Biomedical subjects

Gunda I Georg

Publications and source records attributed to Gunda I Georg.

At least 19 recordsLinked to original sources

PubMed2006

Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues.

The design and synthesis of a small library of 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7-hydroxyflavone, and heterocyclic analogues of flavopiridol is reported. The potential activity of these compounds as kinase inhibitors was evaluated by cytotoxicity studies in MCF-7 and ID-8 cancer cell lines and inhibition of CDK2-Cyclin A enzyme activity in vitro. The antiproliferative and CDK2-Cyclin A inhibitory activity of these analogues was significantly lower than the activity of flavopiridol. Molecular docking simulations were carried out and these studies suggested a different binding orientation inside the CDK2 binding pocket for these analogues compared to flavopiridol.

Adenosine Triphosphate↗

PubMed2006

Amino acid-derived enaminones: a study in ring formation providing valuable asymmetric synthons.

A new reaction for the preparation of enaminones has been discovered. This method employs beta-amino acids as starting materials to allow diversification as well as incorporation of chirality. The beta-amino acids, once converted to ynones, are readily cyclized to the desired six-membered enaminone via a two-step, one-pot protocol. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond making and bond breaking, thus changing the mode of addition.

Amino Acids↗

PubMed2006

Support vector machines in HTS data mining: Type I MetAPs inhibition study.

This article reports a successful application of support vector machines (SVMs) in mining high-throughput screening (HTS) data of a type I methionine aminopeptidases (MetAPs) inhibition study. A library with 43,736 small organic molecules was used in the study, and 1355 compounds in the library with 40% or higher inhibition activity were considered as active. The data set was randomly split into a training set and a test set (3:1 ratio). The authors were able to rank compounds in the test set using their decision values predicted by SVM models that were built on the training set. They defined a novel score PT50, the percentage of the test set needed to be screened to recover 50% of the actives, to measure the performance of the models. With carefully selected parameters, SVM models increased the hit rates significantly, and 50% of the active compounds could be recovered by screening just 7% of the test set. The authors found that the size of the training set played a significant role in the performance of the models. A training set with 10,000 member compounds is likely the minimum size required to build a model with reasonable predictive power.

Algorithms↗

PubMed2006

Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds.

We have shown that lipopolyamines bind to the lipid A moiety of lipopolysaccharide, a constituent of Gram-negative bacterial membranes, and neutralize its toxicity in animal models of endotoxic shock. In an effort to identify non-polyamine scaffolds with similar endotoxin-recognizing features, we had observed an unusually high frequency of hits containing guanylhydrazone scaffolds in high-throughput screens. We now describe the syntheses and preliminary structure-activity relationships in a homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities. These first-generation compounds bind and neutralize lipopolysaccharide with a potency comparable to that of polymyxin B, a peptide antibiotic known to sequester LPS.

Animals↗

PubMed2005

Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells.

A single-site modification of paclitaxel analogs at the C10 position on the baccatin III core that reduces interaction with P-glycoprotein in bovine brain microvessel endothelial cells is described. Modification and derivatization of the C10 position were carried out using a substrate controlled hydride addition to a key C9 and C10 diketone intermediate. The analogs were tested for tubulin assembly and cytotoxicity, and were shown to retain potency similar to paclitaxel. P-glycoprotein interaction was examined using a rhodamine assay and it was found that simple hydrolysis or epimerization of the C10 acetate of paclitaxel and Taxol C can reduce interaction with the P-glycoprotein transporter that may allow for increased permeation of taxanes into the brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Synthesis and interactions of 7-deoxy-, 10-deacetoxy, and 10-deacetoxy-7-deoxypaclitaxel with NCI/ADR-RES cancer cells and bovine brain microvessel endothelial cells.

7-Deoxypaclitaxel, 10-deacetoxypaclitaxel and 10-deacetoxy-7-deoxypaclitaxel were prepared and evaluated for their ability to promote assembly of tubulin into microtubules, their cytotoxicity against NCI/ADR-RES cells and for their interactions with P-glycoprotein in bovine brain microvessel endothelial cells. The three compounds were essentially equivalent to paclitaxel in cytotoxicity against NCI/ADR-RES cells. They also appeared to interact with P-glycoprotein in the endothelial cells with the two 10-deacetoxy compounds having less interaction than paclitaxel and 7-deoxypaclitaxel.

Animals↗

PubMed2005

Chemoenzymatic synthesis of cryptophycin/arenastatin natural products.

Microbially derived modular polyketide synthase and nonribosomal peptide synthetase biosynthetic pathways are a rich source of novel natural products. Development of these systems for the engineered biosynthesis of diverse secondary metabolites continues to progress as a robust source of chemical diversity. Recent efforts that employ individual enzymes and catalytic domains for the production or modification of small molecules have met with growing success. In this study, the thioesterase domain from the cryptophycin biosynthetic pathway was isolated and its function evaluated with a series of linear chain elongation intermediates in developing a novel chemoenzymatic synthesis of the cryptophycin/arenastatin class of antitumor agents. The results show the high efficiency of the thioesterase in generating the 16-membered depsipeptide ring of this important natural product system. Moreover, analysis of selected substrates revealed considerable tolerance for structural variation within the seco-cryptophycin unit C beta-alanine residue, but strict structural requirements at the phenyl group position of the unit A delta-hydroxy octadienoate chain elongation intermediates.

Amino Acid Sequence↗

PubMed2005

Formal total syntheses of the (-)-salicylihalamides A and B from D-glucose and L-rhamnose.

[reaction: see text] Two formal total syntheses of the (-)-salicylihalamides, based on chiral pool approaches, are reported. D-glucose and L-rhamnose were used to prepare advanced intermediates 23 and 54, which can be converted in three or four steps, respectively, to the target compounds. The synthesis of 23 from a known D-glucose-derivative was accomplished in 12 steps and 17% overall yield, and the synthesis of 54 from a known L-rhamnose-derivative was done in nine steps and 6% overall yield. A key step in the synthesis was a ring-closing metathesis reaction to prepare the macrocyclic ring system. It was demonstrated that the phenolic protecting group was critical for inducing the preferential formation of the desired E isomer. It was further shown that the protecting group at the C13 hydroxyl group had no significant influence on the E:Z ratio during the ring-closing metathesis reaction.

Bridged Bicyclo Compounds, Heterocyclic↗

PubMed2005

Chemical modification of paclitaxel (Taxol) reduces P-glycoprotein interactions and increases permeation across the blood-brain barrier in vitro and in situ.

The purpose of this work was to introduce a chemical modification into the paclitaxel (Taxol) structure to reduce interactions with the product of the multidrug resistant type 1 (MDR1) gene, P-glycoprotein (Pgp), resulting in improved blood-brain barrier (BBB) permeability. Specifically, a taxane analogue, Tx-67, with a succinate group added at the C10 position of Taxol, was synthesized and identified as such a candidate. In comparison studies, Tx-67 had no apparent interactions with Pgp, as demonstrated by the lack of enhanced uptake of rhodamine 123 by brain microvessel endothelial cells (BMECs) in the presence of the agent. By contrast, Taxol exposure substantially enhanced rhodamine 123 uptake by BMECs through inhibition of Pgp. The transport across BMEC monolayers was polarized for both Tx-67 and Taxol with permeation in the apical to basolateral direction greater for Tx-67 and substantially reduced for Taxol relative to basolateral to apical permeation. Taxol and cyclosporin A treatments also did not enhance Tx-67 permeation across BMEC monolayers. In an in situ rat brain perfusion study, Tx-67 was demonstrated to permeate across the BBB at a greater rate than Taxol. These results demonstrate that the Taxol analogue Tx-67 had a reduced interaction with Pgp and, as a consequence, enhanced permeation across the blood-brain barrier in vitro and in situ.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

A convenient method to remove ruthenium byproducts from olefin metathesis reactions using polymer-bound triphenylphosphine oxide (TPPO).

Ruthenium byproducts from ring-closing metathesis reactions can be removed by refluxing the crude reaction mixture with resin-bound triphenylphosphine oxide (TPPO) in toluene or by stirring with dimethyl sulfoxide (DMSO) and silica gel at room temperature. Residual levels of ruthenium can be achieved that are as low as 0.04 microg per 5 mg of product when a combination of TPPO, DMSO, and silica gel is used. The polymer-bound TPPO retained its efficiency after being recycled six times.

Alkenes↗

PubMed2004

Synthesis and anti-tubulin activity of a 3'-(4-azidophenyl)-3'-dephenylpaclitaxel photoaffinity probe.

The synthesis and biological evaluation of a novel paclitaxel photoaffinity probe is described. The synthesis involved the preparation of an azide-containing C13 side chain through a Staudinger cycloaddition followed by a lipase-mediated kinetic resolution to obtain the azetidinone in 99% ee. Coupling of the enantiopure side chain precursor to 7-TES-baccatin III and subsequent silyl ether deprotection afforded 3'-(4-azidophenyl)-3'-dephenylpaclitaxel, which was shown to be as active as paclitaxel in tubulin assembly and cytotoxicity assays.

Antineoplastic Agents↗

PubMed2004

Total synthesis and anti-tubulin activity of epi-c3 analogues of cryptophycin-24.

Epi-C3-cryptophycin-24, epi-C3-m-chlorobenzyl-cryptophycin-24, and the corresponding styrenes were synthesized and tested in vitro against the MCF-7 and multidrug-resistant MCF-7/ADR breast cancer cell lines and in an in vitro tubulin assembly assay. The results demonstrate that the S configuration at the C3 stereocenter is not required to induce potent cytotoxicity and the m-Cl substituent present on the C10 side chain did not induce any large change in activity.

Antineoplastic Agents↗

PubMed2004

[Bis(2-methoxyethyl)amino]sulfur trifluoride, the Deoxo-Fluor reagent: application toward one-flask transformations of carboxylic acids to amides.

The use of the Deoxo-Fluor reagent is a versatile method for acyl fluoride generation and subsequent one-flask amide coupling. It provides mild conditions and facile purification of the desired products in good to excellent yields. We have explored the utility of this reagent for the one-flask conversion of acids to amides and Weinreb amides and as a peptide-coupling reagent.

Amides↗

PubMed2004

Synthesis, modeling, and anti-tubulin activity of a D-seco paclitaxel analogue.

[reaction: see text] We have previously described a model of paclitaxel-microtubule binding that led to the prediction that analogues of paclitaxel lacking any D ring could stabilize microtubules as well as paclitaxel if the substituent present at C4 did not have unfavorable steric interactions with the binding pocket. We report the synthesis of a 4-methyl paclitaxel analogue, compound 1, which bears this prediction out. Compound 1 is as potent as paclitaxel at microtubule stabilization in vitro; however, it has only about one-four-hundredth the cytotoxicity of paclitaxel.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Total synthesis and antitubulin activity of c10 analogues of cryptophycin-24.

The unsubstituted, 3'-Cl, 4'-C1, and 3',4'-diCl C10 analogues of cryptophycin-24 were prepared via total synthesis and tested in vitro for cytotoxicity against MCF-7 and multi-drug-resistant MCF-7/ADR breast cancer cell lines and in a tubulin assembly assay. The ED(50) values ranged from 7.2 to 15.8 microM in the tubulin assay and from 0.05 to 3.4 nM in the cell assays. The presence of a 3'-C1 and/or 4'-C1 substituent on the C10 phenyl ring increased cytotoxicity in the MCF-7 cell line compared to the unsubstituted phenyl ring. The most potent compound in this series possessed a 3'-C1 substituent on the C10 phenyl ring. The 3'-C1 analogue had ED(50) values of 50 and 580 pM in the MCF-7 and MCF-7/ADR cell lines, respectively. Its activity was very similar to the parent compound cryptophycin-24. Substitution of the 4'-MeO group in cryptophycin-24 with a 4'-C1 moiety did not significantly affect cytotoxicity against MCF-7 and MCF-7/ADR cells compared to the parent compound. These results demonstrated that the 4'-MeO group in cryptophycin-24 is not essential and can be replaced with 3'-C1 or 4'-C1 substituents.

Antineoplastic Agents↗

PubMed2003

Formal total synthesis of (+)-salicylihalamides A and B: a combined chiral pool and RCM strategy.

The formal total synthesis of the (+)-salicylihalamides A and B is detailed, utilizing a chiral pool approach to generate the three stereogenic centers and a ring-closing metathesis (RCM) for the formation of the macrocyclic ring structure. Starting from a known glucose-derived alcohol, the formal total synthesis was achieved in an efficient 13-step protocol in 26% overall yield. It was found that substitution at the remote phenolic group significantly influenced the ratio of the E- and Z-double bond products in the RCM step. The introduction of phenol protecting groups provided E-isomers preferentially and also enhanced the rates of the RCM reactions.

Bridged Bicyclo Compounds, Heterocyclic↗

PubMed2003

Studies toward the synthesis of oximidines I and II.

The synthesis of compound 1, a precursor for the synthesis of the oximidine II core structure 2, is described. An undesired C8-C9 isomerization occurred during the intramolecular Castro-Stephens reaction leading to macrocyle 3. The thermodynamic driving force for this unexpected isomerization was established by DFT and MP2 calculations. [reaction: see text]

Alkenes↗

PubMed2003

Synthesis of cryptophycins via an N-acyl-beta-lactam macrolactonization.

An efficient and concise approach to the synthesis of the macrolide core of the cryptophycins has been developed. A novel macrolactonization utilizing a reactive acyl-beta-lactam intermediate incorporates the beta-amino acid moiety within the 16-membered macrolide core. This modular approach, involving a cyanide-initiated acyl-beta-lactam ring opening followed by cyclization, was successfully applied to the total synthesis of cryptophycin-24. The strategy was also used in an efficient synthesis of the 6,6-dimethyl-substituted dechlorocryptophycin-52. In this case, the cyanide-initiated ring opening of the bis-substituted 2-azetidinone followed by macrolactonization was achieved through a catalytic process.

Acylation↗