182 research outputs found
Synthetic MMP Inhibitors: Slow-Binding Behaviour of Enantioselective N-O-Sulphonamido Based Inhibitors Directed to Specific Matrixins
No full textArylsulfonamido compounds as metalloprotease inhibitors and their preparation, pharmaceutical compositions and use as diagnostic as well as radiotherapeutic agents
No full textThe invention relates to aryl-sulphonamido compounds endowed with affinity against metallo proteases MMP, having formula (I) below wherein R, R 1 , R 2 , R 3 , G and n have the meanings reported in the specification, properly labelled with diagnostic imaging moieties or even radiotherapeutic moieties. The invention also refers to the process for their preparation, to pharmaceutical compositions comprising them and to their use as diagnostic imaging agents or radiotherapeutic agents
Diagnostic Agents Selective agains Metalloproteinases
No full textThe invention relates to aryl-sulfonamido compds. endowed with affinity against metallo proteases MMP, having formula
(I) below wherein R, R1, R2, R3, G and n have the meanings reported in the specification, properly labeled with
diagnostic imaging moieties or even radiotherapeutic moieties. The invention also refers to the process for their prepn.,
to pharmaceutical compns. comprising them and to their use as diagnostic imaging agents or radiotherapeutic agents.
The invention relates to arylsulfonamido compds. of formula I, which endowed with affinity against metalloproteases
MMP and are useful as diagnostic imaging agents. The invention also refers to the process for their prepn., to
pharmaceutical compns. comprising them and to their use as diagnostic imaging agents or radiotherapeutic agents.
Compds. of formula I wherein R is -Ar-X-Ar1; Ar is (un)substituted (hetero)arylene and (un)substituted (hetero)aryl; Ar1 is
(un)substituted (hetero)aryl and H; X is a single bond, (un)branched C1-4 alkylene, O, S, SO2, CO, NH and derivs.,
NHCO and derivs., and CONH and derivs.; R1 is H, OH, Ra and ORa; Ra is (un)branched C1-4 alkyl, C2-4 alkenyl and -
(CH2)0-4-Z-(CH2)0-4-W; Z is a single bond, O, NH and derivs., NHCO and derivs., and CONH and derivs.; W is
(un)substituted Ph and (un)substituted 5- to 6-membered heterocycle; R2 and R3 are independently H, (un)substituted
(un)branched C1-4 alkyl and a zinc binding group; G is (un)branched C1-6 alkyl, (hetero)aryl, arylalkyl and -(CH2)1-6-
NH2 and derivs.; and their pharmaceutically acceptable salts thereof, are claimed. Example compd. II·2CF3COOH was
prepd. via hydroxyamidation of the corresponding acid with O-(tert-butyldimethylsilyl)hydroxylamine. All the invention
compds. were evaluated for their metalloprotease inhibitory activity. From the assay, it was detd. that II exhibited the
IC50 value of 0.3 ± 0.03 nM and 0.2 ± 0.01 nM against MMP2 and MMP13, resp
Synthetic MMP Inhibitors: Slow-Binding Behaviour of Enantioselective N-O-Sulfonamido Based Inhibitors Directed to Specific Matrixins
No full textThe kinetic behavior of some newly synthesized hydroxamate inhibitors on the matrixins MMP2 and MMP13 was
evaluated. Our enantiomeric N-O-alkylsulfonamido-based MMP inhibitors (R)-EN73 and (S)-EN73, which show IC50
values in the nanomolar range on these matrixins, were found to display slow-binding kinetics. On the contrary, their
achiral analogs devoid of the P1 substituent, such as CC27, or other model inhibitors bearing different substituents in P2'
as the N-alkylsulfonamido-based SM3 or the N-H sulfonamido-based FO8, displayed a kinetic behavior consistent with a
rapid equil. interaction with these enzymes. This behavior, however, was not obsd. when the same enantiomeric
compds. were tested on a different matrixin, e.g., MMP-1, that shows a far higher IC50 value for these inhibitors.
Considering shape and size differences of the S1' pocket of these matrixins, we carried on this kinetic characterization
also on P1' small arom. substituted inhibitors belonging to these sulfonylated ligands. An enlarged and compared anal.
regarding the potency and selectivity of these inhibitors, against some target and antitarget MMPs involved in cancer and
arthritic diseases, was developed
From taxuspine X to structurally simplified taxanes with remarkable P-Glycoprotein inhibitory activity
No full textThree simplified “non-natural” natural taxanes, related to taxuspine X, were synthetized and assayed as P-glycoprotein (P-gp) inhibitors. One of them (6) proved to be a very efficient P-gp inhibitor with an IC50 = 7.2 × 10−6 M. In addition, to rationalize biological data, a pharmacophoric model was built through a ligand-based approach. This model represents the first example of a pharmacophore, which describes interactions of taxanes with P-gp
Disegno, sintesi e valutazione biologica di nuovi inibitori selettivi della Metalloelastasi a struttura arilsolfonica
No full textLa MMP-12 o “metalloelastasi dei macrofagi” è una endopeptidasi zinco dipendente appartenente alla famiglia delle metalloproteasi della matrice extracellulare (MMPs). Essa gioca un ruolo importante nel rimodellamento e distruzione del tessuto polmonare, infatti, sono stati ritrovati alti livelli di MMP-12 nei tessuti polmonari dei malati di COPD (malattia polmonare cronica ostruttiva). Argomento del mio lavoro di Tesi è stato lo sviluppo e la sintesi di una nuova serie di derivati arilsolfonici capaci di inibire selettivamente la MMP-12. In particolare, il derivato morfolinico 2c ha dimostrato di essere un potente inibitore della MMP-12 e di avere una buona selettività verso le MMP -1, -9 e -14 nei saggi in vitro sugli enzimi isolati.
MMP-12 is a member of the matrix metalloproteinases family (MMPs), zinc dependent endoproteinases that participate in extracellular matrix degradation. MMP-12 plays a significant role in airway inflammation and remodeling. In fact, increased expression and production of MMP-12 has been found in the lung of human COPD (chronic obstructive pulmonary disease) patients. During my Thesis research work, a new series of arylsulfone compounds was synthesized as selective inhibitors of MMP-12. Particularly, the morpholine derivative 2c demonstrated to be a potent MMP-12 inhibitor and showed selectivity towards MMP -1, -9 and -14 in in vitro assays on purified enzymes
Studies toward Taxuspine X, a potent Multidrug - Resistance Reversing Agent, via ring closing metathesis strategy
No full textThe synthesis of bicyclic 3,8-secotaxane diterpenoids, which includes Taxuspine U and X, has been achieved through an approach that involves a ring closing metathesis reaction as key step for the macrocycle formation
Stereoselective synthesis of advanced intermediates en route to Taxuspine U and X: a study of macrocyclization via ring closing metathesis to highly constrained twelve-membered rings
No full textThe stereoselective synthesis of an advanced intermediate of Taxuspine U and X has been accomplished using a ring closing metathesis strategy. The feasibility of ring closing metathesis in synthesizing highly constrained and functionalized macrocycles has been demonstrated provided the appropriate substrate structure and substitution pattern are chosen. © 2006 Elsevier Ltd. All rights reserved
Duties of so-called quoted joint stock companies
No full textDuties of so-called quoted joint stock companies Thesis author: Mgr. Marek Novotný Thesis supervisor: prof. JUDr. Stanislava Černá, CSc. This thesis is concerned with the regulation of duties of quoted joint stock companies (especially the duty of information) and its various institutes. The purpose of this thesis is to describe the legislation in this area of law and its development, with emphasis on the transposition of European legislation, and subject them to critical evaluation. In the first chapter the theoretical framework is defined by describing key legal concepts (the term "quoted joint stock company", "regulated markets") and the development of the most important legal regulation in this area - Act No. 256/2004 Coll., on Business Activities on the Capital Market. The second chapter is devoted to regulated markets and subject information duty. The third chapter deals with the admission of a security to trading on a regulated market and associated initial information duty of joint stock company, which is willing to become quoted. I describe mainly the prospectus and its essential elements. In the fourth chapter I analyze in detail the different types of regular (periodic) information duties, which are the annual report, semi-annual report and interim report. The following fifth chapter is..
Didactic principles of John Amos Comenius and their application in today's teaching of German language
No full textMASTER THESIS TITLE: Didactic principles of John Amos Comenius and their application in today's teaching of German language AUTHOR: Stanislava Černá DEPARTMENT: Department of Germanics SUPERVISOR: PaedDr. Dagmar Švermová This master thesis is focused on the personality of meaningful Czech thinker J. A. Comenius and his didactical principles, many of which are nowadays still relevant. The most emphasized principles are activity, motivation and student's perception with the use of all senses. The last mentioned principle can be ensured by the activity-oriented teaching; student can be motivated and exacerbated by problem-oriented or project teaching. Theoretical part of the thesis is dedicated to the definition of principles, understanding of the activity principle before and today, its use in the foreign language teaching and the definition of aims and key competencies. Following practical part describes realization of two projects where was validated that inclusion of projects into German language teaching is suitable motivating and exacerbating means in case the aims and methods are selected appropriately. KEY WORDS: J. A. Comenius, didactical principles, teaching of German language, activity, activity-oriented teaching, project teachin
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