anticancer agent podophyllotoxin: Topics by catchsomeair.us
A series of 4β-[(4-substituted)-1,2,3-triazolyl] podophyllotoxin congeners have been designed and . activity and were free from ulcerogenecity liability of common NSAIDs. Structure–activity relationships were also briefly discussed. The SAR development of substituted purine derivatives as selective CB2 Gastric-sparing nitric oxide-releasable 'true' prodrugs of aspirin and naproxen . Synthesis and insecticidal activity of new oxime derivatives of podophyllotoxin- based. The structure–activity relationship (SAR) and molecular modeling group discovered that the conjugate of podophyllotoxin and aspirin (5, Fig.
For the most active compounds competition concentration—response curves were generated. The binding of these complex samples with DNA has been investigated by electronic absorption spectroscopy, emission spectroscopy and gel retardation assay.
Electrostatic interactions between DNA molecule and polymer—copper II complex molecule containing many high positive charges have been observed. Besides these ionic interactions, van der Waals interactions, hydrogen bonding and other partial intercalation binding modes may also exist in this system.
The polymer—copper II complex with higher degree of copper complex content was screened for its antimicrobial activity and antitumor activity.
Some polymer—copper II complex samples containing 1,phenanthroline ligand with varying amounts of copper II complex content in the polymer chain were prepared and characterized. DNA binding properties of these samples have been found out using different physico-chemical methods. Polymer—copper II complexes; Antitumor activity; Antimicrobial activity; DNA binding; Polyethyleneimine; Synthesis and biological evaluation of amide derivatives of 5,6-dimethoxy-2,3-dihydro-1H-indenyl acetic acid as anti-inflammatory agents with reduced gastrointestinal ulcerogenecity by Meenakshi Sharma; S.
A variety of amide derivatives of 5,6-dimethoxy-2,3-dihydro-1H-indenyl acetic acid were synthesized and screened for their analgesic and anti-inflammatory activities. The compounds were found to have longer activity profile exceeding that of indomethacin in carrageenan-induced rat paw edema model. Few selected compounds were also screened for their antipyretic, anti-arthritic and ulcerogenecity potential.
The test compounds failed to prevent the development of secondary inflammation in adjuvant-induced arthritis assay. A series of 5,6-dimethoxy-2,3-dihydro-1H-indenyl acetic acid amides were synthesized and screened for their anti-inflammatory and related biological activities. The synthesized compounds showed long duration of anti-inflammatory activity and were free from ulcerogenecity liability of common NSAIDs. Multi-drug resistance to commonly used antitubercular drugs has propelled the development of new structural classes of antitubercular agents.
This paper reports the synthesis, evaluation and 3D-QSAR analysis of a set of substituted N-phenylmethyloxophenyl-1,2,3,4-tetrahydropyrimidinecarboxamides as antitubercular agents. Substituted acetoacetanilides were reacted with various aromatic aldehydes and urea which yielded the tetrahydropyrimidine derivatives with a phenyl carbamoyl group at C5 position, and with various substitutions on the 4-phenyl and the N-phenyl aromatic rings.
All compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The QSAR models were generated on a training set of 23 molecules. The molecules were aligned using the atom-fit and field-fit techniques. The 3D-QSAR models were externally validated against a test set of 7 molecules for which the predictive r 2 r pred 2 is recorded as 0.
However, reaction of 1a and b with a variety of aryl- alkylisocyanates or isothiocyanates 2a—f afforded the corresponding bisurea and their thio-analogues 3a—l. Bisbenzenamines; Bisureas; Bisthioureas; Macrocycles; Anti-inflammatory; Synthesis and antimicrobial activity of some new heterocycles incorporating antipyrine moiety by Samir Bondock; Ramy Rabie; Hassan A. Treatment of aminopyrazole 9 with nitrous acid, 1,3-dicarbonyl compounds, enaminone, and DMF—DMA led to the formation of pyrazolo[3,4-d]triazine 10, pyrazolo[1,5-a]pyrimidines 11, 12, 14, and pyrazolo[3,4-d]pyrimidine 13, respectively.
Condensation of 9 with isatin afforded Schiff base Representative compounds of the synthesized products were tested and evaluated as antimicrobial agents. A series of novel pyrrolidine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 MMP-2 and aminopeptidase N AP-N. The results showed that these pyrrolidine derivatives exhibited highly selective inhibition against MMP-2 as compared with AP-N.
The binding mode of the most potent compound 8a with MMP-2 was proposed. Structure—activity relationships were also briefly discussed.
Podophyllotoxin Analogues Active versus Trypanosoma brucei
The binding mode of the most potent compound 8a withMMP-2 was proposed. The reaction between carnitine and bovine serum albumin BSA in aqueous solution has been studied by fluorescence spectroscopy and absorbance spectra.
The binding interaction between optical isomer, d-carnitine and l-carnitine, with BSA has been compared. Based on the site-binding model and florescence quenching, practical formulas for small molecular ligand binding to bio-macromolecule have been used, and the binding parameters were measured.
The effect of carnitine on the BSA conformation has been analyzed by using synchronous fluorescence spectroscopy.
As a conclusion, molecular identification of BSA to carnitine isomer has been suggested preliminary. Carnitine; Bovine serum albumin; Fluorescence spectroscopy; Ultraviolet spectroscopy; Synthesis and structure guided evaluation of estrogen agonist and antagonist activities of some new tetrazolyl indole derivatives by Uma Sharan Singh; Ravi Shankar; Gaya P.
Several regioisomeric tetrazolyl indole derivatives with structurally modified alkyl substituents at the tetracyclic indole nitrogen containing N-ethyl amino tetrazole moiety have been synthesized and screened for their ER binding affinity, agonist estrogenicantagonist antiestrogenic and anti-implantation activities.
Molecular docking studies carried out in comparison to estradiol and raloxifene showed different binding modes of the two regioisomers to the binding site. Several regioisomeric tetrazolyl indole derivatives with structually modified alkyl substituents at the tetracyclic indole nitrogen containing N-ethyl amino tetrazole moiety have been synthesized and screened for their ER binding affinity, agonist estrogenicantagonist antiestrogenic and anti-implantation activities.
In order to obtain QSAR model with high predictive ability, the original dataset was randomly divided into a training set comprising 26 compounds and a test set comprising the rest 6 compounds. The same model was further applied to predict pGC50 values of the 6 compounds in the test set, and the resulting predictive correlation coefficient R pred 2 reaches 0. It is very interesting to find that the cytotoxicities of these compounds against HeLa appear to be mainly governed by two quantum-chemical factors, i.
Here the possible action mechanism of these compounds was analyzed and discussed in detail, in particular, the fact why the flavone derivatives have considerably higher cytotoxicity than isoflavone derivatives was reasonably explained. Based on this QSAR equation, 5 new compounds with higher cytotoxicity have been theoretically designed. Such results can offer useful theoretical references for experimental works. A simple and clear QSAR equation with excellent predictive ability was established.
Five new compounds with higher cytotoxicity were theoretically designed. Molecular structures of flavone A and isoflavone B derivatives. The results showed that the superoxide radical scavenging effect of 2- 4 or 2 -hydroxylchloride-1,3-benzene-di-sulfanimide -chitosan was higher than chitosan. The NSAIDs are nonselective cyclooxygenase inhibitors often experience dyspepsia and upper gastrointestinal GI adverse effects, and frequently require GI co-medications and diagnostic procedures.
Previous clinical approaches for reducing the risks of ulcer complications or symptomatic ulcers in patients who use nonsteroidals have involved the coadministration of misoprostol or proton-pump inhibitors.
Unfortunately, there are little data demonstrating that this risk can be reduced by co-administration of protective medications. COX catalyzes the conversion of arachidonic acid to prostaglandins, which mediate the development and maintenance of a physiologic protective barrier in the upper gastrointestinal tract. By inhibiting this key enzyme, mucosal protection is diminished and there is a resultant propensity for patients to develop gastroduodenal ulcers and ulcer complications.
Approximately 10 years ago, it was shown that COX exists as 2 isoforms: COX-1 is constitutively expressed in the gastrointestinal tract and is responsible for maintaining mucosal protection; COX-2 is responsible for the inflammatory process.
Because NSAIDs and aspirin inhibit both the isoforms somewhat equally at therapeutic doses, patients who use these medications are at risk for UGI ulcers and ulcer complications through the inhibition of COX Over the past several years, a new class of agents known as the COX-2 inhibitors celecoxib and rofecoxib has been developed.
Results vary considerably depending on which system is used and there is little agreement on which should be the gold standard. Currently, a whole blood assay is the most widely accepted in vitro system. Particular indoyl amides include amides comprising an amino sugar. However, neither of these patents say anything about whether the amides have selective COX-1 or COX-2 inhibitory activities.
According to the present invention, by linking an NSAID to a sugar residue, one obtains a conjugate that offers many advantages. When administered orally, the conjugate will be more soluble than the underivatized NSAID and, thus, is expected to cause less stomach irritation. The conjugate will then be actively taken up by the GI tract, thus leading to lessened time in the GI tract.
The present invention relates in particular to compounds of the Formula I: The invention also relates to pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating or preventing pain, an inflammatory disease or cancer, comprising administering to an animal in need thereof an effective amount of a compound of the invention.
European Journal of Medicinal Chemistry (v.43, #10)
The invention also relates to a method of preparing a compound of Formula Iwhich comprises condensing a protected sugar with an NSAID. The protecting groups may then be partially or completely removed. Another group of NSAIDs that have utility in connection with the instant invention are the proprionic acid derivatives.
Included in this group, for example, are ibuprofen and naproxen. A further group of NSAIDs employable herein are the fenamates and compounds closely related to them structurally. These may be illustrated by such compounds as mefenamic acid, meclofenamic acid and diclofenac. Two naproxan-glucosamine conjugates of the invention have the formulae: Other compounds of the invention have the formulae: Preferably, R2 and R3 are not identical radicals selected from hydrido, carboxyl and ethoxycarbonyl; further preferably R2 cannot be carboxyl when R3 is hydrido and when R4 is phenyl; and further preferably R4 is sulfamyl or N-alkylsulfamyl when R1 is halo; or a pharmaceutically-acceptable salt thereof.
Particular examples of compounds related to celecoxib that may be used to prepare the conjugates of the invention may found in U. A particular example of a conjugate of the invention has the formula: When the compounds are related to rofecoxib, they have the formula: Particular examples of compounds useful to make the sugar conjugates of the invention may be found in U.
A preferred example is the glucosamide of ibuprofen: When the NSAID is related to mefenamic acid, meclofenamic acid and diclofenac, the compounds have the formula: R25 is lower alkyl, lower alkoxy, fluoro or chloro; each of R23 and R24 is hydrogen, lower alkyl, chloro or fluoro; R26 is hydrogen, lower alkyl, lower alkoxy, chloro, fluoro or bromo; R27 is hydrogen or lower alkyl; R28 is hydrogen, lower alkyl or when R5 is hydrogen, benzyl; and R29 is hydrogen, lower alkyl or benzyl.
A particular example is the glucosamide of mefenamic acid having the formula: Another particular example is the glucosamide of meclofenamic acid having the formula: Another particular example is the glucosamide of diclofenac having the formula: A particular example is the glucosamide of piroxicam: When the compounds of the invention are related to etodolac, they have the formula: A particular example is the glucosamide of etodolac: Other compounds of the invention include the sugar conjugates of aspirin such as the glucosamide having the formula: Sugar Residues Sugar residues that are useful in the practice of the present invention include glucose, glucosamine, glucuronic acid, ribose, and the 2-deoxy derivatives thereof, e.
In a preferred embodiment, the sugar residue is glucose which renders the conjugate more polar and water soluble, thus ameliorating any solubility problems of the NSAID. Other sugar residues that may be used in the practice of the invention include derivatives of glucose, glucosamine and glucuronic acid. Relationship to Water Solubility and Boiling Point. Relationship to Partition Coefficient. Relationship to Biological Activity.
Specific Treatment of Heteroatoms.
Benz, Symposum Ed Irl Publ. Kier, Trends in Biochem. Di Paolo, and L. Kier, In Anti- epileptic Agents.
European Journal of Medicinal Chemistry (v, #10) | catchsomeair.us
Kier, In The Psychopharmacology of Hallucinogens. Yalkowski and a Sinkula,Eds. Relations Using Molecular Connectivity. Human Welfare and Environment.
Pergamon Press, Oxford, England. Hanko Novak, and L. Kier in Reviews of Computational Chemistry. Solute Hydration Behavior in various Solvent Systems. Hall, in Advances in Drug Research Vol.
Md. Jashim Uddin, Ph.D.
Kier in The Chemistry of Alkanes and Cycloalkanes. Inhibition of MAO by Hydrazides. Role of Higher Order Path Counts: Escom, Leiden, The Netherlands, pp. Graphics, 14, The E-State Fields.