Synthesis of a Highly Potent Antitumor Saponin OSW-1 and its Analogues (original) (raw)
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New Analogues of the Potent Cytotoxic Saponin OSW-1
Journal of Medicinal Chemistry, 2007
Saponin OSW-1 (5e-G2; 3 ,16 ,17R-trihydroxycholest-5-en-22-one 16-O-{O-[2-O-(4-methoxybenzoyl)--D-xylopyranosyl]-(1f3)-2-O-acetyl-R-arabinopyranoside}) analogues: with modified side chain (5a/d-G2), 22-deoxo-23,24,25,26,27-pentanor-(14), 22-deoxo-23-oxa-(17), glycosylated with various monosaccharides (5e-G4/G6/G8), and OSW-1 structural isomer (10) were obtained. The analogues were synthesized using a previously published method for the synthesis of OSW-1. The structures of analogues were fully confirmed by spectroscopic methods, and the S-chirality at C-22 of the structural isomer was established by conformational analysis combined with the NMR spectrometry. The cytotoxicity of the analogues toward several types of malignant tumor cells was examined and compared with that of OSW-1. The results suggest that modification of the steroidal aglycone may lead to compounds with high cytotoxicity.
The Journal of Organic Chemistry, 2004
Two natural saponins 1 and 2, isolated from Solanum indicum L., and containing 2,3-branched sugar moieties, have been efficiently synthesized. Partially protected monosaccharide and disaccharide donors were used to facilitate target synthesis. Stereo factors were critical in incorporating 2,3-branched sugars on steroid aglycones. Saponin 1 was synthesized in five steps and 30% overall yield, while saponin 2 was obtained using six straightforward sequential reactions in 31% overall yield. Saponin 2 shows promising cytotoxic activity toward human hepatocellular carcinoma BEL-7402 with an IC 50 of <6 µg/mL. Saponins constitute a structurally and biologically diverse class of molecules that are widely distributed in terrestrial plants and in certain marine organisms. 1 Most traditional Chinese medicines contain saponins as major components and, thus, represent glycoconjugate templates in drug design and development. 2 Dioscin (diosgenyl 2,4-di-O-R-L-rhamnopyranosyl--D-glucopyranoside), Pa (diosgenyl R-L-rhamnopyranosyl-(1f2)-[R-L-arabinofuranosyl-(1f4)]--D-glucopyranoside), methyl protodioscin (3-O-(2,4-di-O-R-L-rhamnopyranosyl--D-glucopyranosyl)-26-O-( -D-glucopyranosyl)-22-methoxy-25(R)furost-5-ene-3 ,26-diol), and balanitin 7 (diosgenyl R-Lrhamnopyranosyl-(1f2)-[ -D-xylopyranosyl-(1f3)--Dglucopyranosyl-(1f4]--D-glucopyranoside) are all clinically recognized for their cardiovascular, antifungal, and antitumor activities. 3 Both the carbohydrate and steroid
Oleanane-type Saponins from Glochidion hirsutum and Their Cytotoxic Activities
Chemistry & biodiversity, 2017
Five new oleanane-type saponins, hirsutosides A-E, were isolated from the leaves of Glochidion hirsutum (Roxb.) Voigt. Their structures were elucidated as 21β-benzoyloxy-3β,16β,23,28-tetrahydroxyolean-12-ene 3-O-β-D-glucopyranoside (1), 21β-benzoyloxy-3β,16β,23,28-tetrahydroxyolean-12-ene 3-O-β-D-glucopyranosyl-(1→3)-β-D-glucopyranoside (2), 21β-benzoyloxy-3β,16β,23,28-tetrahydroxyolean-12-ene 3-O-6-acetyl-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranoside (3), 21β-benzoyloxy-3β,16β,23,28-tetrahydroxyolean-12-ene 3-O-β-D-glucopyranosyl-(1→3)-α-L-arabinopyranoside (4), and 21β-benzoyloxy-3β,16β,23-trihydroxyolean-12-ene-28-al 3-O-β-D-glucopyranosyl-(1→3)-α-L-arabinopyranoside (5). All isolated compounds were evaluated for cytotoxic activities on four human cancer cell lines, HepG-2, A-549, MCF-7, and SW-626 using the SRB assay. Compounds 1, 2, 4, and 5 showed significant cytotoxic activities against all human cancer cell lines with IC50 values ranging from 3.4 to 10.2 μM. Compound 3 cont...
Structural analogues of diosgenyl saponins: Synthesis and anticancer activity
Bioorganic & Medicinal Chemistry, 2009
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-b-D-glucopyranosyl residue or an a-L-rhamnopyranosyl-(1?4)-2-amino-2-deoxy-b-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.
Design, synthesis and cytotoxic activity of N-Modified oleanolic saponins bearing A glucosamine
European journal of medicinal chemistry, 2017
A series of N-acyl, N-alkoxycarbonyl, and N-alkylcarbamoyl derivatives of 2'-deoxy-glucosyl bearing oleanolic saponins were synthesized and evaluated against HL-60, PC-3, and HT29 tumor cancer cells. The SAR studies revealed that the activity increased in order of conjugation of 2' -amino group with carbamate > amide > urea derivatives. Lengthening the alkyl chain increased the cytotoxicity, the peak activity was found to around heptyl to nonyl substitutions. 2'-N-heptoxycarbonyl derivative 56 was found to be the most cytotoxic (IC50 = 0.76 μM) against HL-60 cells. Due to the interesting SARs of alkyl substitutions, we hypothesized that their location in the cell was different, and pursued a location study using 2'-(4″-pentynoylamino) 2'-deoxy-glucosyl OA, which suggested that these compounds distributed mainly in the cytosol.
Chemistry and pharmacology of saponins: special focus on cytotoxic properties
Botanics: Targets and Therapy, 2011
Saponins are bioactive compounds produced mainly by plants but also by some marine organisms and insects. In the recent past, there has been unforeseen interest in the clinical utilization of saponins as chemotherapeutic agents. The research on saponins in various forms as a treatment for cancer has generated a lot of potential. The advent of nanotechnology and the cytotoxicity enhancing properties of saponins are some of the highlights of the current decade. This review gives an updated overview of the clinical potential that saponins hold as cytotoxic agents, and covers the literature for 1957-2011, with the main focus on research conducted in the last decade. It is conceivable that saponins hold a lot of therapeutic potential and could be a lead for identification of synthetic or semisynthetic molecules for the treatment of cancer via membrane-mediated or transport-mediated pathways.
Synthesis and Biological Activity of 22-Deoxo-23-oxa Analogues of Saponin OSW-1
Journal of Medicinal Chemistry, 2011
Analogues of the potent cytotoxic saponin OSW-1 were prepared from the readily available steroidal 16β,17R,22triol. The new 22-deoxo-23-oxa analogues of OSW-1 were screened against eight cancer cell lines and normal human fibroblasts. The analogues proved to be slightly less active than OSW-1 but also less toxic to normal cells. They induce concentration-and time-dependent apoptosis of mammalian cancer cells with caspase-3 activation.
Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activity
Vaccine, 2000
Aldehyde-containing triterpene saponins have adjuvant properties, but only those from Quillaja saponaria Molina stimulate the production of cytotoxic T lymphocytes (CTL) against exogenous antigens. Quillaja saponins have two normonoterpene ester moieties, linked linearly to their fucosyl residue, that play a critical role in the stimulation of CTL. These ester moieties are also responsible for these saponins' instability and toxicity. Based on the structure±activity relationships for the dierent groups of Q. saponaria saponins, new semi-synthetic analogs were developed that have the adjuvanticity of quillaja saponins, yet with less toxicity and greater stability in aqueous solutions. The quillaja saponin analogs were prepared by replacing their hydrolytically unstable ester groups with another lipophilic chain linked by a stable amide bond on these saponins' glucuronic acid residue. One of these analogs, GPI-0100, is a dodecylamide saponin derivative that stimulates an antibody isotype pro®le that corresponds to a Th1 type immune response, as well as CTL production against exogenous antigens. 7