Search results for "Drug Design"
showing 10 items of 232 documents
What place does molecular topology have in today’s drug discovery?
2020
Introduction: Most methods in molecular and drug design are currently based on physicochemical descriptors. However, molecular topology, which relies on topological descriptors, has also shown value for molecular design even if it does not take into account the physical or chemical properties of ligands and receptors, including the ligand-receptor interaction itself. Areas covered: Herein, the authors provide new insights into the importance of molecular topology according to some of the latest discoveries in physics and chemistry. Furthermore, the authors report on the most significant achievements in drug design using molecular topology over the last 5 years and give their expert perspect…
Advances in DNA-ligands with groove binding, intercalating and/or alkylating activity: chemistry, DNA-binding and biology.
2005
It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a variety of significant biological responses. In this context the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in treatment of cancers, in diagnosis as well as in molecular biology. In the present review recent results about analogues of netropsins, distamycin A and of some lexitropsins and combilexins or related hybrid molecules with sequence reading, intercalati…
Polymeric prodrug for release of an antitumoral agent by specific enzymes.
2001
The clinical usefulness of antitumor chemotherapy has been strongly limited by the lack of specificity of most anticancer drugs, which act also against healthy cells. The aim of this work was to design, synthesize, and evaluate a macromolecular prodrug of Cytarabine, a known antitumor drug, which is a specific substrate for plasmin enzyme whose concentration is high in various kinds of tumor mass as a result of plasminogen activator secretion. alpha,beta-Poly(N-hydroxyethyl)-DL-aspartamide (PHEA), a known synthetic and biocompatible polyamino acid, was used as a drug carrier, and Cytarabine was linked to PHEA by D-Val-Leu-Lys spacer synthesized beginning from Cbz-D-Val-LeuOH dipeptide and N…
Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators.
2012
We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used …
Design, synthesis, and SAR analysis of cytotoxic sinapyl alcohol derivatives.
2005
Five series totalling 51 of sinapyl alcohol derivatives were designed and synthesized. Their cytotoxicity analyses were performed oil six human tumor cell lines Such as PC-3. CNE, KB, A549, BEL-7404, and HeLa. Certain sinapyl alcohol derivatives showed significant cytotoxic activities. Compound 14d exhibited especially potent cytotoxicity against the BEL-7404 cell line with an IC50 value of 0.7 mu M, which showed more cytotoxic activity than the positive control, cisplatin. The structure-cytotoxicity relationships were discussed and the CoMFA analysis was performed using the cytotoxic data against HeLa cells as a template. (c) 2005 Elsevier Ltd. All rights reserved.
Design, Synthesis, and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors
2006
The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 microM and reduced angiogenesis in the in vivo chick embryo model. Interestingly, in a series of 2,3-diarylmaleimides closely related to this lead, no other compound was found to be active in the tubulin polymerization assay. However, by screening in the in vivo chick embryo assay 10 was identified as a potent angiogenesis inhibitor indicating an alternative target. Indeed, molecular modeling studies suggest a reasonable binding mode of 10 at the ATP-binding site of the model kinase CDK2. Motivated by these results, analogues of 10 were screened for inhibitory activity in…
3-Aryl-2-[1H-benzotriazol-1-yl]acrylonitriles: a novel class of potent tubulin inhibitors.
2011
During a screening for compounds that could act against Mycobacterium tuberculosis, a series of new cellular antiproliferative agents was identified. The most cytotoxic molecules were evaluated against a panel of human cell lines derived from hematological and solid human tumors. In particular, (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-methoxyphenyl)acrylonitrile (1) was found to be of a potency comparable to etoposide and greater than 6-mercaptopurine in all cell lines tested. Accordingly, a synthesis of a new series of (E)-2-(5,6-dichloro-1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-R-phenyl)acrylonitriles was conducted in order to extend the studies of structure-activity relationship (SAR) f…
Synthesis of enantiopure pyrrolidine-derived peptidomimetics and oligo-beta-peptides via nucleophilic ring-opening of beta-lactams.
2006
The synthesis of the two enantiomers of pyrrolidine-derived spiro beta-lactams by resolution with D- and L-Boc phenylalanine is described. The potential of these optically active spiro beta-lactams on the synthesis of peptidomimetics as analogues of melanostatin is evaluated. Theoretical studies of several models, at the Becke3LYP/6-31+G* level of theory, together with previous experimental evidences from our group, gathered by NMR, allow us to design structures that can efficiently mimic some biologically active peptide-type molecules. On the other hand, the spiro beta-lactams have shown their utility in the preparation of beta-peptides. As an example, a homo-tetra-beta-peptide was synthes…
Design of Triads for Probing the Direct Through Space Energy Transfers in Closely Spaced Assemblies
2013
Using a selective stepwise Suzuki cross-coupling reaction, two trimers built on three different chromophores were prepared. These trimers exhibit a D(^)A1-A2 structure where the donor D (octa-β-alkyl zinc(II)porphyrin either as diethylhexamethyl, 10a, or tetraethyltetramethyl, 10b, derivatives) through space transfers the S1 energy to two different acceptors, di(4-ethylbenzene) zinc(II)porphyrin (A1; acceptor 1) placed cofacial with D, and the corresponding free base (A2; acceptor 2), which is meso-meso-linked with A1. This structure design allows for the possibility of comparing two series of assemblies, 9a,b (D(^)A1) with 10a,b (D(^)Â1-A2), for the evaluation of the S1 energy transfer for…
Docking and multivariate methods to explore HIV-1 drug-resistance: a comparative analysis
2007
In this paper we describe a comparative analysis between multivariate and docking methods in the study of the drug resistance to the reverse transcriptase and the protease inhibitors. In our early papers we developed a simple but efficient method to evaluate the features of compounds that are less likely to trigger resistance or are effective against mutant HIV strains, using the multivariate statistical procedures PCA and DA. In the attempt to create a more solid background for the prediction of susceptibility or resistance, we carried out a comparative analysis between our previous multivariate approach and molecular docking study. The intent of this paper is not only to find further supp…