Click chemistry inspired one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles and their Src kinase inhibitory activity

Two classes of 1,4-disubstituted 1,2,3-triazoles were synthesized using one-pot reaction of α-tosyloxy ketones/α-halo ketones, sodium azide, and terminal alkynes in the presence of aq PEG (1:1, v/v) using the click chemistry approach and evaluated for Src kinase inhibitory activity. Structure–activity relationship analysis demonstrated that insertion of C6H5– and 4-CH3C6H4– at position 4 for both classes and less bulkier aromatic group at position 1 in class 1 contribute critically to the modest Src inhibition activity (IC50 = 32–43 μM) of 1,4-disubstituted 1,2,3-triazoles. [Refer to PDF for graphical abstract

4-Aryl-4H-Naphthopyrans Derivatives: One-Pot Synthesis, Evaluation of Src Kinase Inhibitory and Anti-Proliferative Activities

Background: A series of 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives were synthesized and evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines. Methods: The one-pot, three-component reaction of α or β-naphthol, malonitrile and an aromatic aldehyde in the presence of diammonium hydrogen phosphate was afforded the corresponding 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives, All target compounds were evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines. Results: Among all tested compounds, unsubstituted 4-phenyl analog 4a showed Src kinas inhibitory effect with IC50 value of 28.1 μM and was the most potent compound in this series. In general, the compounds were moderately active against BT-20. 3-Nitro-phenyl 4e and 3-pyridinyl 4h derivatives inhibited the cell proliferation of BT-20 cells by 33% and 31.5%, respectively, and found to be more potent compared to doxorubicin (25% inhibition of cell growth). Conclusion: The data indicate that 4-aryl-4H-naphthopyrans scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds

Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities

A series of two classes of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates were synthesized using click chemistry approach. All compounds were evaluated for inhibition of Src kinase and human ovarian adenocarcinoma (SK-Ov-3), breast carcinoma (MDA-MB-361), and colon adenocarcinoma (HT-29). Hexyl triazolyl-substituted 3-phenylpyrazolopyrimidine exhibited inhibition of Src kinase with an IC50 value of 5.6 μM. 4-Methoxyphenyl triazolyl-substituted 3-phenylpyrazolopyrimidine inhibited the cell proliferation of HT-29 and SK-Ov-3 by 73% and 58%, respectively, at a concentration of 50 μM. [Refer to PDF for graphical abstract portion

Synthesis, Anticancer Activities, and Cellular Uptake Studies of Lipophilic Derivatives of Doxorubicin Succinate

A number of lipophilic 14-substituted derivatives of doxorubicin were synthesized through conjugation of doxorubicin-14-hemisuccinate with different fatty amines or tetradecanol to enhance the lipophilicity, cellular uptake, and cellular retention for sustained anticancer activity. The conjugates inhibited the cell proliferation of human leukemia (CCRF-CEM, 69–76%), colon adenocarcinoma (HT-29, 60–77%), and breast adenocarcinoma (MDA-MB-361, 66–71%) cells at a concentration of 1 μM after 96–120 h of incubation. The <i>N</i>-tetradecylamido derivative of doxorubicin 14-succinate (<b>10</b>) exhibited consistently comparable antiproliferative activity to doxorubicin in a time-dependent manner (IC₅₀ = 77 nM in CCRF-CEM cells). Flow cytometry analysis showed a 3-fold more cellular uptake of <b>10</b> than doxorubicin in SK-OV-3 cells. Confocal microscopy revealed that the conjugate was distributed in cytoplasmic and perinuclear areas during the first 1 h of incubation and slowly relocalized in the nucleus after 24 h. The cellular hydrolysis study showed that 98% of compound <b>10</b> was hydrolyzed intracellularly within 48 h and released doxorubicin

Hydrophobicity drives the cellular uptake of short cationic peptide ligands

Short cationic linear peptide analogs (LPAs, prepared as Arg-C n -Arg-C n -Lys, where C n represents an alkyl linkage with n = 4, 7 or 11) were synthesized and tested in human breast carcinoma BT-20 and CCRF-CEM leukemia cells for their application as targeting ligands. With constant LPA charge (+4), increasing the alkyl linkage increases the hydrophobic/hydrophilic balance and provides a systematic means of examining combined electrostatic and hydrophobic peptide-membrane interactions. Fluorescently conjugated LPA-C11 (F-LPA-C11) demonstrated significant uptake, whereas there was negligible uptake of the shorter LPAs. By varying temperature (4°C and 37°C) and cell type, the results suggest that LPA-C11 internalization is nonendocytic and nonspecific. The effect of LPA binding on the phase behavior, structure, and permeability of model membranes composed of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylserine (DPPC/DPPS, 85/15) was studied using differential scanning calorimetry (DSC), cryogenic transmission electron microscopy (cryo-TEM), and fluorescence leakage studies to gain insight into the LPA uptake mechanism. While all LPAs led to phase separation, LPA-C11, possessing the longest alkyl linkage, was able to penetrate into the bilayer and caused holes to form, which led to membrane disintegration. This was confirmed by rapid and complete dye release by LPA-C11. We propose that LPA-C11 achieves uptake by anchoring to the membrane via hydrophobicity and forming transient membrane voids. LPAs may be advantageous as drug transporter ligands because they are small, water soluble, and easy to prepare. © 2011 European Biophysical Societies\u27 Association

Fatty Acyl Amide Dderivatives of Doxorubicin: Synthesis and In Vitro Anticancer Activities

Doxorubicin is an anticancer drug extensively used in anticancer therapy. Doxorubicin is highly hydrophilic, has short half-life, and its use is associated with severe side effects at high doses. Fatty acyl amide derivatives of doxorubicin were synthesized with the expectation to improve the lipophilicity and anticancer activity of the drug. The lipophilicity was enhanced with the increase in chain length of fatty acyl moiety. Conjugation of 4-amino group with fatty acids through an amide bond reduced the anticancer activity in leukemia, breast, ovarian, and colon cancer cell lines, suggesting that the presence of free amino group is required for anticancer activity of doxorubicin. Dodecanoyl-doxorubicin derivative was consistently the most effective among the synthesized derivatives and inhibited the proliferation of colon (HT-29) and ovarian (SK-OV-3) cancer cells by 64% and 58%, respectively, at a concentration of 1 µM after 96 h incubation

New dendrimer - Peptide host - Guest complexes: Towards dendrimers as peptide carriers

Adamantyl urea and adamantyl thiourea modified poly(propylene imine) dendrimers act as hosts for N-terminal tert-butoxycarbonyl (Boc)-protected peptides and form chloroform-soluble complexes. investigations with NMR spectroscopy show that the peptide is bound to the dendrimer by ionic interactions between the dendrimer outer shell tertiary amines and the C-terminal carboxylic acid of the peptide, and also through host-urea to peptide-amide hydrogen bonding. The hydrogen-bonding nature of the peptide dendrimer interactions was further confirmed by using Fourier transform IR spectroscopy, for which the NH- and CO-stretch signals of the peptide amide moieties shift towards lower wave-numbers upon complexation with the dendrimer. Spatial analysis of the complexes with NOESY spectroscopy generally shows close proximity of the N-terminal Boc group of the peptide to the peripheral adamantyl groups on the dendrimer host. The influence of side-chain motif on interactions with the host is analyzed by using seven different N-Boc-protected tripeptides as guests for the dendrimer, Downfield shifts of up to 1.3 ppm were observed for the guest amide NH-proton signals. These shifts decrease with increasing 'bulkiness' of the amino acid side chains. Despite this, the dendrimer was capable of making multiple peptide-dendrimer complexes when presented with a library of seven peptides. The different peptides were all present in the host, which did not show specific preferences, and could be released under mild acidic conditions. These results show the general nature of the peptide dendrimer interactions in the formation of either single- or multiple-peptide-dendrimer complexe

Extracellular biosynthesis of silver nanoparticles using the fungus Fusarium oxysporum

The development of reliable, eco-friendly processes for the synthesis of nanomaterials is an important aspect of nanotechnology today. One approach that shows immense potential is based on the biosynthesis of nanoparticles using biological micro-organisms such as bacteria. In this laboratory, we have concentrated on the use of fungi in the intracellular production of metal nanoparticles. As part of our investigation, we have observed that aqueous silver ions when exposed to the fungus Fusarium oxysporum are reduced in solution, thereby leading to the formation of an extremely stable silver hydrosol. The silver nanoparticles are in the range of 5-15 nm in dimensions and are stabilized in solution by proteins secreted by the fungus. It is believed that the reduction of the metal ions occurs by an enzymatic process, thus creating the possibility of developing a rational, fungal-based method for the synthesis of nanomaterials over a range of chemical compositions, which is currently not possible by other microbe-based methods