Zi-Hua Jiang

Structural analogues of diosgenyl saponins: Synthesis and anticancer activity

Saponins display various biological activities including anti-tumor activity. Recently intensive research has been focused on developing saponins for tumor therapies. The diosgenyl saponin dioscin is one of the most common steroidal saponins and exhibits potent anticancer activity in several human cancer cells through apoptosis-inducing pathways. In this paper, we describe the synthesis of several diosgenyl saponin analogues containing either a 2-amino-2-deoxy-beta-d-glucopyranosyl residue or an alpha-l-rhamnopyranosyl-(1-->4)-2-amino-2-deoxy-beta-d-glucopyranosyl residue with different acyl substituents on the amino group. The cytotoxic activity of these compounds was evaluated in MCF-7 breast cancer cells and HeLa cervical cancer cells. Structure-activity relationship studies show that the disaccharide saponin analogues are in general less active than their corresponding monosaccharide analogues. The incorporation of an aromatic nitro functionality into these saponin analogues does not exhibit significant effect on their cytotoxic activity.

Novel lipid A mimetics derived from pentaerythritol: synthesis and their potent agonistic activity

Abstract A pentaerythritol unit is substituted for glucosamine as its functional mimic at the reducing end of lipid A disaccharide. Two such pentaerythritol derived lipid A mimetics 3 and 4 , carrying three identical fatty acyl moieties, have been designed and synthesized. An efficient strategy, which involves simultaneous introduction of lipids onto two amino groups, is described for the synthesis of compounds 3 and 4 . The biological activity profile of these two novel lipid A mimetics 3 and 4 is surprisingly similar to the natural lipid A product isolated from Salmonella minnesota R595. An in vitro cell activation assay, using human adherent antigen presenting cells, has demonstrated that both 3 and 4 induce the secretion of high levels of cytokines such as tumour necrosis factor-α (TNF-α), IL-6 and IL-8. Also, in a totally synthetic liposomal vaccine system, 3 and 4 exhibit strong immunostimulatory adjuvant property in enhancing antigen specific T-cell activation.

Synthesis and tumor cell growth inhibitory activity of biotinylated annonaceous acetogenins.

Nineteen biotinylated squamocin/bullatacin derivatives have been synthesized for targeted delivery to biotin receptor overexpressed tumor cells. Most biotinylated squamocin and bullatacin derivatives show similar in vitro cytotoxicity against the biotin receptor non-overexpressed L1210 cells as squamocin and bullatacin, respectively, while against biotin receptor overexpressed 4T1 and P815 tumor cells, several derivatives show significantly higher potency and better selectivity. Among all the synthesized compounds, 15,28-di-O-(6-biotinylamidohexanoyl)squamocin (16) is the most potent, which is 10 and 26 times more active than squamocin against 4T1 and P815 cells, respectively. Compound 16 also appears to be six and fifteen times more selective than squamocin towards 4T1 and P815 cells, respectively, against L1210 cells. The structure activity relationship analysis has revealed that the preferred site for biotinylation is different for squamocin and bullatacin, and it also depends on whether a linking spacer is present.

Lipid A structures containing novel lipid moieties: synthesis and adjuvant properties

Structurally well-defined immune stimulatory molecules are important components of new generation molecular vaccines. In this paper, the design and synthesis of two lipid A analogues containing an unnatural tri-lipid acyl group are described. In a totally synthetic liposomal vaccine system, these re-designed lipid A analogues demonstrate potent immune stimulatory properties including antigen specific T-cell activation.

Synthesis and cytotoxic activity of diosgenyl saponin analogues

Diosgenyl saponins are steroidal glycosides that are often found as major components in many traditional oriental medicines. Recently, a number of naturally occurring diosgenyl saponins have been shown to exert cytotoxic activity against several strains of human cancer cells. Use of these saponin compounds for cancer treatment is hampered due to the lack of understanding of their action mechanism as well as limited access to such structurally complicated molecules. In the present paper, we have prepared a group of diosgenyl saponin analogues which contain a beta-D-2-amino-2-deoxy-glucopyranose residue having different substituents at the amino group. Moderate cytotoxic activity is found for most analogues against neuroblastoma (SK-N-SH) cells, breast cancer (MCF-7) cells, and cervical cancer (HeLa) cells. The analogue 13 that contains an alpha-lipoic acid residue exhibits the highest potency against all three cancer cell lines with IC(50) ranging from 4.8 microM in SK-N-SH cells to 7.3 microM in HeLa cells. Preliminary mechanistic investigation with one saponin analogue (10) shows that the compound induces cell cycle arrest at G(1) phase in SK-N-SH cells, but the same compound induces cell cycle arrest at G(2) phase in MCF-7 cells. This result suggests that the cytotoxic activity of these saponin analogues may involve different action mechanisms in cell lines derived from different cancer sites.

Improving the immunostimulatory potency of diethanolamine-containing lipid A mimics.

Lipid A is the active principal of gram negative bacterial lipopolysaccharide (LPS) in the activation of Toll-like receptor 4 (TLR4). Given the important role TLR4 plays in innate immunity and the development of adaptive immune responses, ligands that can modulate TLR4-mediated signaling have great therapeutic potential. Recently, we have reported a series of monophosphorylated lipid A mimics as potential ligands of TLR4, in which a diethanolamine moiety is employed to replace the reducing end (d-glucosamine). In this paper, we describe the synthesis of two further diethanolamine-containing lipid A mimics, 3 and 4, in an effort to mimic more closely the di-phosphate nature of natural lipid A. Both mimic 3, with an additional phosphate on the diethanolamine acyclic scaffold, and mimic 4, with a terminal carboxylic acid moiety as a phosphate bioisostere, serve to increase the potency of the immunostimulatory response induced, as measured by the induction of the cytokines TNF-α, IL-6, and IL-1β in the human monocytic cell line THP-1. In addition, mechanistic studies involving the known TLR4 antagonist lipid IVa confirm TLR4 as the target of the diethanolamine-containing lipid A mimics.

Synthesis of a dimeric monosaccharide lipid A mimic and its synergistic effect on the immunostimulatory activity of lipopolysaccharide

Bacterial endotoxin lipopolysaccharide (LPS) is a potent immune stimulant, with the recognition of LPS and its active principal lipid A mediated by the Toll-like receptor 4 (TLR4)/MD-2 receptor complex. Due to the broad downstream implications of TLR4-mediated signalling, TLR4 ligands show great potential for immunotherapeutic manipulations. In this paper a dimeric monosaccharide lipid A mimic (3) has been designed as a potential TLR4 ligand. The chemical synthesis and the preliminary biological studies are described. Compound 3 shows a significant synergistic effect on LPS-induced ICAM-1 expression in human monocytic THP-1 cells.

Resin glycosides from the aerial parts of Operculina turpethum.

Three glycosidic acids, turpethic acids A-C, and two intact resin glycosides, turpethosides A and B, all having a common pentasaccharide moiety and 12-hydroxy fatty acid aglycones of different chain lengths, were obtained from the aerial parts of Operculina turpethum. Their structures were elucidated by spectroscopic analyses and chemical correlations. The aglycones were characterized as 12-hydroxypentadecanoic acid in two compounds, 12-hydroxyhexadecanoic acid in two other components, and 12-hydroxyheptadecanoic acid in the fifth compound, which were all confirmed by synthesis. The absolute configurations of these aglycones were all established as S by Moshers method. These compounds represent the first examples of resin glycosides with a monohydroxylated 12-hydroxy fatty acid as an aglycone, and one compound is the first described resin glycoside having a hydroxylated C(17) fatty acid as its aglycone.

Synthesis and immunostimulatory activity of diethanolamine-containing lipid A mimics

Toll-like receptor (TLR) 4 plays important roles in the innate immunity and the development of adaptive immune responses. TLR4 ligands that can modulate the TLR4-mediated signalling pathways therefore have great potential for therapeutic applications. In this paper, we describe the synthesis of three lipid A mimics (2–4) as potential TLR4 ligands, in which a diethanolamine moiety is employed to replace the reducing end (D-glucosamine) of the archetypical lipid A disaccharide structure. Biological studies indicate that the lipid A mimic with six acyl chains (2) exhibits potent immune stimulatory activity in that it induces a significant increase in the ICAM-1 expression of human pre-monocytic THP-1 cells, as well as significant production of the cytokines TNF-α, IL-6, and IL-1β. The mimic with eight acyl chains (3) is inactive towards both the induction of ICAM-1 expression, and the cytokines TNF-α, and IL-6, yet induces significant production of IL-1β when tested at higher concentration. Finally, the lipid A mimic 4, a derivative of 2, that contains an additional 1-hydroxybutyl group as a result of an unexpected ring opening reaction of a tetrahydrofuran molecule, is active in all respects tested, albeit with reduced potency. These data suggest that diethanolamine-containing lipid A mimics can be potent immune stimulating agents.

Quinazoline Alkaloids from Streptomyces michiganensis

Two new quinazoline alkaloids, 2-(2-carboxyethyl)-8-hydroxyquinazolin-4(3H)-one (1) and 2-(2-carboxyethyl)6-hydroxyquinazolin-4(3H)-one (2), along with the previously synthesized 2-(4-hydroxyphenyl)quinazolin4(3H)-one (3), were isolated from the solid cultures of Streptomyces michiganensis strain SC0642. Their structures were elucidated by spectroscopic methods.