  24. BASICITY AND PROPERTIES

  25. INFLUENCE ON pdr SYSTEM OFYEAST Deletions: a) PDR5, SNQ2; b) PDR5, SNQ2, YOR1; c) PDR1, PDR3 (inhibition zone for stream without deletionsi = 100)

  26. RESEARCH TEAM University of Wroclaw: prof. Tadeusz M. Lachowicz, dr Ewa Obłąk dr Anna Krasowska, dr Małgorzata Bień. Wrroclaw University of Life Scientes: prof. Stanisław Przestalski, prof. Janina Kuczera, prof. Halina Kleszczyńska, dr Janina Gabrielska. Wroclaw Unicersity of Technology: dr Jacek Łuczyński, mgr Bogdan Rutkowski, Jolanta Radwańska

  27. RESEARCH TEAM Catholiv University, Louvain-la-Neuve, Belgia prof. Andre Goffeau, dr Marcin Kołaczkowski, dr Anna Kołaczkowska, Józef Nader. Institute of Mikrobiology Czech Akademy of Sciences, Praha: prof. Karel Sigler

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