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Načrtovanje, sinteza in vrednotenje novih trinemskih protimikrobnih učinkovin : doktorska disretacija
Plantan, Ivan (Author), Urleb, Uroš (Mentor) More about this mentor... This link opens in a new window

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Abstract
V svetu se zopet povečuje smrtnost zaradi nalezljivih bolezni. Glavni razlog za to sta pojav rezistence bakterij ter upad števila novih antibiotikov, ki bi bili kos tej novodobni grožnji. Čeprav so v terapiji in raziskavah prisotni že več kot pol stoletja, so beta-laktamski antibiotiki še vedo zelo zanimivi za znanost, industrijo in terapijo. Trinemi so triciklični karbapenemi z zelo dobrimi antibiotičnimi lastnostmi. Delujejo na širok spekter po Gramu pozitivnih in po Gramu negativnih bakterij z inhibicijo encimov, ki so pomembni za sintezo peptidoglikana – pomembnega biopolimera bakterijske celične stene. V doktorskem delu smo se ukvarjali z načrtovanjem in s sintezo trinemskih učinkovin. Kot spojini vodnici sta nam služili sanfetrinem in LK-157. V prvem delu smo načrtovali in sintetizirali derivata LK 157 z namenom doseganja boljše aktivnosti ter izboljšave farmakokinetičnih parametrov. Sintetizirali smo natrijevo sol (8S,9R)-10-(E)-etiliden-4-(S)-butoksi-11-okso-azatriciklo[7.2.0.03,8]undek-2-en-karboksilata (LK-170) ter natrijevo sol (8R,9R)-10-(E)-etiliden-4-(R)-butoksi-11-oksoazatriciklo[7.2.0.03,8]undek-2-en-karboksilata (LK-171). Spojini sta dobra inhibitorja razreda A -laktamaz (predvsem LK-171 – IC50 = 12 nM), toda slabša inhibitorja beta-laktamaz razreda C glede na spojino vodnico. Kristalna struktura aciliranega kompleksa LK-171 z beta-laktamazo razreda C (AmpC P99) je razkrila glavne interakcije med encimom in inhibitorjem. V drugem delu smo se lotili sintezno bolj zahtevne substitucije osnovnega trinemskega skeleta z modifikacijo hidroksietilne verige, ki je prisotna pri večini karbapenemov in trinemov, z uvedbo fluora na konec etilne verige. Med pomembnejšimi sinteznimi stopnjami je stereoselektivna redukcija etil 2-benzamidometil-4-fluoro-3-okso-butanoata v etil (2S,3S)-2-benzamidometil-4-fluoro-3-oksobutanoat z ee = 96 % in de = 66 % z uporabo Ru asimetričnega transfer hidrogeniranja. V nadaljnjih stopnjah smo zadnji intermediat pretvorili do (1’S,3R)-4-acetoksi-3-[2’-fluoro-1’-trimetilsililoksietil]-2-azetidinona, ki je zanimiva izhodna spojina za več možnih karbapenemov in drugih derivatov beta-laktamov. Končna produkta drugega dela sta bili spojini LK-180 – natrijeva sol (4S,8S,9R,10S)-4-metoksi-10-[2-fluoro-1-(S)-trimetilsililoksietil]-11-okso-azatriciklo-[7.2.0.03,8]undek-2-en-2-karboksilata (7.25), ter LK-181 – natrijeva sol (8S,9R)-10-(E)-etiliden-4-(S)-metoksi-11-okso-azatriciklo[7.2.0.03,8]undek-2-en-karboksilata. Spojina LK-180 ima odličen antibiotičen učinek in deluje na več sevov patogenih bakterij, vključno s sevi, ki tvorijo razširjen spekter beta-laktamaz. Prav tako je spojina LK-180 odličen inhibitor beta-laktamaze razreda C AmpC P99 (IC50 < 0,5 nM). V drugem sklopu smo poskusili tudi z alternativno sintezo LK-180, ki nas je pripeljala do zanimivega derivata s cikličnim sulfatom – (1R,6S,9bR)-1-(1S)-2,2-diokso-[1,3,2]-dioksatiolan-1-il)-6-metoksi-4,4-dimetiloktahidroazeto[1,2-c]benzo[e][1,3]oksazin-2(4H)-ona.

Language:Slovenian
Keywords:protimikrobne učinkovine, betalaktamski antibiotiki, bakterijska rezistenca, načrtovanje, sinteza, molekularno modeliranje, disertacije
Work type:Dissertation (m)
Tipology:2.08 - Doctoral Dissertation
Organization:FFA - Faculty of Pharmacy
Year:2009
Publisher:[I. Plantan]
Number of pages:V, 133 str.
Place:Ljubljana
UDC:615.281.9(043.3)
COBISS.SI-ID:2668913 This link opens in a new window
Views:217
Downloads:37
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Secondary language

Language:English
Title:Design, synthesis and evaluation of novel trinem compounds with antimicrobial activity
Abstract:
The number of worldwide deaths associated with infectious diseases is incresing. One of the main reasons for that is the developement of resistance of bacteria to available antibiotics and the decline in the number of new antibiotics entering the market that would be effective against resistant strains. Despite their frequent use in therapy and over half a century of research, beta-lactam antibiotics still represent an interesting compound – for science, the industry and in treatment. Trinems are tricyclic carbapenems with very good antimicrobial activity. They are active against Grampositive and Gram-negative microorganisms by inhibiting enzymes responsible for the synthesis of peptidoglican – a crucial biopolymer and main constituent of the bacterial cell wall. In the thesis we used known trinemic compounds, sanfetrinem and LK-157, as leads for further development. In the first part, we designed and synthesized derivatives of LK-157 with the aim of achieving better activity against beta-lactamases and better pharmacokinetic properties. We have synthesized sodium salt of (8S,9R)-10-(E)-ethylidene-4-(S)-butoxy-11-oxo-azatricyclo[7.2.0.03,8]undec-2-en-carboxylate (LK170) and sodium salt of (8R,9R)-10-(E)-ethylidene-4-(R)-butoxy-11-oksoazatricyclo[ 7.2.0.03,8]undec-2-en-carboxylate (LK-171). The compounds are good inhibitors of class A beta-lactamases (especially LK-171 – IC50 = 12 nM), but with modest activity against class C beta-lactamases compared to lead compound. The crystal structure of the acylated complex of LK-171 with AmpC P99 revealed the main interactions between the enzyme and the inhibitor. In the second part, we wanted to modify the hydroxyethyl side chain, which is present in most clinicaly important carbapenems and most known trinems, substituting it with fluorine at the end of the ethyl chain. Starting with ethyl fluoroacetate, one of the most important synthetic steps was the stereo selective reduction of 2-benzamidomethyl-4-fluoro-3-oxo-butanoate into ethyl (2S,3S)-2-benzamidomethyl-4-fluoro-3-oxobutanoate with ee = 96 % and de = 66 %. This was achieved with the use of Ru-catalyzed asymmetric transfer hydrogenation. In subsequent steps, we transformed this intermediate to a synthetically useful precursor (1’S,3R)-4-acetoxy-3-[2’-fluoro-1’-trimethylsilyloxyethyl]-2-azetidinone, which is an interesting starting point for a variety of carbapenems or other derivatives with a beta-lactam structure. The final compounds of the second part were LK-180 – as sodium salt of (4S,8S,9R,10S)-4-methoxy-10-[2-fluoro-1-(S)-trimethilsilyloxyethyl]-11-oxoazatricyclo-[7.2.0.03,8]undec-2-en-2-carboxylate and LK-181 as sodium salt of (8S,9R)-10-(E)-ethylidene-4-(S)-methoxy-11-oxo-azatricyclo[7.2.0.03,8]undec-2-en-carboxylate. LK-180 has a very good antibiotic activity against a broad spectrum of pathogenic bacteria, including strains which produce extended spectrum beta-lactamases. LK-180 is also a very good inhibitor of beta-lactamases, especially of the class C enzymes AmpCP99 (IC50 < 0.5 nM ). One of our goals was also an alternative synthesis of LK-180 which would be cheaper, have better yield and would be sutiable for scale-up. This produced a very interesting intermediate with a cyclic sulfate group - (1R,6S,9bR)-1-((1S)-2,2-dioxo-[1,3,2]-dioxathiolan-1-il)-6-methoxy-4,4-dimethyloctahydroazeto[1,2- c]benzo[e][1,3]oxazin-2(4H)-one.


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