Frequency and types of mutations in BRCA genes in families with positive history of breast/ovarian cancer in Serbia

Uvod: Proteinski produkti gena BRCA1 i BRCA2 uključeni su u važne ćelijske procese, kao što su kontrola ćelijskog ciklusa i popravka oštećenja DNK. Mutacije u jednom od ovih gena predstavljaju korak bliže gubitku kontrole nad genomskom stabilnošću i ćelijskom deobom, pa osobe koje naslede mutacije u ovim genima češće oboljevaju od karcinoma dojke i/ili jajnika. Geni BRCA su veliki, mutacije su raspoređene duž celih gena bez grupisanja, što dodatno otežava njihovu detekciju. Spektar mutacija u genima BRCA različit je u različitim etničkim grupama. U nekim populacijama sa visokom učestalošću zastupljene su mutacije koje su u drugim populacijama retke. U isto vreme, veliki deo mutacija u genima BRCA detektovane su samo jednom, pa se može reći da većina porodica pod rizikom ima svoju sopstvenu porodičnu mutaciju. Mutacija 5382insC u 20. egzonu gena BRCA1 karakteristična je za slovenske populacije i njena učestalost opada od istoka ka zapadu Evrope. Oko 6-7% svih karcinoma dojke i oko 10% svih karcinoma jajnika je nasledno, povezano sa mutacijama germinativnih ćelija u genima BRCA1 i BRCA2. Nosioci mutacija u genima BRCA nose 5 do 8 puta veći životni rizik za oboljevanje od karcinoma dojke i 10 do 20 puta veći životni rizik za karcinom jajnika. Cilj istraživanja je bio da se otkriju najučestalije mutacije u genima BRCA1/2 u našoj populaciji i utvrdi koje se od njih mogu smatrati osnivačkim mutacijama, kako bi se ubrzalo, pojednostavilo i pojeftinilo BRCA testiranje. Da bi se ovaj cilj ostvario, bilo je neophodno utvrditi tipove i učestalosti mutacija u genima BRCA1 i BRCA2 kod osoba sa pozitivnom porodičnom istorijom za karcinom dojke i/ili jajnika u Srbiji. Osim toga, u sistematskom uzorku karcinoma dojke bilo je potrebno utvrditi učestalost mutacije 5382insC u genu BRCA1 kao potencijalne osnivačke mutacije u našoj populaciji. U ispitivanoj grupi osoba koje su testirane na prisustvo mutacija u genima BRCA1/2 procenjivana je i efikasnost predviđanja BRCAPRO programa. Materijal i metode: Analizirano je 85 uzoraka periferne krvi osoba sa povećanim rizikom za karcinom dojke i/ili jajnika koje potiču iz 69 porodica. Takođe, analiziran je i sistematski uzorak karcinoma dojke koji se sastoji od 257 uzoraka krvi obolelih. Prisustvo mutacija u genima BRCA analizirano je automatskim sekvenciranjem, dok je prisustvo mutacije 5382insC u genu BRCA1 u sistematskom uzorku određivano PCR-om specifičnim za alel. Za statističku obradu podataka korišćeni su testovi neparametrijske statistike: χ2 test i Fišerov test. Rezultati: Učestalost oštećujućih mutacija u uzorku porodica sa naslednim karcinomom dojke i/ili jajnika iznosi 10,59% (9/85). Sve detektovane oštećujuće mutacije su po tipu frameshift mutacije. Detektovane su i 3 nove porodično-specifične mutacije (1 u genu BRCA1 i 2 u genu BRCA2). Učestalost mutacije 5382insC u genu BRCA1 u sistematskom uzorku karcinoma dojke je 0,39% (1/257). Podizanjem granice BRCAPRO verovatnoće na 40% moguće je uočiti razliku između benignih polimorfizama i oštećujućih mutacija. Nije bilo moguće subgrupisanje neklasifikovanih varijanti na osnovu vrednosti BRCAPRO verovatnoće. BRCAPRO verovatnoća, sem sa srodnicima prvog i drugog stepena srodstva, koreliše i sa brojem obolelih srodnika u široj porodici. U odnosu na anatomsku lokalizaciju, BRCAPRO verovatnoća koreliše sa brojem srodnika obolelih od karcinoma dojke, ali ne i od karcinoma jajnika. Zaključak: Učestalost mutacija u genima BRCA1/2 kod ispitanika pod rizikom za nastanak naslednog karcinoma dojke i/ili jajnika u Srbiji slična je učestalostima dobijenim u drugim populacijama. Osim već poznatih mutacija u genima BRCA1/2 pokazane su i nove porodično-specifične mutacije. Nisu detektovane mutacije koje bi se mogle okarakterisati kao osnivačke mutacije za našu populaciju. BRCAPRO program se pokazao kao koristan pri odabiru osoba za BRCA testiranje, ali pri odabiru kandidata za testiranje, usled nedostataka BRCAPRO programa, treba analizirati i rodoslov. Podizanje granice BRCAPRO verovatnoće prilikom odabira ispitanika za BRCA testiranje sa 10% na 40% moglo bi da poveća efikasnost BRCA testiranja.Background: Protein products of BRCA1 and BRCA2 genes are included in important cellular processes, such as cell cycle control and DNA repair. Mutations in one of these genes is a step thowards losing control over genomic stability and cell division, and individuals who inherit mutations in these genes develop breast and/or ovarian cancer more frequently. BRCA genes are large, mutations are scattered throughout whole genes without clustering, which makes mutation detection even more difficult. The spectrum of BRCA mutations is different for each ethnic group. Mutations that are highly frequent in some populations are rare in other populations. At the same time, large proportion of BRCA mutations have been detected only once, and it can be said that majority of families under risk have their own family mutation. Mutation 5382insC in BRCA1 exon 20 is characteristic for Slavic populations and its frequency decreases from east to west of Europe. About 6-7% of all breast cancer cases and about 10% of all ovarian cancer cases are hereditary, associated to germ line mutations in BRCA1 and BRCA2 genes. BRCA mutation carriers have 5 to 8 times higher lifetime risk for breast cancer and 10 to 20 times higher lifetime risk for ovarian cancer. Aim of this study was to identify the most frequent BRCA1/2 mutations in our population and to find out which of them may be regarded as founder mutations, in order to make BRCA testing faster, easier and less expensive. In order to achieve this goal, it was necessary to identify types and frequencies of BRCA1/2 mutations in individuals with positive family history of breast and/or ovarian cancer in Serbia. In addition, it was necessary to identify the frequency of BRCA1 mutation 5382insC in breast cancer consecutive sample, as possible founder mutation in our population. In analysed group of individuals tested for the presence of BRCA1/2 mutations the efficiency of BRCAPRO software prediction was assessed. Material and methods: Eighty five peripheral blood samples from high risk individuals for breast and/or ovarian cancer from 69 families was analyzed. In addition, consecutive sample that included 257 blood samples from breast cancer patients was analyzed. The presence of BRCA gene mutations was analyzed by automatic sequencing, while the presence of 5382insC mutation in BRCA1 gene was determined by alel-specific PCR. For statistic analyses, non-parametric tests were used: χ2 test and Fisher test. Results: The frequency of deleterious mutations in sample of families with hereditary breast and/or ovarian cancer is 10.59% (9/85). All detected deleterious mutations are frameshift mutations. Three novel family-specific mutations have been detected (one in BRCA1 and two in BRCA2 gene). The frequency of BRCA1 mutation 5382insC in breast cancer consecutive sample is 0.39% (1/257). By raising the treshold of BRCAPRO probability to 40% it is possible to observe the difference between benign polymorphisms and deleterious mutations. Subgrouping of unclassified variants according to the value of BRCAPRO probability was not possible. BRCAPRO probability, in addition to the first and second degree relatives, correlates also with the number of more distant relatives who developed cancer. In relation to anatomic localisation, BRCAPRO probability correlates with the number of relatives who developed breast cancer, but not with the number of those who developed ovarian cancer. Conclusion: The frequency of BRCA1/2 mutations in probands under rsk for hereditary breast and/or ovarian cancer in Serbia is similar to those determined in other populations. In addition to already known BRCA1/2 mutations, new family-specific mutations have been detected. Mutation that could be qualified as founder mutations for our population have not been detected. BRCAPRO software has been shown to be useful in selection of probands for BRCA testing, but in this selection, due to BRCAPRO limitations, the pedigree should be analysed too. Raising the treshold for BRCAPRO probability in proband selection for BRCA testing from 10% to 40% could raise the efficiency of BRCA testing

Genetics of breast cancer: Contribution of BRCA1/2 genes alterations to hereditary predisposition

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Sinteza i fizičko‐hemijska karakterizacija tri novosintetisana derivata sulfhidroksamske kiseline kao potencijalnih dualnih inhibitora enzima ciklooksigenaze‐2 i 5‐lipooksigenaze

Inflammatory mediators derived from arachidonic acid by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) are involved in the pathogenesis of various inflammatory diseases. Inhibition of the COX pathway is thought to lead to potentiation of the LOX pathway, and inhibition of both pathways represents a rational approach to the design and development of more effective and safer anti-inflammatory drugs (1). The aim of this study was the synthesis and physico-chemical characterization of 1f, 1g and 1h derivatives derived from a previously conducted 3D-QSAR study and molecular docking (2). The sulfhydroxamic acid derivative 1f was synthesized in a two-step process. Sulfonyl chloride was synthesized from commercially available sulfonic acid and thionyl chloride in the presence of a catalytic amount of DMF. Sulfhydroxamic acid was further obtained from previously synthesized sulfonyl chloride and hydroxylamine hydrochloride in the presence of 10% NaHCO3 solution. Sulfhydroxamic acid derivatives, 1g and 1h were synthesized from commercially available sulfonyl chlorides and hydroxylamine hydrochloride in the presence of 10% NaHCO3 solution. The reaction mixtures were purified by liquid-liquid extraction and preparative TLC to give derivatives 1f, 1g, 1h in yields: 26%, 53% and 63%. The structure and purity of the synthesized compounds were confirmed by determination of the melting points and spectroscopic techniques (ATR-FTIR, 1H-NMR, 13C-NMR, MS/MS). Based on a previously conducted in silico study, the voluminous sulfhydroxamic group is responsible for iron chelation within 5-LOX active center and for COX-2 selectivity, as COX-2 has wider side pocket, so potent inhibition of COX-2 and 5-LOX enzymes is expected.Inflamatorni medijatori koji nastaju iz arahidonske kiseline posredstvom enzima ciklooksigenaze (COX) i lipooksigenaze (LOX) učestvuju u patogenezi brojnih inflamatornih oboljenja. Smatra se da inhibicija COX puta dovodi do potenciranja LOX puta, te inhibicija oba puta predstavlja racionalan pristup dizajniranja i razvoja novih, efikasnijih i bezbednijih antiinflamatornih lekova (1). Cilj rada je bila sinteza i fizičko-hemijska karakterizacija derivata 1f, 1g i 1h proisteklih iz prethodno sprovedene 3D-QSAR studije i molekulskog docking-a (2). Derivat sulfhidroksamske kiseline 1f je sintetisan u dvostepenom postupku pri čemu se najpre iz komercijalno dostupne sulfonske kiseline i tionil hlorida u prisustvu katalitičke količine DMF dobija odgovarajući sulfonil hlorid. Odgovarajuća sulfhidroksamska kiselina (1f) se dobija u drugom koraku iz prethodno sintetisanog sulfonil hlorida i hidroksilamin-hidrohlorida u prisustvu 10% rastvora NaHCO3 . Derivati sulfhidroksamske kiseline, 1g i 1h su sintetisani jednostepenim postupkom iz komercijalno dostupnih sulfonil hlorida i hidroksilamin-hidrohlorida u prisustvu 10% rastvora NaHCO3 . Nakon postupka sinteze jedinjenja su prečišćena tečno-tečnom ekstrakcijom i preparativnom TLC pri čemu se dobijaju derivati 1f, 1g, 1h u prinosima 26%, 53% i 63%. Struktura i čistoća sintetisanih jedinjenja je potvrđena određivanjem temperature topljenja i spektroskopskim (ATR-FTIR, 1 H-NMR, 13 C-NMR, MS/MS) tehnikama. Na osnovu prethodno sprovedene in silico studije, voluminozni centar i sulfhidroksamska grupa sintetisanih derivata su odgovorni za COX-2 selektivnost zbog prisustva šireg vezivnog mesta unutar COX-2 enzima, dok sulfhidroksamska grupa unutar 5-LOX enzima helira gvožđe aktivnog centra i inhibira enzim, te se očekuje potentna dualna COX-2 i 5-LOX inhibitorna aktivnost sintetisanih derivata.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

The use of PAMPA for skin permeability and retention evaluation of metilprednisolone - derived cortienic acid derivatives as potential soft glucocorticoids

Amidi ili estri kortienske kiseline metilprednizolona predstavljaju potencijalne soft glukokortikoide sa manje izraženim neželjenim efektima u odnosu na konvencionalne glukokortikoide. Retencija i permeabilnost su važne osobine soft glukokortikoida za primenu na kožu koje mogu značajno uticati na njihovu aktivnost i pojavu neželjenih efekata. Jedna od in vitro metoda koja se najčešće koristi za procenu ovih osobina je PAMPA (Parallel Artificial Membrane Permeability Assay). Cilj ovog rada je procena permeabilnosti i retencije u koži pet amida (MPMA, MPMAB, MPMAIB, MPMGB i MPPA) i jednog tioestra (MPEMP) kortienske kiseline metilprednizolona primenom PAMPA testa. Procena permeabilnosti i retencije u koži izvršena je na hidrofobnoj Millipore PVDF PAMPA mikrotitarskoj ploči sa 96 odeljaka. Praćena je difuzija ispitivanih jedinjenja kroz membranu koju čine 70 % silikonsko ulje i 30 % izopropilmiristat. Koncentracije u polaznim rastvorima, donorskim i akceptorskim odeljcima određene su primenom LC‐MS/MS metode. Primenom PAMPA testa određeni su koeficijenti permeabilnosti (logPe) i retencije (R). Vrednosti logPe su u opsegu od ‐6,81 do ‐5,09, dok su vrednosti R u opsegu 1,52 ‐ 65,25. Jedinjenje sa najnižom vrednošću logPe je MPMGB, dok su za MPEMP određene najviše vrednosti parametara logPe i R, te se od ovog derivata mogu očekivati najveća permeabilnost i retencija u koži. Permeabilnost i retencija u koži pet amida (MPMA, MPMAB, MPMAIB, MPMGB i MPPA) i jednog tioestra (MPEMP) kortienske kiseline metilprednizolona procenjeni su primenom PAMPA testa. Najviše vrednosti parametara logPe i R su dobijene za MPEMP, te se ovaj derivat izdvaja kao najpovoljniji za primenu na kožu.Amides or esters of methylprednisolone‐derived cortienic acid are potential soft glucocorticoids with fewer side effects in comparison to traditional glucocorticoids. Retention and permeability are important properties of soft glucocorticoids for local skin application which could significantly influence their activity and occurrence of side effects. PAMPA (Parallel Artificial Membrane Permeability Assay) is one of the mostly used in vitro methods for the estimation of these properties. The aim of this study was estimation of skin permeability and retention of five amides (MPMA, MPMAB, MPMAIB, MPMGB and MPPA) and one thioester (MPEMP) of metilprednisolone ‐ derived cortienic acid using PAMPA. Estimation of skin permeability and retention was performed on hydrophobic Millipore PVDF PAMPA microtiter 96‐well plate. Diffusion of tested compounds through membrane, consisting of 70% silicon oil and 30% isopropyl myristate, was tested. Concentrations in starting solutions, as well as in donor and acceptor compartments were determined using LC‐MS/MS method. PAMPA permeability coefficients (logPe) and retention (R) were determined. logPe values ranged from ‐6.81 to ‐5.09, whereas R values ranged from 1.52 to 65.25. Derivative with the lowest value of logPe was MPMGB, whereas the highest values of logPe and R were determined for MPEMP. Therefore, highest skin permeability and retention could be expected from MPEMP. Skin permeability and retention of five amides (MPMA, MPMAB, MPMAIB, MPMGB and MPPA) and one thioester (MPEMP) of metilprednisolone ‐ derived cortienic acid was estimated by use of PAMPA. The highest values of logPe and R were calculated for MPEMP, which could be considered the best candidate for skin application.VII Kongres farmaceuta Srbije sa međunarodnim učešćem Zajedno stvaramo budućnost farmacije, Beograd, 10-14. oktobar 2018

Unveiling Anticancer Potential of COX-2 and 5-LOX Inhibitors: Cytotoxicity, Radiosensitization Potential and Antimigratory Activity against Colorectal and Pancreatic Carcinoma

Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still not well understood. In our study, the cytotoxicity of thirteen COX-2 and 5-LOX inhibitors previously presented by our group (1–13) was tested on three cancer cell lines (HCT 116, HT-29 and BxPC-3) and one healthy cell line (MRC-5). Compounds 3, 5, 6 and 7 showed moderate cytotoxicity, but good selectivity towards cancer cell lines. IC50 values were in the range of 22.99–51.66 µM (HCT 116 cell line), 8.63–41.20 µM (BxPC-3 cell line) and 24.78–81.60 µM (HT-29 cell line; compound 7 > 100 µM). In comparison to tested, commercially available COX-2 and 5-LOX inhibitors, both cytotoxicity and selectivity were increased. The addition of compounds 6 and 7 to irradiation treatment showed the most significant decrease in cell proliferation of the HT-29 cell line (p < 0.001). The antimigratory potential of the best dual COX-2 and 5-LOX inhibitors (compounds 1, 2, 3 and 5) was tested by a wound-healing assay using the SW620 cell line. Compounds 1 and 3 were singled out as compounds with the most potent effect (relative wound closure was 3.20% (24 h), 5,08% (48 h) for compound 1 and 3.86% (24 h), 7.68% (48 h) for compound 3). Considering all these results, compound 3 stood out as the compound with the most optimal biological activity, with the best dual COX-2 and 5-LOX inhibitory activity, good selectivity towards tested cancer cell lines, significant cell antimigratory potential and a lack of toxic effects at therapeutic doses

Identifying and testing for hereditary susceptibility to breast/ovarian cancer in Serbia: Where are we now?

About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers - 4 to 8 and 10 to 20 fold higher respectively. Due to the small proportion of hereditary form of disease, as well as to the high cost, BRCA testing is not screening test for general population. It is addressed to selected part of population that fit to recommended criteria. Full coding region sequencing of both genes is "gold standard" for detection of BRCA mutation. Concerning BRCA testing in Serbia, complete or partial sequencing of BRCA1/2 coding region was performed in 60 samples. The presence of 4 BRCA1 known mutations, previously detected elsewhere, has been shown: 185delAG, C61G, 3447del4 and 5382insC (detected twice). In BRCA1 gene, exon 16, an unclassified variant M1652I was found. Polymorphic variants in BRCA1 (8 polymorphisms) and BRCA2 (5 polymorphisms) genes were also detected. The majority of found BRCA1 and BRCA2 polymorphic variants are the missense ones and their influence on breast/ovarian cancer risk in our population has to be proved. Identification of BRCA mutations carriers and establishment of spectra and frequency of BRCA mutations should enable introduction of BRCA1/2 testing into the clinical practice of Serbia.

Estimation of lipophilicity of newly synthesized potential COX-2 and 5-LOX inhibitors using RP-HPLC analysis

The chronic inflammatory process is associated with the development and progression of many diseases such as cancer, arthritis, autoimmune diseases, etc. Dual COX-2 and 5-LOX inhibitors have been developed to provide more potent anti-inflammatory agents with a better safety profile [1]. Nineteen newly synthesised potential dual COX-2 and 5-LOX inhibitors [2] were selected and their retention properties were tested in different RP-HPLC systems. RP-HPLC analysis was performed using a C18, a cyano and an amino column. The mobile phases were binary combinations of acetonitrile and phosphate buffer (pH 5.5 and pH 7.4) as well as methanol and phosphate buffer (pH 5.5 and pH 7.4) in different ratios. The amino column proved to be inadequate as the tested compounds were not retained on it. According to preliminary results, methanol was not suitable as an organic modifier in the mobile phase as the retention time of the compounds was increased several times compared to acetonitrile. Acetonitrile was chosen as the organic modifier. The logarithmic values of the retention factors (logk) were calculated for each sample and plotted with the percentage of organic modifier in the mobile phase. The chromatography parameters logkw, a and ϕ0 were determined according to equation (1) and equation (2) (S-percentage of organic modifier in the mobile phase). Logk = logkw + aS (1) ϕ0 = - logkw/a (2) On C18 and cyano columns, seven compounds (1A, 1G, 1ME, 1PE, and 2D) had no retention properties, which is consistent with their very low logD values, while three (1F, 1H, and QSAR17) compounds were outlayers. Systems consisting of C18 and cyano columns (on both pH 5.5 and 7.4) showed good correlation coefficients between the chromatography parameters logkw, a, and ϕ0 and the logD values determined with MarvinSketch. The most suitable system consisted of a C18 column, acetonitrile, and phosphate buffer pH 7.4, as it had the highest correlation coefficient between the chromatography parameter logkw and the logD value (R2=0.9023) (3 compounds were discarded)

Antimelanoma Potential of New Telmisartan Analogues Without AT1 Receptor Activity

Melanoma is one of the most aggressive malignancies, where the prognosis for metastatic patients remains extremely poor. Our group has shown that the antihypertensive drug telmisartan has antimelanoma potential1. Given that the antihypertensive effect is not favorable in cancer patients, the aim of this study was to design and test novel telmisartan derivatives without the angiotensin receptor 1 (AT1R) binding activity. New derivatives were designed by modification of the carboxylic group, in order to alter telmisartan geometry and its AT1R binding properties. Eight derivatives, from which the lack of AT1R antagonistic activity could be expected based on molecular docking, were synthetized and selected for in vitro testing. After the cytotoxicity test on human melanoma cell lines A375 and 518a2, three derivatives that were twice more potent than telmisartan itself were selected for further analysis. The new derivatives induced mitochondrial fragmentation, generation of the mitochondrial reactive oxygen species, and decrease of mitochondrial membrane potential in melanoma cells, the mechanism we previously shown for induction of apoptosis by telmisartan in melanoma cells. As the new derivatives showed more potent effect on melanoma cells than telmisartan these results lay a ground for further preclinical testing in melanoma

Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis

Inflammation is a part of immune system's response to harmful intrinsic and extrinsic stimuli, such as infection or injury. It has an important role in progression of some diseases, such as cancer, arthritis, stroke [1]. It is considered that inhibition of COX 2 and 5 LOX pathways of production of inflammation mediators provides a new strategy for development of more effective anticancer drugs [2]. The aim of this study was designing of novel COX 2/5 LOX inhibitors with improved activity towards both enzymes using quantitative structure activity relationships (QSAR). QSAR modeling was applied on a literature data set consisting of 28 dual COX 2/5 LOX inhibitors and obtained pharmacophoric features were used in design of novel compounds. Regarding prediction of activity of novel COX 2 and 5 LOX inhibitors, two models were developed. Based on values of Q2 (0.53 (COX 2 model) and 0.71 (5 LOX model)) and R2 pred (0.85 (for both COX 2 and 5 LOX models)), developed models have good predictive ability and can be used for activity prediction of novel designed compounds. Obtained values of r2m, r'2m, and r ̅2m were higher than 0.5 and Δr2m was lower than 0.2 indicating high predictive quality of developed models. Applicability domain (AD) was defined using Leverage approach and all compounds were inside the AD. In order to get more potent dual inhibitors of COX 2 and 5 LOX enzymes, compounds with high pIC50 values were chosen for design of novel compounds. As a result, 32 novel compounds were designed and according to predicted pIC50 values can be considered promising dual COX 2 and 5 LOX inhibitors

A review of published data on acridine derivatives with different biological activities

Acridine ring can be found in molecules used in many different spheres, including industry and medicine. Nowadays, even acridines with antibacterial activity are of research interest due to increasing bacterial resistance. Some acridine derivatives showed antimalarial or antiviral activity. Acridine derivatives were also investigated for antitumor activity due to the interaction with topoisomerase II and DNA base pairs. Considering these possible uses of acridine derivatives, this work was made as overview of all significant structure characteristics for specific action of these compounds