9 research outputs found
Antileukemic activity of sulfonamide conjugates of arabinosylcytosine
Aim: Cytosine arabinoside is routinely used for treatment of leukemias and lymphomas. However, because of its extensive metabolic inactivation and limited activity in chemotherapy, new analogues of araC are being tested. The aim of this work was to synthetize two araC conjugates and evaluates their cytotoxic/antileukemic activity. Methods: Synthesis of araC-sulfonamide conjugates A and B was performed in anhydrous conditions using cyclostyling and 5β-chlorocyclocytidine as starting material. Elemental analysis and NMR, IR and UV spectrometry were used for structure confirmation. The synthesized araC conjugates were tested for their cytotoxicity in L1210 leukemia cells in vitro and for therapeutic activity and toxicity in vivo in leukemia L1210-bearing mice. Results: The cytotoxic activities of araC and two synthesized conjugates A and B were expressed as IC50 (Β΅mol/l) and were compared respectively. The conjugate A is 303-times less active and the conjugate B is 757-times less active than araC. Consequently, the antileukemic activity and the acute toxicity of these compounds were examined in experiments involving leukemia L1210-bearing mice. Statistically significant therapeutic outcome was observed when the dosage of both araC conjugates was increased 10-times compared to araC. Next, the ration of cytotoxicity vs therapeutic activity for araC and both conjugates was performed. It was recorded that the ration between cytotoxicity and therapeutic activity for araC is 3333, for the conjugate A and B, the ration is significantly lower (110 and 44). This indicates that the inactivation of araC conjugate A is 30-times slower and the inactivation of conjugate B is 75-times slower as araC inactivation. Conclusions: The differences in cytotoxic and therapeutic activity registered in araC treatment and between two araC-analogues are most probably caused by slow liberation of araC from both conjugates. We are considered that prolonged araC liberation protected them from inactivation and extended the time period of therapeutic action both araC conjugates. The obtained results can serve as stimuli for further investigation of new araC-analogues.Π¦ΠΈΡΠΎΠ·ΠΈΠ½Π°ΡΠ°Π±ΠΈΠ½ΠΎΠ·ΠΈΠ΄ (araC) ΠΈΡΠΏΠΎΠ»ΡΠ·ΡΡΡ ΠΏΡΠΈ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ Π»Π΅ΠΉΠΊΠ΅ΠΌΠΈΠΈ ΠΈ Π»ΠΈΠΌΡΠΎΠΌΡ, ΠΎΠ΄Π½Π°ΠΊΠΎ Π²Π²ΠΈΠ΄Ρ Π΅Π³ΠΎ Π°ΠΊΡΠΈΠ²Π½ΠΎΠΉ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΎΠΉ ΠΈΠ½Π°ΠΊΡΠΈΠ²Π°ΡΠΈΠΈ ΠΈ Π»ΠΈΠΌΠΈΡΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΡΠΎΠ·Π΄Π°ΡΡΡΡ ΠΈ ΠΈΡΠΏΡΡΡΠ²Π°ΡΡΡΡ Π½ΠΎΠ²ΡΠ΅ Π°Π½Π°Π»ΠΎΠ³ΠΈ araC. Π¦Π΅Π»Ρ ΡΠ°Π±ΠΎΡΡ β ΡΠΈΠ½ΡΠ΅Π· Π΄Π²ΡΡ
ΠΊΠΎΠ½Ρ-
ΡΠ³Π°ΡΠΎΠ² araC ΠΈ ΠΎΡΠ΅Π½ΠΊΠ° ΠΈΡ
ΡΠΈΡΠΎΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠΎΠΉ/ΠΏΡΠΎΡΠΈΠ²ΠΎ-Π»Π΅ΠΉΠΊΠ΅ΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ. ΠΠ΅ΡΠΎΠ΄Ρ: ΡΠΈΠ½ΡΠ΅Π· ΡΡΠ»ΡΡΠΎΠ½Π°ΠΌΠΈΠ΄Π½ΡΡ
ΠΊΠΎΠ½ΡΡΒΠ³Π°ΡΠΎΠ²
araC A ΠΈ B ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΠ»ΠΈ Π² Π±Π΅Π·Π²ΠΎΠ΄Π½ΠΎΠΌ ΡΠ΅ΠΆΠΈΠΌΠ΅ Ρ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ 5-Ρ
Π»ΠΎΡΡΠΈΠΊΠ»ΠΎΡΠΈΡΠΈΠ΄ΠΈΠ½Π° Π² ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΠΈΡΡ
ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΌΠ°ΡΠ΅ΡΠΈΠ°Π»Π°. ΠΠ»Ρ
ΠΏΠΎΠ΄ΡΠ²Π΅ΡΠΆΠ΄Π΅Π½ΠΈΡ ΡΡΡΡΠΊΡΡΡΡ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π»ΠΈ ΡΠ»Π΅ΠΌΠ΅Π½ΡΠ½ΡΠΉ Π°Π½Π°Π»ΠΈΠ·, Π―ΠΠ , ΠΠ ΠΈ Π£Π€ ΡΠΏΠ΅ΠΊΡΡΠΎΠΌΠ΅ΡΡΠΈΡ. Π‘ΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½Π½ΡΠ΅ ΠΊΠΎΠ½ΡΡΠ³Π°ΡΡ
araC ΠΈΡΠΏΡΡΡΠ²Π°Π»ΠΈ Π½Π° ΡΠΈΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΡ ΠΏΡΠΎΡΠΈΠ² ΠΊΠ»Π΅ΡΠΎΠΊ Π»Π΅ΠΉΠΊΠ΅ΠΌΠΈΠΈ Π»ΠΈΠ½ΠΈΠΈ L1210 in vitro, Π° ΡΠ°ΠΊΠΆΠ΅ Π½Π° Π½Π°Π»ΠΈΡΠΈΠ΅ ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΠΎΠΉ
Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈ ΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΠΈ in vivo Π½Π° ΠΌΡΡΠ°Ρ
Ρ ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΠΎΠΉ ΠΎΠΏΡΡ
ΠΎΠ»ΡΡ L1210. Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ: ΡΠΈΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΡΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ
araC ΠΈ ΠΊΠΎΠ½ΡΡΠ³Π°ΡΠΎΠ² A ΠΈ B Π²ΡΡΠ°ΠΆΠ°Π»ΠΈ ΠΊΠ°ΠΊ 50 (Β΅Π/Π»). ΠΠΎΠ½ΡΡΒΠ³Π°Ρ A ΠΎΠΊΠ°Π·Π°Π»ΡΡ Π² 303 ΡΠ°Π·Π° ΠΌΠ΅Π½Π΅Π΅ Π°ΠΊΡΠΈΠ²Π½ΡΠΌ, Π° ΠΊΠΎΠ½ΡΡΒΠ³Π°ΡΒ Π β Π²Β 757
ΡΠ°Π· ΠΌΠ΅Π½Π΅Π΅ Π°ΠΊΡΠΈΠ²Π΅Π½, ΡΠ΅ΠΌ araC. ΠΡΠΎΡΠΈΠ²ΠΎΠΎΠΏΡΡ
ΠΎ Π»Π΅Π²ΡΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΈ ΠΎΡΡΡΡΡ ΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΡ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π»ΠΈ Π² ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Ρ
in vivo. Π‘ΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈ Π·Π½Π°ΡΠΈΠΌΡΠ΅ ΡΠ°Π·Π»ΠΈΡΠΈΡ Π² ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΠΎΠΉ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² ΠΎΡΠΌΠ΅ΡΠ°Π»ΠΈ ΠΏΡΠΈ ΡΡΠ»ΠΎΠ²ΠΈΠΈ, Π΅ΡΠ»ΠΈ
Π΄ΠΎΠ·Ρ ΠΊΠΎΠ½ΡΡΠ³Π°ΡΠΎΠ² Π±ΡΠ»ΠΈ Π² 10 ΡΠ°Π· Π²ΡΡΠ΅, ΡΠ΅ΠΌ ΡΠ°ΠΊΠΎΠ²ΡΠ΅ araC. ΠΡΠΌΠ΅ΡΠ΅Π½ΠΎ, ΡΡΠΎ Π² ΡΠΎ Π²ΡΠ΅ΠΌΡ ΠΊΠ°ΠΊ ΡΠΎΠΎΡΠ½ΠΎΡΠ΅Π½ΠΈΠ΅ ΠΌΠ΅ΠΆΠ΄Ρ ΡΠΈΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΡΡ
ΠΈ ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡΡ Π΄Π»Ρ araC Π±ΡΠ»ΠΎ 3333, ΡΠΎ Π΄Π»Ρ ΠΊΠΎΠ½ΡΡΠ³Π°ΡΠΎΠ² A ΠΈ B ΡΡΠ° Π²Π΅Π»ΠΈΡΠΈΠ½Π° Π±ΡΠ»Π° Π·Π½Π°ΡΠΈΡΠ΅Π»ΡΠ½ΠΎ Π½ΠΈΠΆΠ΅ (110
ΠΈ 44Β ΡΠΎΠΎΡΠ²Π΅ΡΡΡΠ²Π΅Π½Π½ΠΎ), ΡΡΠΎ ΡΠΊΠ°Π·ΡΠ²Π°Π΅Ρ Π½Π° ΡΠΎ, ΡΡΠΎ ΠΈΠ½Π°ΠΊΡΠΈΠ²Π°ΡΠΈΡ ΠΊΠΎΠ½ΡΡΠ³Π°ΡΠΎΠ² Π ΠΈ Π araC ΠΏΡΠΎΠΈΡΡ
ΠΎΠ΄ΠΈΡ Π² 30 ΠΈ 70 ΡΠ°Π· ΠΌΠ΅Π΄Π»Π΅Π½Π½Π΅Π΅
ΡΠΎΠΎΡΠ²Π΅ΡΒΡΡΠ²Π΅Π½Π½ΠΎ, ΡΠ΅ΠΌ ΠΈΠ½Π°ΠΊΡΠΈΠ²Π°ΡΠΈΡ araC. ΠΡΠ²ΠΎΠ΄Ρ: ΡΠ°Π·Π»ΠΈΡΠΈΡ Π² ΡΠΈΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠΎΠΉ ΠΈ ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ araC ΠΈ Π°ΡΠΎΠ²
Π²Π΅ΡΠΎΡΡΒΠ½Π΅Π΅ Π²ΡΠ΅Π³ΠΎ ΠΎΠΏΡΠ΅Π΄Π΅Π»ΡΡΡΡΡ ΠΌΠ΅Π΄Π»Π΅Π½Π½ΡΠΌΠ²ΡΡΠ²ΠΎΠ±ΠΎΠΆΠ΄Π΅Π½ΠΈΠ΅ΠΌ araC, Π° ΠΏΡΠΎΠ΄ΠΎΠ»ΠΆΠΈΡΠ΅Π»ΡΠ½ΡΠΉ ΠΏΡΠΎΡΠ΅ΡΡ Π²ΡΡΠ²ΠΎΠ±ΠΎΠΆΠ΄Π΅Π½ΠΈΡ araC Π·Π°ΡΠΈΡΠ°Π΅Ρ
Π°ΠΊΡΠΈΠ²Π½ΠΎΠ΅ Π²Π΅ΡΠ΅ΡΡΠ²ΠΎ ΠΎΡ ΠΈΠ½Π°ΠΊΡΠΈΠ²Π°ΡΠΈΠΈ ΠΈ ΡΠ²Π΅Π»ΠΈΡΠΈΠ²Π°Π΅Ρ ΠΏΡΠΎΠ΄ΠΎΠ»ΠΆΠΈΡΠ΅Π»ΡΠ½ΠΎΡΡΡ ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ Π΄Π΅ΠΉΡΡΠ²ΠΈΡ ΠΊΠΎΠ½ΡΡΠ³Π°ΡΠΎΠ²
Main targets of tetraaza macrocyclic copper complex on L1210 murine leukemia cells
Several metal complex agents have already been introduced into clinical tumor therapy and others are subject of antitumor studies. In this study we focused on the tetraaza macrocyclic copper complex (Cu(TAAB)Cl-2). We studied the influence of the substance on cell growth, cell cycle, membrane integrity, necrosis, apotosis and glutathione level on the leukemic cell line L1210 in 1-day (22 h) and 3-day (72 h) experiments. The metal complex shows a dose-dependent antiproliferative effect, without affecting cell cycle phases. The present results confirm that copper complex can damage plasmatic membranes and trigger apoptosis, and that after treatment of leukemic cells with the copper complex, glutathione levels were increased. (C) 2002 Elsevier Science Ltd. All rights reserved