Promoter-Controlled Synthesis and Conformational Analysis of Cyclic Mannosides up to a 32-mer.

Cyclodextrins are widely used as carriers of small molecules for drug delivery owing to their remarkable host properties and excellent biocompatibility. However, cyclic oligosaccharides with different sizes and shapes are limited. Cycloglycosylation of ultra-large bifunctional saccharide precursors is challenging due to the constrained conformational spaces. Herein we report a promoter-controlled cycloglycosylation approach for the synthesis of cyclic α-(1→6)-linked mannosides up to a 32-mer. Cycloglycosylation of the bifunctional thioglycosides and (Z)-ynenoates was found to be highly dependent on the promoters. In particular, a sufficient amount of a gold(I) complex played a key role in the proper preorganization of the ultra-large cyclic transition state, providing a cyclic 32-mer polymannoside, which represents the largest synthetic cyclic polysaccharide to date. NMR experiments and a computational study revealed that the cyclic 2-mer, 4-mer, 8-mer, 16-mer, and 32-mer mannosides adopted different conformational states and shapes.

Synthesis and Biological Evaluation of Paclitaxel-aminoguanidine Conjugates for Suppressing Breast Cancer.

BACKGROUND: A combination of paclitaxel with antineoplastic agents or paclitaxel alone was used clinically for the treatment of metastatic breast cancer. However, paclitaxel has poor water solubility and limited effect on some metastatic breast cancers. Hence, novel paclitaxel derivatives are in demand. In addition, the inducible nitric oxide synthase inhibitor, and aminoguanidine has a synergistic antitumor effect with chemotherapeutics. OBJECTIVE: This study aims to design and synthesize the paclitaxel-aminoguanidine conjugates. Upon cellular internalization, the novel paclitaxel-aminoguanidine conjugates could release paclitaxel and aminoguanidine with the aid of esterase and weak acids in cancer cells. METHODS: Paclitaxel-aminoguanidine conjugates were synthesized using click chemistry. The biological activity of paclitaxel-aminoguanidine conjugates was evaluated by MTT assay, determination of nitric oxide, analysis of apoptosis and cell cycle, and wound healing assay. RESULTS: Here, a novel paclitaxel-aminoguanidine conjugate was synthesized using click chemistry. Compared with paclitaxel, the water solubility of paclitaxel-aminoguanidine conjugates increased obviously. Upon cellular internalization, the novel paclitaxel-aminoguanidine conjugates released paclitaxel and aminoguanidine to synergistically inhibit the proliferation and metastasis of breast cancer cells with the aid of esterase and weak acids in cancer cells. The results of the MTT assay showed that compared with paclitaxel or the mixture of paclitaxel and aminoguanidine, the cytotoxicity of compound 4 against 4T1 cells was enhanced. As for apoptosis induced by these compounds, the paclitaxel-aminoguanidine conjugates also had a stronger ability to induce apoptosis than paclitaxel or the mixture of paclitaxel and aminoguanidine. The results of the scratch test showed that the anti-metastatic effect of the conjugate was the strongest among these tested compounds. CONCLUSION: These findings indicate that paclitaxel-aminoguanidine conjugate is a promising anticancer agent worthy of further study.

Synthesis of Nucleosides and Deoxynucleosides via Gold(I)-Catalyzed N-Glycosylation of Glycosyl (Z)-Ynenoates.

Nucleoside analogues are widely used as anticancer and antiviral drugs. Here, we develop a highly efficient gold(I)-catalyzed N-glycosylation approach for versatile synthesis of various types of nucleosides and deoxynucleosides with glycosyl (Z)-ynenoates as donors. The wide scope of the N-glycosylation approach was demonstrated by the synthesis of 31 pyrimidine nucleosides and 8 purine nucleosides. Remarkably, the gold(I)-catalyzed N-glycosylation of pyranosyl (Z)-ynenoates with purines was found to be very effective for regioselective synthesis of pyranosyl N9 purine nucleosides. Based on the catalytic N-glycosylation approach, convenient synthesis of two 5'-deoxynucleosides drugs (capecitabine and galocitabine), four 2'-deoxynucleoside drugs (floxuridine, trifluridine, decitabine and cladribine), four 3',5'-dideoxynucleoside analogues, and four 2',5'-dideoxynucleoside analogues was achieved in a collective manner.