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Background: In recent years, the anticancer effects of biguanide drugs have received considerable attention. However, the effective concentration of biguanide drugs to kill cancer cells is relatively high. Thus, we focus on structural modification of biguanides to obtain better antitumor candidates. A previous study in our laboratory has found that a biguanide compound containing the n-heptyl group has potent anticancer activity. However, the effect of different substituents on the benzene ringside of the biguanides on the anti-proliferative activity is unknown. Objective: A series of n-heptyl-containing biguanide derivatives whose benzene rings were modified by halogen substitution based on the intermediate derivatization method were further synthesized to find new compounds with improved antiproliferative activities. Method: Ten n-heptyl-containing biguanide derivatives were synthesized via established chemical procedures. The activities of these derivatives were explored by MTT assay, clonogenic assay, and scratch assay. The protein levels were detected via Western blotting to explore the underlying mechanisms. Results: The optimal biguanide derivatives 10a-10c, 11d exhibited IC50 values of 2.21-9.59 μΜ for five human cancer cell lines, significantly better than the control drug proguanil. The results of clonogenic and scratch wound healing assays also confirmed the inhibitory effects of derivatives 10a- 10c, 11d on the proliferation and migration of human cancer cell lines. Western blot results demonstrated that one representative derivative, 10c upregulates the AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K. Conclusion: All biguanide derivatives containing n-heptyl groups are more active than proguanil, indicating that the modification of n-heptyl-containing biguanide derivatives provides a novel approach for the development of novel high efficient antitumor drugs.

Ten novel mitochondria-targeted dihydroartemisinin ether derivatives were designed, synthesized, and evaluated for antitumor activity against five cancer cell lines in vitro. Profoundly, compound

Background Bladder cancer is the second most common genitourinary malignancy and the eleventh most common cancer worldwide. Dihydroartemisinin (DHA), a first-line antimalarial drug, has been found to have potent antitumor activity. In our previous study, a novel dihydroartemisinin derivative Mito-DHA5 synthesized in our laboratory has a stronger anti-tumor activity than DHA. In this study, we investigated the apoptotic effect of Mito-DHA5 on bladder cancer T24 cells and molecular mechanisms underlying. Methods Antitumor activity in vitro was evaluated by MTT, wound healing and cloning formation assays. Mitochondrial membrane potential (MMP) was detected by JC-1 probe and ROS levels were measured by specific kit. The expression of caspase-3, cleaved-caspase3, mitochondrial Cyt-C, Bcl-2, Bax and PARP in T24 cells was evaluated by Western blotting. Results The results showed that Mito-DHA5 reduced cell viability with an IC50 value of 3.2 µM and induced T24 cell apoptosis in a dose-dependent manner, increased the production of ROS and decreased MMP. Mito-DHA5 could down-regulate the expression of Bcl-2, mitochondrial Cyt-C, Caspase-3, PARP and up-regulate the expression of Bax and cleaved Caspase-3. Conclusions These data suggested that Mito-DHA5 had a potent inhibitory effect on T24 bladder cancer cell growth and induced these cells apoptosis associated with mitochondrial pathway.

A series of novel artemisinin ester derivatives were designed and synthesized for targeting mitochondria. Cytotoxicity against SMMC-7721, HepG2, OVCAR3, A549 and J82 cancer cell lines was evaluated. Compound 2c (IC50 = 3.0 μM) was the most potent anti-proliferative molecule against the OVCAR3 cells with low cytotoxicity in normal HUVEC cells. The mechanism of action of compound 2c was further investigated by analyzing cell apoptosis, mitochondrial membrane potential (Δψm) and intracellular ROS generation. The results indicated that compound 2c targeted mitochondria and induced cell apoptosis. ROS and heme attributed to the cytotoxicity and cell apoptosis of compound 2c. These promising findings indicated the compound 2c could serve as a great candidate against ovarian cancer for further investigation.

Sugammadex sodium is the first selective relaxant binding agent (SRBA) indicated for reversal of neuromuscular blockade induced by rocuronium or vecuronium during surgery. The chemical synthesis of sugammadex involved the nucleophilic substitution reaction between 6-per-deoxy-6-per-halo-γ-cyclodextrin and 3-mercaptopropionic acid under basic conditions. During the manufacture of sugammadex sodium, an unknown process-related impurity was observed in pilot batches in the range of 0.21-1.9 % based upon HPLC analysis. The same impurity was also detected in commercial Bridion® samples at the levels of more than 0.1 %. Thus this unknown impurity was enriched from the mother liquor of reaction by preparative HPLC and characterized by LC-MS/QTOF, 1D-NMR (1H, 13C, DEPTQ) and 2D-NMR (1H-1H COSY, TOCSY, HSQC, HMBC, NOESY) techniques. Based on spectroscopic analysis and the synthetic route of sugammadex sodium, this new impurity was identified as monocyanoethyl sugammadex (impurity-I). The prospects to the formation mechanism and control strategy of impurity-I were discussed in detail. Moreover, the toxicological properties of impurity-I were evaluated using ADMET Predictor® software.

Proguanil, a member of biguanide family, has excellent anti-proliferative activities. Fluorine-containing compounds have been demonstrated to have super biological activities including enhanced binding interactions, metabolic stability, and reduced toxicity. In this study, based on the intermediate derivatization methods, we synthesized 13 new fluorine-containing proguanil derivatives, and found that 7a,7d and 8e had much lower IC50 than proguanil in 5 human cancerous cell lines. The results of clonogenic and scratch wound healing assays revealed that the inhibitory effects of derivatives 7a,7d and 8e on proliferation and migration of human cancer cell lines were much better than proguanil as well. Mechanistic study based on representative derivative 7a indicated that this compound up-regulates AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K. In conclusion, these new fluorine-containing derivatives show potential for the development of cancer chemotherapeutic drugs.

Interleukin-35 (IL-35) is a newly discovered anti-inflammatory cytokine predominantly released by regulatory T cells (Tregs) and may serve an important role in the pathogenesis of autoimmune diseases. The levels of IL-35 and corresponding Treg frequencies in patients with rheumatoid arthritis (RA) have scarcely been reported. The present study aimed to detect serum IL-35 levels and Treg frequencies in patients with RA, and analyze their association with each other and with indicators of RA. A total of 55 patients with RA, including 37 active-phase (AP) and 18 chronic-phase (CP) cases, as well as 20 healthy controls (HC), were recruited. Clinical parameters, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody and 28-joint disease activity score (DAS28) were assessed. The Treg frequency in peripheral blood (PB) was determined by flow cytometry. IL-35 mRNA in PB mononuclear cells of the patients with RA was measured by reverse transcription-quantitative polymerase chain reaction analysis, and IL-35 levels in the serum were detected by ELISA. The correlations between IL-35 levels and the abovementioned indexes were analyzed by determining Pearson's correlation coefficient. The results of the present study indicated that the Treg frequency was significantly decreased in patients with RA compared with that in HC. No significant difference in Treg frequency between the AP and CP groups of RA patients was identified. In addition, the serum IL-35 levels and mRNA expression in RA patients were obviously lower than those in the HC. Of note, the serum IL-35 levels were negatively correlated with the ESR and DAS28 of patients with RA, while no correlation with CRP, RF or anti-CCP antibodies was identified. In addition, a significant positive correlation was revealed between serum IL-35 levels and the Treg frequency. These results suggest that IL-35 and Tregs have a protective role regarding the development of RA.