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Primerjava citotoksičnosti aromatskih aminov 2-aminobenzotiazolov in njihovih amidnih derivatov
Permanšek, Tjaša (Avtor), Peterlin Mašič, Lucija (Mentor) Več o mentorju... Povezava se odpre v novem oknu

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Izvleček
In vitro testiranje citotoksičnosti spojin predstavlja pomemben del odkrivanja in sinteze novih učinkovin. Ker je kot farmakološki učinek citotoksičnost pri večini učinkovin nezaželena, jo ugotavljamo že zgodaj v procesu razvoja novih učinkovin. S tem zagotavljamo varnost ter prihranimo čas, pa tudi sredstva, ki bi jih porabili za razvoj učinkovine, ki sicer zaradi neustreznega toksikološkega profila ne bi imela potenciala za nadaljnji razvoj. Za vrednotenje citotoksičnosti spojin so na voljo številne različice testov, pri katerih izkoriščamo spremembo ene od lastnosti celic po tem, ko so te izpostavljene testnim spojinam. Najpogosteje v ta namen določamo njihovo encimsko aktivnost, permeabilnost celične membrane ali pa sintezo ATP. Rezultati enostavnih in vitro testov citotoksičnosti so dobra osnova za nadaljnja in vivo testiranja. Aromatski amini predstavljajo strukturno osnovo številnih učinkovin, a se pogosteje omenjajo v povezavi z njihovimi zdravju škodljivimi učinki, predvsem genotoksičnim in kancerogenim delovanjem. Uvrščamo jih med prokancerogene, tj. med spojine, ki se z metabolično aktivacijo v telesu pretvorijo v aktivne metabolite, ti pa so odgovorni za toksične učinke. V raznolikih reakcijah metabolizma nastajajo predvsem visoko reaktivne elektrofilne zvrsti, med katerimi so najnevarnejši znani metaboliti nitrenijevi ioni. V okviru magistrske naloge smo z MTS testom na celični liniji MCF-7 vrednotili citotoksičnost potencialnih protimikrobnih učinkovin, amidov, katerih skupna strukturna lastnost je 2-aminobenzotiazolno ogrodje. Ker lahko med metabolizmom le-teh pride do hidrolize amidne vezi in nastanka aromatskih aminov, smo testirali tudi citotoksičnost teh, nato pa rezultate primerjali med seboj. Zanimalo nas je, ali se amidi in amini razlikujejo v citotoksični aktivnosti, pa tudi, kako strukturne lastnosti spojin vplivajo na tovrstno delovanje. Med amini smo med trinajstimi spojinami določili sedem spojin s citotoksično aktivnostjo, med amidi pa osem. S primerjavo strukture spojin smo tako pri aminih kot amidih ugotovili trend večanja citotoksične aktivnosti spojin z večanjem molekulske mase substituenta, pripetega na mestu 4 benzotiazolnega ogrodja. Večjo citotoksično aktivnost smo določili spojinam, ki so imele v stranskih verigah vezane bazične skupine. Zaznali smo tudi nekatere podobnosti v strukturnih elementih med spojinami s podobno citotoksično aktivnostjo, a bi morali za zanesljivejše ugotovitve raziskati in testirati citotoksičnost večjega števila spojin. Pričakovali smo, da bodo med testiranimi spojinami aromatski amini izkazovali večjo citotoksično aktivnost v primerjavi z njihovimi amidnimi derivati, a tega nismo potrdili. Med dvanajstimi pari spojin smo le pri treh parih večjo citotoksičnost določili aminu, pri šestih parih smo večjo citotoksično aktivnost določili amidu, pri treh parih pa sta bili obe spojini v paru necitotoksični. Enega para spojin zaradi neustreznih rezultatov nismo vključili v primerjavo. Dobljeni rezultati so osnova in vodilo za nadaljnje raziskovalno delo ter sintezo učinkovin.

Jezik:Slovenski jezik
Ključne besede:citotoksičnost, 2-aminobenzotiazoli, aromatski amini, metabolična aktivacija, MCF-7
Vrsta gradiva:Magistrsko delo/naloga (mb22)
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2020
Število ogledov:168
Število prenosov:108
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
 
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:Cytotoxicity comparison of 2-aminobenzothiazole aromatic amines and their amide derivatives
Izvleček:
In vitro cytotoxicity testing of compounds represents an important part of the detection and synthesis of new active substances. Because cytotoxicity is undesirable in most active substances as a pharmacological effect, it is detected early in the process of the development of new active substances. This ensures the safety and saves time, as well as the funds that would be spent on the development of the active ingredient which, otherwise, would not have the potential for further development because of the inadequate toxicological profile. To evaluate the cytotoxicity of compounds, several test variants are available in which we take advantage of a change in one of the properties of the cells after they have been exposed to the test compounds. For this purpose, we determine their enzymatic activity, cell membrane permeability, or ATP synthesis most often. The results of simple in vitro cytotoxicity tests are a good basis for further in vivo testing. Aromatic amines represent the structural basis of many active substances but are more often mentioned in connection with their harmful effects, mostly genotoxic and carcinogenic effects. They are classified as procarcinogens, compounds that are converted into active metabolites by metabolic activation in the body. They are responsible for toxic effects. In various metabolic reactions, highly reactive electrophilic species are formed. Among them, nitrenium ions are the most dangerous known metabolites. Within the framework of the master's thesis, we used the MTS test on the MCF-7 cell line to evaluate the cytotoxicity of potential antimicrobial agents, amides, whose common structural property is the 2-aminobenzothiazole backbone. Since amide bond cleavage and aromatic amine formation can occur during their metabolism, we also tested the cytotoxicity of these and then compared the results with each other. We were interested in whether amides and amines differ in cytotoxic activity, as well as how the structural properties of compounds affect this type of action. Among the amines, seven compounds with cytotoxic activity were identified among thirteen compounds and eight among the amides. By comparing the structure of the compounds, we found a trend of increasing the cytotoxic activity of the compounds in both amines and amides by increasing the molecular weight of the substituent attached at site 4 of the benzothiazole backbone. Higher cytotoxic activity was determined for compounds that had basic centers bound in side chains. We also detected some similarities in structural elements between compounds with similar cytotoxic activity. However, the cytotoxicity of a larger number of compounds should be investigated and tested for more reliable ascertainments. We expected aromatic amines to exhibit greater cytotoxic activity among their test compounds compared to their amide derivatives but this was not confirmed. Among the twelve pairs of compounds, higher cytotoxicity was determined for amine in only three pairs. Higher cytotoxic activity was determined for amide in six pairs. Both compounds were non-cytotoxic in three pairs. One pair of compounds was not included in the comparison due to inadequate results. The obtained results are the basis and guide for further research work and synthesis of active ingredients.

Ključne besede:cytotoxicity, 2-aminobenzothiazoles, aromatic amines, metabolic activation, MCF-7

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