Design, synthesis, and anti-tumor activity of derivatives of ring A and C-28 of asiatic acid.

Based on computer-aided drug design (CADD), the active groups of the known active small molecule compounds that can bind to EGFR target protein were analyzed through the molecular docking method. Then, 12 novel asiatic acid derivatives were synthesized by introducing active groups at ring A and C-28 positions of asiatic acid. The structures of these novel compounds were determined by NMR and MS. Furthermore, the anti-tumor activities of these derivatives on human lung cancer cells (A549) and human breast cancer cells (MCF-7) were evaluated by MTT assay. In conclusion, compounds I4 and II3 have stronger anti-cancer activity than parent compounds, the activities were stronger than gefitinib and comparable to afatinib, which may be potential candidate compounds for tumor therapy.

Design, synthesis and anti-tumor activity of asiatic acid derivatives as VEGF inhibitors.

The VEGF receptor is mock-coupled with a known active compound and the active groups of the inhibitor which can bind to VEGF were analyzed. Using asiatic acid as a lead compound, 10 novel skeleton candidate compounds were designed through introduction of the active groups onto the special location and synthesized simultaneously. Furthermore, the structure of these compounds was determined by 1H NMR, 13C NMR and MS and 9 compounds were identified as the new compounds. Moreover, the in vitro anti-tumor activities of these new compounds were determined by MTT assay on two cancer cell lines (HepG2 and SGC-7901). The results showed that compounds I1 and II2 have more potent anticancer activity than positive control drugs such as gefitinib and paclitaxel.

Design, synthesis, and antitumor activity of novel oleanolic acid analogues targeting EGFR.

Based on the simulated docking of Epidermal growth factor receptor inhibitors with known active small molecule compounds, computer-aided drug design technology was used to analyze key amino acid fragments and determine the active groups binding with key sites. Then, twelve novel analogues of oleanolic acid (OA) were synthesized by introducing active groups at the C-3 and C-28 positions of OA. The structures of these novel analogues were confirmed by NMR and MS. Furthermore, the antitumor activities of these novel analogues were evaluated by MTT assay. As a result, compounds I3 and II3 showed stronger cytotoxicity on tumor cells than positive controls. In conclusion, our study synthesized twelve novel analogues of OA and determined compounds I3 and II3 had better antitumor effect, which may be potential candidate compounds for tumor therapy.

Synthesis and anti-tumor activity of asiatic acid derivatives targeting VEGFR.

To discovery novel VEGFR inhibitors, 12 novel asiatic acid derivatives were designed by computer-aided drug design (CADD) technology. Then, these novel asiatic acid derivatives were synthesized by introducing active groups at ring A and C-28 positions of asiatic acid. The structures of these novel analogues were confirmed by NMR and MS. Moreover, the anti-tumor activities of these novel asiatic acid derivatives on human hepatoma cells HepG2 and human gastric cancer cells SGC7901 were evaluated by MTT assay. As a result, compounds I2 and II4 showed stronger cytotoxicity on tumor cells than asiatic acid and positive control drugs such as gefitinib and paclitaxel. In conclusion, our study synthesized twelve novel asiatic acid derivatives and determined compounds I2 and II4 had better anti-tumor effect which may be potential candidate compounds for tumor therapy.

Highly Fluorinated Peptide Probes with Enhanced In Vivo Stability for 19 F-MRI.

A labeling strategy for in vivo 19 F-MRI (magnetic resonance imaging) based on highly fluorinated, short hydrophilic peptide probes, is developed. As dual-purpose probes, they are functionalized further by a fluorophore and an alkyne moiety for bioconjugation. High fluorination is achieved by three perfluoro-tert-butyl groups, introduced into asparagine analogues by chemically stable amide bond linkages. d-amino acids and ß-alanine in the sequences endow the peptide probes with low cytotoxicity and high serum stability. This design also yielded unstructured peptides, rendering all 27 19 F substitutions chemically equivalent, giving rise to a single 19 F-NMR resonance with <10 Hz linewidth. The resulting performance in 19 F-MRI is demonstrated for six different peptide probes. Using fluorescence microscopy, these probes are found to exhibit high stability and long circulation times in living zebrafish embryos. Furthermore, the probes can be conjugated to bovine serum albumin with only amoderate increase in 19 F-NMR linewidth to ≈30 Hz. Overall, these peptide probes are hence suitable for in vivo 19 F-MRI applications.

Asymmetric catalytic alkynylation of thiazolones and azlactones for synthesis of quaternary α-amino acid precursors.

Asymmetric alkynylation of thiazolones and azlactones with alkynylbenziodoxolones as the electrophilic alkyne source catalyzed by thiourea phosphonium salt is described. By using thiazolones as nucleophiles, the desired alkyne functionalized thiazolones were obtained in 55-89% yields with 31-86% ee. Azlactones gave the desired products in comparable yields with lower enantioselectivities. Ring-opening of the alkynylation products led to α,α-disubstituted α-amino acid derivatives efficiently without loss of enantioselectivity.

Diastereo- and Enantioselective Synthesis of Quaternary α-Amino Acid Precursors by Copper-Catalyzed Propargylation.

A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is described. This method allows the preparation of a series of non-proteinogenic quaternary α-amino acid precursors featuring two contiguous stereogenic centers and a terminal alkyne moiety in high yields with good to excellent diastereo- and enantioselectivities in most cases. The propargylated adducts were elaborated into a diverse set of quaternary α-amino acid derivatives.

Synthesis of ß-1,3-glucan esters showing nanosphere formation.

Polysaccharide nanoparticles are versatile functional materials used in drug delivery applications. Here we describe a method for the synthesis of ß-1,3-glucan esters which show the formation of nanoparticles. Pyridine-soluble ß-1,3-glucan formate was first synthesized as an intermediate and then reacted with various anhydrates to yield ß-1,3-glucan acetate and hexaonate. The resultant esters were soluble in common organic solvents like acetone, pyridine and dimethylacetamide. By using a simple dialysis process, homogeneous hollow or solid nanospheres with diameter from 132 to 487 nm were prepared. The chemical structures of the obtained ß-1,3-glucan esters were characterized and the morphologies of the ß-1,3-glucan based nanoparticles were evaluated. These new types of nanoparticles could be potentially used for the encapsulation of hydrophobic drugs targeting immune cells.