Abstract
The antitumor activity of certain anti-inflammatory drugs is often attributed to an indirect effect based on the inhibition of COX enzymes. In the case of anti-inflammatory prodrugs, this property could be attributed to the parent molecules with mechanism other than COX inhibition, particularly through formulations capable of slowing down their metabolic conversion. In this work, a pilot docking study aimed at comparing the interaction of two prodrugs, nabumetone (NB) and its tricyclic analog 7-methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (MC), and their common active metabolite 6-methoxy-2-naphthylacetic acid (MNA) with the COX binding site, was carried out. Cytotoxicity, cytofluorimetry, and protein expression assays on prodrugs were also performed to assess their potential as antiproliferative agents that could help hypothesize an effective use as anticancer therapeutics. Encouraging results suggest that the studied compounds could act not only as precursors of the anti-inflammatory metabolite, but also as direct antiproliferative agents.
Highlights
The correlations between inflammation and cancer onset and progression are in many cases proven by increasingly clear evidence
The results show that the poses obtained through our blind docking experiments were within 2 Å from the crystallographic ligand for both methoxy-2-naphthylacetic acid (MNA) and MC, whereas for NB, the distance was slightly larger due to the extended conformation of its –CH2–CH2–CO–CH3 tail
The binding modes of the ligands were analyzed through visual inspection, and interactions energies and distances were quantified by using Molecular Operating Environment (MOE) 2018.01 (Chemical Computing Group ULC, Montreal, MTL, Canada)
Summary
The correlations between inflammation and cancer onset and progression are in many cases proven by increasingly clear evidence. NS-398, a selective COX-2 inhibitor structurally related to nimesulide, was found to possess antiproliferative activity against colorectal cancer cell lines [7] The latter result was recently confirmed when the overexpression of COX-2, together with higher levels of VEGF, was indicated to be able to promote endothelial lumens formation and neovascularization, favoring cancer cells growth and metastasis. This effect could be counteracted by COX-2 targeting agents, which would inhibit the enzyme production [28,29,30,31]. XF-u1ritnhecramncoerreh, aths ebereonlereocfeCntOlyXr-e1- in ccaonncsiedrehreads.bIneefnacrte, aceltnhtoluygrhectohinssiisdoeforerdm. wInasfaccotn, saildtehroeudgahs tchoinsstiistouftoivremanwdatshceonnisnivdoelrveeddas cinonpshtyitsuiotilvoegiacnaldptrhoecnesisnevs,oilnvcerdeaisnedphleyvseilosloofgCicOalXp-1rowceesreseosc,ciansciroenaaslelydrleepvoerltseodfinCOdiXff-e1rewntere otycpcaessioofncaalnlycerre,ppoarrtteicdulianrldyifdfeurreinngt ttyhpe eesarolyf cpahnacseers, opfatrhtiecduilsaeralysed[u37ri]n. g the early phases of the dAiscecaosred[i3n7g]l.y, our study started with a preliminary in silico assay based on the evaluationAocfctohrediinntgelrya,cotiuornsotuf dthyesmtaortleedcuwleisth(NaBp,rMelCim, iannadryMiNn Asil)icwoitahssthaye tbharseeed-doinmtehnesieovnaalluatsitoruncotuf rteheofinttheeraCcOtioXns aocfttihvee msitoel.eTchuelerse(sNulBts, MobCta,iannedd sMuNggAes)twaitphosthsiebltehraeceti-vdiitmy efonrsiaolnl al sthtreucthturreee odfetrhiveaCtiOveXss, aacntdivethseitee.vTidheenrceesuolftsthoebthaiignheedrsMugNgAestaantpio-isnsfilbalme macatitvoirtyy afoctrivaliltythe twhoreuelddebreivaantiovbesv,ioaunsd ctohneseevqiudeenncceeooff tthhee phhigahrmeraMcoNkiAneatinctit-riannflsafmormmaattioornysa. cItnivoirtydewr otould basecaenrtaoibnvtihoeuisr pcoontesnetqiauleansceanotfictahnecperhaagrmenatcso, tkhienetwticotprarondsfrourgms aNtiBonans.dInMoCrdaserwteollaascsetrhteain tmheeitrabpooltietentMiaNl aAs awnetirceainncveersatiggeanttesd, tihnevtiwtroo pinrotdwrougbsreNaBstacnadncMerCmaosdwelesl,l bays tchyetomtoextaicbiotylite MasNsaAysw, felorewincvyetosmtigeatrtyed, ainndviitmrominuntowbolobtrtienagstecxapnecreimr menotds.eMls,obryeocvyetro,tothxeicsittyudaisesdaycso,mfl-ow cpyotuonmdestwrye, raentdesitmedminunanobalnottit-ienngzyemxpaetircimasesnaytsa. gMaionrsetobvoethr, CthOeXsitsuodfoierdmcs.oDmupeotuonadpsrwefe- re teersetnetdiailnaacntivainttyi-oennzCymOXat-i2c aanssdaya alagcakinostf btooxthiciCtyOoXnishoefoalrtmhys. cDelulse, tbooathprperfoedrernutgisalcaocutilvdity orenpCreOseXn-t2satanrdtinaglapcokinotfstfooxritchiteydoenvehloeaplmtheyntceolflsa,ltbeornthatpivreodanrutigcasnccoeurladgreenptsr.esent starting points for the development of alternative anticancer agents
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