Termičko ponašanje i biološka aktivnost [co2(cl)2 tpmc](bf4)2 kompleksa

A large number of interesting Co (II) complexes with macrocyclicligands have been synthesized and the recognition of its complexes as important bioactive compounds in vitro and in vivo has aroused growing interest in these agents as potential drugs for therapeutic use in various diseases. Numerous available information on their bioinorganic properties and mode of action in several biological systems, combined with the new possibilities imposed by the development of medical chemistry, opens space for the development of a new generation of highly active drugs with minimized side effects which could add significantly to the current clinical research and practice. In this paper we attempt to present some properties of the earlier isolated the first Co(II)tpmc complex for which crystal structure confirmed chair conformation of macrocycle. Complex with formula [Co2(Cl)2tpmc](BF4)2 (tpmc = N,N',N'',N'''-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane), was studied on thermal behaviour and biological activity. TG-DTA analysis indicates that complex decomposition in a single step in the range of 365-435 °C. Investigated cytotoxic activity against two human cancer cell lines: HeLa (human cervix adenocarcinoma) and K562 (human myelogenous leukaemia). Complex was also preliminary assayed in vitro toward bacteria, fungi and mould together with the starting material for the synthesis (ligands, simple salts and solvents) as test substances. Investigated complex showed a moderate activity against strains of bacteria and were inactive against the tested fungi and mould. Minimal inhibitory concentration suppressing the visible growth of bacteria was determined. Biological investigations show the complex has significant cytotoxic potential.Poznavanje biološke uloge kobalta i prepoznavanje njegovih kompleksa kao važnih bioaktivnih jedinjenja razlozi su sve veće zainteresovanosti za potencijalnu terapijsku primenu ovih kompleksa kod različitih bolesti. Brojne dostupne informacije o njihovim osobinama i načinu delovanja u nekoliko bioloških sistema, u kombinaciji sa novim mogućnostima koje nameće razvoj medicinske hemije, otvaraju prostor za razvoj nove generacije visoko aktivnih lekova sa minimalnim nuspojavama. U ovom radu smo ispitali neke osobine ranije izolovanog Co (II) tpmc kompleksa, prvog kod koga je rendgenska strukturna analiza potvrdila da se makrciklični ligand nalazi u konformaciji stolice. Ispitivane su termogravimetrijske I biološke osobine kompleksa [Co2(Cl)2tpmc](BF4)2 (tpmc = N, N', N'', N'''-tetrakis (2-piridilmetil) -1,4,8,11-tetraazaciklotetradekan). TG-DTA analiza ukazuje da je razlaganje kompleksa u jednom koraku u rasponu temperature od 365 -435 ° C. Ispitivana je citotoksična aktivnost na dve ljudske ćelijske linije karcinoma: HeLa (adenokarcinom grlića maternice) i K562 (mijelogena leukemija). Antimikrobno djelovanje kompleksa kvantifikovano je određivanjem minimalne inhibitorne koncentracije (MIC) korišćenjem bakterija Staphylococcus saprophyticus, Staphylococcus xylosus, Bacillus cereus, soja kvasca Candida albicans i plesni Aspergillus niger. Biološka ispitivanja su pokazala da kompleks ima značajan citotoksični potencijal I umerenu aktivnost prema bakterijama soja Staphylococcus

Novi mešovito-ligandni kompleksi Co (II)- sinteza, karakterizacija i antimikrobna aktivnost

A new complexes with general formula [Co2(X)2tpmc](BF4)2·Y (X= F-, Y=CH3CN; X= Br-, Y= H2O; tpmc = N,N',N'',N'''-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane), were isolated and their composition, some of physical and chemical properties and their tentative geometries were evaluated based on: elemental analysis (C, H, N), conductometric and magnetic measurements, spectroscopic data (UV/Vis, IR) respectively. Then, we compared synthesized complexes with early described chloro analogous. Both complexes are binuclear with proposed chair conformation of macrocycle. Complex compounds were also preliminary assayed in vitro toward some Gram (+) and Gram (-) bacteria, fungi and mould together with the starting material for the synthesis (ligands, simple salts and solvents) as test substances. In some cases certain antimicrobial activity of the complexes was detected. Minimal inhibitory concentration suppressing the visible growth of bacteria was determined. Both investigated complexes showed a moderate activity against strains of bacteria and were inactive against the tested fungi and mould. Under the same conditions and applied the same concentration of the control group did not show activity.Pripremlljena su dva nova kompleksa opšte formule [Co2(X)2tpmc](BF4)2·Y (X= F-, Y=CH3CN; X= Br-, Y= H2O; tpmc = N,N',N'',N'''-tetrakis(2-piridilmetil)-1,4,8,11- tetraazaciklotetradekan), čiji su sastav, neke fizičke i hemijske osobine kao i približne geometrije određene na osnovu elementalne analize (C, H, N), konduktometrijskih i magnetnih merenja i spektroskopskih podataka (UV/Vis, IR). Podaci su upoređeni sa ranije sintetisanim i opisanim hloro analogom. Oba nova kompleksa Co(II) su dinuklearna sa pretpostavljenom egzo koordinacijom makrocikla u konformaciji stolice. Kompleksi su preliminarno testirani na neke Gram (+), Gram (-) bakterije, plesni i kvasce zajedno sa startnim supstancama za sintezu (ligandima, prostim solima i rastvaračima) koje su služile kao test supstance. Određivana je minimalna inhibitorna koncentracija koja sprečava rast bakterija. U nekim slučajevima je nađena izvesna antimikrobna aktivnost. Oba kompleksa su pokazala aktivnost prema bakterijama ali su inaktivni prema gljivicama i kvascima dok je pod istim uslovima i istim primenjenim koncentracijama kontrolna grupa bila neaktivna

Uporedni prikaz antimikrobne aktivnosti srodnih Co(II)/Cu(II) kompleksa

The aim of this paper is to compare the efficiency of some analogue of Co (II) and Cu (II) complexes to bacteria pathogenic to humans, which can contaminate vegetables and fruit at any stage of its production. The complexes of Cu(II) and Co(II) with N, N’, N’’, N’’’ - tetrakis (2-pyridylmethyl) -1,4,8,11-tetraazacyclotetradecane (tpmc) and various additional ligands were tested against Gram (+) and Gram (-) bacteria and some strains of fungi. As a control group the free salts of Co(II) and Cu(II) which were used as starting substances in the synthesis, as well as ligands and solvents were tested. The minimum inhibition concentrations suppressing the visible growth of bacteria (MIC) were also screened. Investigated complexes showed a moderate activity against strains of bacteria. Complexes of Co(II) generally showed higher activity then Cu(II) analogues. Under the same conditions and the same concentrations, the control group showed no activity. No compound showed antifungal activity.Cilj ovog rada je poređenje efikasnosti nekih analognih kompleksa Co(II) i Cu(II) na bakterijske vrste patogene za čoveka koje mogu kontaminirati povrće i voće u bilo kojoj fazi njegove proizvodnje. Kompleksi Cu (II) i Co (II) sa N, N’, N’’, N’’’ - tetrakis (2-piridilmetil) -1,4,8,11-tetraazaciklotetradekanom (tpmc) i različitim dodatnim ligandima su testirani na Gram (+) i Gram (-) bakterije i neke sojeve gljiva. Kao kontrolna grupa su testirane i proste soli Co(II) i Cu(II) koje su korišćene kao polazne supstance u sintezi kao i ligandi i rastvarači. Određene su minimalne inhibitorne koncentracije (MIC) koje sprečavaju rast mikroorganizama. Ispitivani kompleksi pokazuju umerenu aktivnost prema sojevima bakterija. Kompleksi Co(II) su pokazali generalno već u aktivnost u odnosu na Cu (II) analoge. Pod istim uslovima i u primenjenim istim koncentracijama kontrolne grupe nisu pokazale aktivnost. Nijedno jedinjenje nije ispoljilo antigljivično dejstvo

Design of nanoplatforms for electrochemical sensing of biomolecules

The aim of this study was to investigate thermal behavior of the new complex with formula [Cu(ala)cyc](ClO4)2∙2.5H2O. The complex was isolated and previously characterized by: elemental analysis (C, H, N), molar conductivity, UV/Vis and FTIR spectroscopy and magnetic measurements at room temperature. The sixcoordinate octahedral geometry around Cu(II) complexes was proposed. The experimental data suggested that the tetradentate ligand cyclam was coordinated to metals through four N donors and the amino carboxylate ligand coordinated via carboxylate ion. Investigate of thermal stability can be crucial in confirming the structure as well as in assessing the applicability of new compounds. The thermal properties of these complex have been investigated by thermogravimetric (TG) and differential thermal analysis (DTA). Therefore, TG-DTA analysis indicates that investigated complex decomposes exothermally in a single step in the range of 310 - 400 °C

Synthesis, characterization, and in vitro antiproliferative and antibacterial studies of tetraazamacrocyclic complexes of Co(II) and Cu(II) with pyromellitic acid

AbstrcatNew cationic tetranuclear Co(II) and neutral binuclear Cu(II) complexes with tpmc (N,N,N,N-tetrakis-(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane) and bridging pyromellitate ligand pma (tetraanion 1,2,4,5-benzenetetracarboxylic acid) were isolated. The composition of the compounds is proposed based on elemental analyses (C, H, N, M=Cu, Co), molar conductivity determination, UV-Vis, FTIR, EPR, LC-MS and reflectance spectroscopy, magnetic measurements, cyclic voltammetry, as well as TG and DTA. It is proposed that in [Co-4(pma)(tpmc)(2)](ClO4)(4)6H(2)O (1), cobalt(II) is six-coordinate out of cyclam rings and one OCO- from pma participates in coordination with one Co(II). In the case of [Cu-2(pma)tpmc].8H(2)O (2), one OCO- from pma bridges two Cu(II). The cytotoxic activity of 1 and 2 was tested against tumor cell lines human cervix adenocarcinoma (HeLa), estrogen-receptor-positive human breast cancer (MCF-7), human myelogenous leukemia (K562), and the human Caucasian Burkitt's lymphoma (Ramos). The IC50 values for 1 and 2 were within the range 44.66 +/- 2.39 to 152.40 +/- 2.28M, and from 140.88 +/- 3.51 to 192.05 +/- 2.09M, respectively. Both 1 and 2 were tested for antimicrobial activity. We determined that minimal inhibitory concentration for 1 against Staphylococcus aureus, Bacillus subtilis, and Klebsiella pneumoniae was 25mM. Complex 2 did not express activity against tested microbial strains.This is peer-reviewed version of the following article: Nikolić, M. A.; Stanković, J. A.; Tanasković, S. B. Synthesis, Characterization, and in Vitro Antiproliferative and Antibacterial Studies of Tetraazamacrocyclic Complexes of Co(II) and Cu(II) with Pyromellitic Acid. J. Coord. Chem. 2018, 71 (10), 1542–1559. [https://doi.org/10.1080/00958972.2018.1459581

Combined ligand and structure‐based approach in search of 5‐HT2A receptor agonists and antagonists

Serotoninski 5‐HT2A receptori su uključeni u mnogobrojne fiziološke i patofiziološke procese. Strukturno različiti ligandi (agonisti, antagonisti i inverzni agonisti) dovode do različitih konformacionih promena ovih receptora, izazivajući brojne biološke odgovore. Da bi se molekul ponašao kao agonista/antagonista potrebno je da poseduje različite funkcionalne grupe i specifične interakcije sa određenim aminokiselinama u vezujućem mestu receptora. Razumevanje i objašnjavanje različitosti u strukturi i vezivanju za receptor, kod agonista i antagonista, može biti od značaja za racionalni dizajn novih lekova. Za razumevanje strukturnih razlika u farmakoforama, kao i kinetici vezivanja i zmeđu agonista i antagonista korišćeni su ligand‐based i structure‐based pristupi. 3DQSAR (3D‐quantitative structure activity relationship) studije su izvođene na grupama od 79 agonista i 90 antagonista. Uporedo su odrađene četiri simulacije molekularne dinamike: serotoninski 5‐HT2A receptor u kompleksu sa agonistima (serotonin, lorkaserin) i antagonistima (klozapin, ziprazidon). Dobijeni statistički i validacioni parametri za modele agonista i antagonista ukazuju na pouzdanost i dobru predviđajuću moć 3D‐QSAR modela. Najznačajnije varijable formiranih modela daju nam uvid u najvažnije strukturne razlike između njih. Rezultati MD simulacije otkrivaju najvažnije razlike u konformacionim promenama uzrokovane vezivanjem agoniste/antagoniste, kao i interakcije liganada sa ključnim aminokiselinama, odgovornim za vezivanje. Pomoću trajektorije iz MD simulacije izvučeni su modeli, 3D strukture 5‐HT2A receptora u njegovom aktivnom (agonistvezujućem) i inaktivnom (antagonist‐vezujućem) stanju. Na osnovu ovih in silico rezultata moguće je zaključiti da li je jedinjenje agonista ili antagonista. Formirani modeli će dalje biti korišćeni za ligand‐based i structure‐based virtualni skrining i racionalni dizajn novih 5‐HT2A liganada.The serotonin 5‐HT2A receptors have shown a wide range of clinical implications since they are involved in various physiological and pathophysiological processes. Structurally diverse ligands (agonists, antagonists, and inverse agonists) can lead to different biological responses, by provoking different conformational changes of these receptors. To behave like an agonist/antagonist the molecule should have a set of functional groups and specific interactions with certain amino acids in the binding site. Understanding and explaining dissimilarities in agonist/antagonist structure and receptor binding would be beneficial for future rational drug design. To understand structural differences in pharmacophores as well as the binding kinetics of agonists and antagonists, we have combined ligand‐based and structurebased approaches. 3D‐quantitative structure‐activity relationship (3D‐QSAR) studies were performed on a series of 79 agonists and 90 antagonists. Simultaneously, we run four molecular dynamics (MD) simulations: 5‐HT2A in complex with agonists (serotonin, lorcaserin), and antagonists (clozapine and ziprasidone). Obtained statistical and validation parameters for agonists and antagonists model indicated the reliability and good predictive potential of the 3D‐QSAR models. The most influential variables of selected models gave us the insight into major structural dissimilarities between them. Results of MD simulation revealed major differences in conformational changes caused by agonist/antagonist binding, as well as ligand interactions with the key amino acids, responsible for them. Additionally, from MD simulation trajectory, we have extracted 3D structure models of 5‐HT2A in its active (agonist‐bound) and inactive (antagonist‐bound) state. Using these finding we will be able to discriminate whether a compound is agonist or antagonist, in silico. Furthermore, models that we have generated will be further used for ligand‐based and structure‐based virtual screening and rational drug design of novel 5‐HT2A ligands.VII Kongres farmaceuta Srbije sa međunarodnim učešćem Zajedno stvaramo budućnost farmacije Beograd, 10-14. oktobar 201

Novi Cu(II) i Co(II) oktaazamakrociklični kompleksi sa 2-amino-3-fenil-propanskom kiselinom

New cationic Cu(II) and Co(II) complexes with N,N',N'',N'''-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane (tpmc) and the anion of 2-amino-3-phenylpropanoic acid (S-phenylalanine) were prepared. The complexes were analyzed and characterized by elemental analysis, conducto-metric, polarimetric, magnetic and cyclic voltammetric measurements, as well as by spectroscopic data (UV/Vis, IR). Both complexes are binuclear with the general formula [M2(S-Phe)tpmc](ClO4)3·nH2O; S-PheH = S-phenylalanine, M(II)= Cu, n = 7; Co, n = 0. Based on previously reported data for some familiar complexes and the present results, pentacoordinated geometry was proposed. Both of the central metal ions are coordinated with two pyridyl and two cyclam nitrogens and bridged with -N-(CH2)3-N-portions of the cyclam ring and oxygen atoms of the S-phenylalaninate ion. Antimicrobial screening of the complexes, solvent, starting salts and ligands alone was performed against fungi, mould and some bacteria. In certain cases, enhanced activity of Co(II) complex towards bacteria compared with the relevant free ligands and starting salts was detected.Dobijena su dva nova kompleksa Cu(II) i Co(II) sa N,N',N',N'''-tetrakis(2-piridilmetil)-1,4,8,11-ciklotetradekanom (tpmc-om) i anjonom 2-amino-3-fenil-propanske kiseline (S-fenilalanina). Oni su analizirani i okarakterisani: elementalnom analizom, konduktometrijskim, polarimetrijskim, magnetnim i ciklično-voltametrijskim merenjima, kao i spektroskopskim podacima (UV/Vis, IR). Oba kompleksa su dinuklearna opšte formule [M2(S-Phe)tpmc](ClO4)3·nH2O; S-PheH = S-fenilalanin, M(II) = Cu, n = 7; Co, n = 0. Na osnovu ranije dobijenih podataka za srodne komplekse i novih rezultata pretpostavljena je pentakoordinaciona geometrija. Oba centralna metalna jona su koordinovana za po dva piridil i dva ciklamova azota i premošćena -N-(CH2)3-N-fragmentima ciklamovog prstena i kiseonikovim atomima S-fenilalaninato jona. Antimikrobni test kompleksa, rastvarača, polaznih soli i samih liganada je izvršen na gljivice, plesni i bakterije. U izvesnim slučajevima nađena je povećana aktivnost kompleksa Co(II) prema pojedinim bakterijama u odnosu na odgovarajuće slobodne ligande i polazne soli

Thermal stability of new copper(II) cyclam complex with aminocarboxylate co-ligand

The aim of this study was to investigate thermal behavior of the new complex with formula [Cu(ala)cyc](ClO4)2∙2.5H2O. The complex was isolated and previously characterized by: elemental analysis (C, H, N), molar conductivity, UV/Vis and FTIR spectroscopy and magnetic measurements at room temperature. The sixcoordinate octahedral geometry around Cu(II) complexes was proposed. The experimental data suggested that the tetradentate ligand cyclam was coordinated to metals through four N donors and the amino carboxylate ligand coordinated via carboxylate ion. Investigate of thermal stability can be crucial in confirming the structure as well as in assessing the applicability of new compounds. The thermal properties of these complex have been investigated by thermogravimetric (TG) and differential thermal analysis (DTA). Therefore, TG-DTA analysis indicates that investigated complex decomposes exothermally in a single step in the range of 310

Combined 3D-QSAR modeling, molecular dynamics and molecular docking studies in rational drug design of novel 5-HT2A antagonists

Serotonin 5-HT2A receptors are widely distributed in the human brain where they play a key role in many physiological functions. Numerous neurological disorders caused by 5-HT2A malfunction have made it a very attractive target. Therefore, analysis of 3D-structure of the pharmacophore as well as binding kinetics of 5-HT2A antagonists would be beneficial for future rational drug design. Three dimensional quantitative structure-activity relationship (3D-QSAR) study was combined with molecular docking and molecular dynamic (MD) simulation in order to find crucial structural features responsible for high binding affinity and selectivity of 5-HT2A antagonists. This study was performed on wide range of structurally diverse antagonists that were divided into three different clusters: clozapine, ziprasidone, and CHEMBL240876 derivates. We have used 50ns MD simulations to obtain inactive, antagonist bound, conformations of each cluster representative. Subsequently, these conformations were used as templates for docking studies in order to find virtually bioactive conformations of examined compounds. Selected virtually bioactive conformations were used for generation of specific molecular descriptors (Grid Independent Descriptors- GRIND) and 3D-QSAR model building. The 3D-QSAR approach was used to identify the most important structural determinants responsible for the antagonistic activity and to propose structural modifications for novel antagonists of serotonin 5-HT2A receptors. Furthermore, diverse internal and external validation methods were applied. Obtained statistical parameters indicated the reliability and good predictive potential of the created model. Following these findings we have identified differences and similarities in the binding mode and pharmacophores of structurally diverse 5-HT2A antagonists as well as conformational changes they provoke