AIM To search for new artemisinin derivatives with higher immunosuppressive activity. METHODS Two kinds of new artemisinin derivatives containing polyethylene glycol group were synthesized from dihydroartemisinin via condensation and esterification. These compounds were assayed for their inhibitory activity on ConA-induced T cell proliferation and LPS-induced B cell proliferation. RESULTS Twenty three new compounds (2a - 2f, 3a - 3d, 4a - 4f, 6a, 6b and 7a - 7g) were synthesized and identified by 1H NMR and elemental analysis. CONCLUSION These compounds had immunosuppressive activity in vitro. Among them, the symmetrical substituted compound 2 and 6 had higher activity than mono-substituted compound 3, 4 and 7. Especially, compounds 2a - 2f remarkably exhibited higher inhibition in comparison with artemisinin and artesunate.

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A series of novel dihydroartemisinin derivatives were synthesized and evaluated on their immunosuppressive activity in the search for potential immunosuppressive agents with high efficacy and low toxicity. These compounds were assayed in their cytotoxicity of lymphocyte, inhibition activity on concanavalin A (ConA) induced T cell proliferation and lipopolysaccharide (LPS) induced B cell proliferation. Among them, 11b, 13b, 14d, 15b, 16, and 17 remarkably exhibited lower cytotoxicity and higher inhibition activity on the mitogen-induced T cell and B cell proliferation in comparison with artemisinin, artesunate, and artemether in vitro. More significantly, compound 11b displayed reduced cytotoxicity by over 100-fold compared with cyclosporin A (CsA) and comparable inhibition activity (SI = 848) on ConA-induced T cell proliferation to CsA (SI = 963) and more than 4000 times the inhibitory effect (SI = 28473) on LPS-induced B cell proliferation compared with CsA (SI = 7) in vitro. The in vivo experimental results showed that compound 16 could inhibit 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reaction and sheep red blood cell (SRBC) induced antibody production, respectively. The structure and activity relationships (SAR) of these compounds were also discussed.

To study the immunosuppressive activity of SM735 {[3 -(12-β-artemisininoxy)] phenoxyl succinic acid}, a synthetic artemisinin derivative with nonsteroidal anti-inflammatory drug structure, with the aim of finding potential immunosuppressive agents. Concanavalin A (ConA), lipopolysaccharide (LPS), and mixed lymphocyte reaction (MLR), were used to induce the proliferation of splenocytes, and [3H]-thymidine incorporation was used to evaluate the proliferation of splenocytes. Cytokine production was promoted with ConA, LPS, or PMA plus ionomycin, and was detected with the enzyme-linked immunosorbent assay. Dinitrofluorobenzene (DNFB) and sheep red blood cells (SRBC) were used to induce delayed-type hypersensitivity and quantitative hemolysis of SRBC (QHS) mouse models, as criteria for the evaluation of in vivo immune activity. SM735 strongly inhibited the proliferation of splenocytes induced by ConA, LPS, or MLR, with IC50 values of 0.33 μmol/L, 0.27 μmol/L, and 0.51 μmol/L, respectively. When compared with a CC50 value of 53.1 μmol/L, SM735 had a favorable safety range. SM735 dose-dependently inhibited proinflammatory cytokine production [including interleukins (IL)-12, interferon (IFN)-γ and IL-6] induced by LPS or PMA plus ionomycin. Upon ConA stimulation, SM735 suppressed IFN-γ in a dose-dependent manner, but did not affect IL-2 secretion. SM735 also strongly suppressed both T-cell-mediated delayed-type hypersensitivity (DTH) and B-cell-mediated QHS reactions. SM735 had strong immunosuppressive activity in vitro and in vivo, suggesting a potential role for SM735 as an immunosuppressive agent, and established the groundwork for further research onSM735.

A new type of ether of dihydroartemisinin containing cyano and aryl groups was prepared and tested for cytotoxicity to A549, P388, L1210 and HT29 cells using the MTT assay. 12k and 12l were the most cytotoxic compounds. 13 lacking the peroxy group showed a 1000-fold less potency than 12l. Similarly, the inactive compound 14 indicated that the position of cyano groups was also important. Flow cytometry data showed that the compounds caused an accumulation of P388 cells in the G(1)-phase of the cell cycle.

The photooxygenation product of a cyclic enol ether conjugated with an o-phenylene ring is a novel epoxy compound instead of a 1,2,4-trioxane analogue. The structure of the compound was elucidated by X-ray analysis.

A series of 12α-deoxoartemisinyl cyanoarylmethyl dicarboxylates (4a–4o), dicarboxylic acids 12α-deoxoartemisinyl ester cyanoarylmethyl amide (5a–5k), and dicarboxylic acids 12α-deoxoartemisinyl ester N-methylcyanoarylmethyl amide (6a–6l), showing moderate cytotoxicity against P388 and L1210 cells were prepared. They induced the significant accumulation of L1210 and P388 cells in the G1 phase of the cell cycle. This mechanism of action was quite different from that of the majority of cytotoxic compounds used in the chemotherapy of cancer. Compound 4b possessed better cytotoxicity than the other compounds.

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In search of water-soluble artemisinin derivatives that are more stable than sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5) were synthesized and tested in mice. All products tested (except 5a and 5b) are the beta isomers. These basic compounds combined with organic acids (oxalic acid, maleic acid, etc. ) to yield the corresponding salts. Generally, the maleates have better solubility in water than the corresponding oxalates. The aqueous solutions of these salts can be kept at room temperature for several weeks without any discernible decomposition. Compounds 3f, 3h, and 3r are much more active against P. berghei than artesunic acid by oral administration and therefore were further tested in monkeys. However, their oral efficacies are poorer than that of artesunic acid against P. knowlesi in rhesus monkeys. It is interesting to note that 3f, 3h, and 3r showed much lower efficacies against P. berghei when they were administered subcutaneously than orally.