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Nitidumpeptins A and B (1 and 2), two novel cyclic hexapeptides, were isolated from the herb Zanthoxylum nitidum var. tomentosum. Their planar structures were elucidated based on NMR and MS spectrometric analysis, and the absolute configurations were determined by the Marfey's method. Structurally, 1 is a unique peptide with a backbone bearing a pyrrolidine-2,5-dione unit, which is the first occurrence moiety specifically in a naturally occurring cyclohexapeptide. The total synthesis of 1 and 2 was achieved by solution-phase in parallel with solid-phase peptide synthesis, and their absolute configurations were further confirmed. The combination of 2 with gefitinib exhibited synergistic antiproliferative activity in acquired gefitinib-resistant non-small cell lung cancer cells (HCC827-gef). The underlying mechanism for the antiproliferative activity of 2 was in part associated with the suppression of YAP expression in HCC827-gef cells.

A series of novel asiatic acid (AA) derivatives containing α-aminophosphonate were designed and synthesized as antitumor agents. In vitro antitumor activities of these compounds against five cancer cell lines (A549, Hct-116, T24, Spca-2 and SK-OV-3 cell) and a normal cell line (HUVEC cell) were evaluated, employing standard MTT assay. Antitumor activities screening result indicated that many target compounds displayed moderate to high levels of antitumor activities compared with AA, 5-fluorouracil (5-FU) and cisplatin, and exhibited much lower cytotoxicity against normal cell than 5-FU and cisplatin. In addition, the mechanism of representative compound 3d was preliminarily investigated by AO/EB staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, flow cytometry and western blot. Compound 3d inducing apoptosis involved intracellular Ca2+ production, the loss of mitochondrial membrane potential and intracellular reactive oxygen species (ROS) production. Western blot analysis also demonstrated that compound 3d treatment triggered the mitochondrial apoptotic pathway, indicating by changing Bax/Bcl-2 ratios, cytochrome c release, and caspase-9 activation. Moreover, the cell cycle analysis showed that compound 3d may confine T24 cells in G1/S phase mainly through the p53-dependent pathway. Together, these results implied a critical role of ROS, caspase-9 and p53 in compound 3d-inducing G1/S arrest and apoptosis of T24 cells.

Site-specific conjugation of small molecules to antibody molecules is a promising strategy for generation of antibody-drug conjugates. In this report, we describe the successful synthesis of a novel bifunctional molecule, 6-(azidomethyl)-2-pyridinecarboxyaldehyde (6-AM-2-PCA), which was used for conjugation of small molecules to peptides and antibodies. We demonstrated that 6-AM-2-PCA selectively reacted with N-terminal amino groups of peptides and antibodies. In addition, the azide group of 6-AM-2-PCA enabled copper-free click chemistry coupling with dibenzocyclooctyne-containing reagents. Bifunctional 6-AM-2-PCA mediated site-specific conjugation without requiring genetic engineering of peptides or antibodies. A key advantage of 6-AM-2-PCA as a conjugation reagent is its ability to modify proteins in a single step under physiological conditions that are sufficiently moderate to retain protein function. Therefore, this new click chemistry-based method could be a useful complement to other conjugation methods.

A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives showed an improved antitumor activity. Compound 8j (diethyl 1-(3-(4-methyl-2-oxo-2H-chromen-7-yloxy) propanamido)-1-phenylethyl-Phosphonate), with IC50 value of 8.68 μM against HCT-116 cell lines, was about 12 fold than that of unsubstituted parent compound. The mechanism investigation proved that 8c, 8d, 8f and 8j were achieved through the induction of cell apoptosis by G1 cell-cycle arrest. In addition, the further mechanisms of compound 8j-induced apoptosis in HCT-116 cells demonstrated that compound 8j induced the activations of caspase-9 and caspase-3 for causing cell apoptosis, and altered anti- and pro-apoptotic proteins. DNA-binding experiments suggested that some derivatives bind to DNA through intercalation. The results seem to imply the presence of an important synergistic effect between coumarin and aminophosphonate, which could contribute to the strong chelating properties of aminophosphonate moiety.

Chemical investigations of the whole plant ethanol extract of Rubus phoenicolasius led to the isolation and identification of a new pregnane glycoside, 3-O-β-glucopyranosyl-3β,15β-dihydroxypregn-5-en-20-one (1), along with other nine known compounds (2–10). All the isolates were reported from this plant for the first time. The structure of compound 1 was determined by detailed analysis of its spectral data including 1D and 2D NMR. In vitro anti-proliferative activities of compounds 1–3 on MCF-7 and NCI-H460 tumour cell lines were evaluated, and compound 1 was active against the two cell lines with IC50 values of 15.6 and 13.5 μM, respectively.

A novel and efficient Cu(OTf)2-catalyzed sp(3)-sp(2) C-C bond formation reaction through the direct coupling of propargylic alcohols with terminal alkenes has been realized under mild conditions. The reaction is tolerant to air and is atom-economical, in accordance with the concept of modern green chemistry. The present protocol provides an attractive approach to a diverse range of 1,4-enynes in high to excellent yields.

Several rhein-phosphonate derivatives (5a–c) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially compounds 5b exhibited the strongest cytotoxicity against HepG-2 and Spca-2 cells (IC50 was 8.82 and 9.01 µM), respectively. All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. Further experiments proved that 5b could disturb the cell cycle in HepG-2 cells and induce apoptosis. In addition, the binding properties of a model conjugate 5b to DNA were investigated by methods (UV-Vis, fluorescence, CD spectroscopy). Results indicated that 5b showed moderate ability to interact ct-DNA.