Title Novi benzoksaborolni inhibitori autotaksna kao potencijalni antitumorski lijekovi Title (english) Novel benzoxaborole inhibitors of autotaxin as potential anticancer drugs Author Kristina Kraljić Mentor Milan Mesić (mentor)Committee member Karlo Wittine (predsjednik povjerenstva)Committee member Mirela Sedić (član povjerenstva)Committee member Sulejman Alihodžić (član povjerenstva)Committee member Milan Mesić (član povjerenstva)Granter University of Rijeka Defense date and country 2019-12-13, Croatia Scientific / art field, BIOTECHNICAL SCIENCES Universal decimal classificationUDC ) 577 - Biochemistry. Molecular biology. Biophysics Abstract Autotaksin (ATX) je izvanstanični enzim koji hidrolizira lizofosfatidilkolin (engl. lysophosphatidylcholine; LPC) u bioaktivnu lizofosfatidilnu kiselinu (engl. lysophosphatidic acid; LPA) koja promiče upalu, fibrozu i karcinom. ATX je prepoznat kao biološka meta posljednjih deset godina i u fokusu je istraživanja mnogih istraživačkih skupina i farmaceutskih kompanija. Međutim, do danas, samo je jedna molekula, Ziritaxestat (GLPG1690), dosegla fazu kliničkih ispitivanja. Molekula se nalazi u fazi 3 kliničkih ispitivanja kao potencijalnog lijeka za idiopatsku plućnu fibrozu. Istražuje se, također potencijal nekolicine drugih sličnih
molekula u liječenju karcinoma. Među molekulama koje su u fokusu istraživanja su i molekule koje sadrže boronsku kiselinu kao funkcionalnost koja je u interakciji s katalitičkom domenom ATX enzima. U ovom modelu vezivanja za aktivno mjesto enzima boronska kiselina stupa u interakciju s jednim od atoma cinka kao i s aminokiselinskim ostatkom treonina 209. U ovom
je radu opisan dizajn novih potencijalnih ihibitora ATX-a koji sadrže benzokisborolnu funkcionalnost koje oponašaju način vezivanja boronskih kiselina te je sintetizirano 20 novih benzoksaborolnih inhibitora ATX-a. Također je za povezivanje benzoksiborolne funkcionalnosti i lipofilnog dijela molekule dizajnirana stabilnija heterociklička spojnica. Sintetiziranim spojevima određena je in vitro inhibitorna aktivnost prema ATX-u, fizikalno kemijska svojstva te in vitro ADME svojstva. Među sintetiziranim molekulama, identificirana je molekula 37 koja pokazuje sličnu inhibitornu aktivnost kao i molekula HA155 koja je služila
kao komparativni standard. Molekula 37 pokazala je i niži stupanj vezivanja za proteine plazme te dobru topljivost. Stabilnost spomenute molekule u štakorskoj i humanoj plazmi također je bolja od standardne molekule HA155. U in vivo eksperimentu spoj 37 pokazalo je daleko bolje farmakokinetičke značajke u usporedbi s molekulom H155 koja je korištena kao kontrolna supstanca.
Abstract (english) Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) into bioactive lysophosphatidic acid (LPA), which promotes inflammation, fibrosis and cancer. ATX has been recognized as a biological target for the last ten years and has been the focus of research for many research groups and pharmaceutical companies. Until today only one molecule, Ziritaxestat (GLPG1690) entered clinical studies Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules are being investigated as ATX inhibitors and as a potential cancer therapy. Among them several potent molecules containing boronic acid motif that interacts in catalytic domain of autotaxin. The boronic acid interacts with one of the zinc atoms as well as with the amino acid residue of threonine 209. This work describes the design of new potential ATX inhibitors containing benzoxyborole functionality mimicking the mode of binding of boronic acids. 20 new compounds were synthesized as ATX inhibitors. Also, s more stable heterocyclic linker has been designed to connect benzoxyborole functionality to the lipophilic portion of the molecule. The synthesized compounds were determined in in vitro inhibitory activity against ATX. The physicochemical properties of the compounds were eavluated in in vitro ADME assays.
Among the synthesized molecules, molecule 37 was identified as the molecule that exhibit similar inhibitory activity to HA155, which served as a controle substance. Molecule 37 also showed a lower plasma protein binding than HA155 and good solubility. The stability of molecule 37 in rat and human plasma is also better than the standard molecule HA155. The
pharmacokinetic characteristics of compounds 37 and HA155 were determined in an in vivo experiment. In this experiment, the pharmacokinetic parameters of molecule 37 were found to be much better compared to the H155 molecule used in this work as a control substance.
Keywords
autotaksin
lizofosfatidilna kiselina
benzoksaboroli
karcinom
Keywords (english)
Autotaxin (ATX)
lysophosphaditic acid (LPA)
benzoxaboroles
cancer
Language croatian URN:NBN urn:nbn:hr:193:987492 Promotion 2021 Study programme Title: Medicinal chemistry Type of resource Text File origin Born digital Access conditions Access restricted to students and staff of home institution Terms of use Created on 2021-04-26 09:10:45
