Rungnapha Saeeng

Iodine catalyzes C-glycosidation of d-glucal with silylacetylene

Abstract A convenient method for C-glycosidation (alkynylation) with various silylacetylenes to d -glucal by iodine molecule via iodo–oxonium intermediates provided exclusively the α-acetylene glycoside products. Eleven successful examples are shown under this condition.

PARTIAL SYNTHESIS OF CIGUATOXIN (5R)-ABC SEGMENT

Abstract An ABC segment of ciguatoxin has been synthesized in a correct enantiomeric form from a D-glucose derivative based on the route for the opposite enantiomer by switching enantiomerism of a pseudosymmetric intermediate. This route, however, has been improved in several steps and ended up with a vinylthioether group for future extension toward the D ring of ciguatoxin molecule.

New substituted C-19-andrographolide analogues with potent cytotoxic activities.

Andrographolide, the major diterpenoid lactone from Andrographis paniculata, is toxic against cancer cells. In the present study, we investigated the structure-activity relationships (SARs) of 19 andrographolide analogues which were synthesized by modification at the three hydroxyl groups. A number of the andrographolide analogues showed much higher cytotoxic activities than that of the parent compound on cancer cells including P-388, KB, COL-2, MCF-7, LU-1 and ASK cells. SAR studies of the synthetic analogues indicated that the introduction of silyl ether or triphenylmethyl ether group into C-19 of the parent compound led to increase in toxicity against the cancer cells. The 19-O-triphenylmethyl ether analogue 18 showed higher cytotoxic activity than the potent anticancer drug ellipticine, and this analogue may serve as a potential structure lead for the development of new anticancer drugs.

An efficient method for the selective synthesis of 2-deoxy-2-iodo-glycosides by O-glycosidation of d-glucal using I2–Cu(OAc)2

An efficient and convenient method for the synthesis of 2-deoxy-2-iodo-O-glycosides from tri-O-acetyl-D-glucal with various alcohols by using I₂-Cu(OAc)₂ is described. The 21 examples of corresponding glycosides were obtained in high yields, with good anomeric selectivity.

12-Amino-andrographolide analogues: synthesis and cytotoxic activity

Andrographolide, a diterpenoid lactone of the plant Andrographis paniculata, has been shown to be cytotoxic against various cancer cells in vitro. In the present study, a series of β-amino-γ-butyrolactone analogues has been synthesized from naturally occurring andrographolide via one pot tandem aza-conjugate addition–elimination reaction. By using economic procedure without any base or catalyst at room temperature, the products obtained were in fair to excellent yields with high stereoselectivity. The cytotoxicity of all new amino analogues were evaluated against six cancer cell lines and revealed their potential for being developed as promising anti-cancer agents.

Solubility enhancement and in vitro evaluation of PEG-b-PLA micelles as nanocarrier of semi-synthetic andrographolide analogue for cholangiocarcinoma chemotherapy

Abstract Background: Semi-synthetic andrographolide analogue (19-triphenylmethyl ether andrographolide, AG 050) is a C-19 substituted andrographolide which is the major constituent from Andrographis Paniculata Nees (Acanthaceae). The analogue has previously been reported to be highly cytotoxic against several cancer cell lines. Nevertheless, its poor water solubility limits clinical applications of this compound. Objectives: To improve the aqueous solubility and bioavailability of AG 050 by protonation and encapsulation in poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-b-PLA) polymeric micelles. Materials and methods: PEG-b-PLA micelle was employed as a nanocarrier for AG 050. The physicochemical properties and in vitro cytotoxicity against cholangiocarcinoma (CCA) (KKU-M213) cell line were done in this study. Result and discussion: Hydrochloride salt of AG 050 (AG 050-P) greatly enhanced the solubility of this compound (15-fold). PEG-b-PLA was able to encapsulate AG 050-P in hydrophobic core with a significant increase in the amount of AG 050-P in aqueous solution (280-fold). Film sonication method provided greater results in drug-loading study as compared to micelles via solvent evaporation. In addition, the encapsulated AG 050-P exhibited sustained release pattern and excellent cytotoxicity activity against KKU-M213 with IC50 of 3.33 µM. Conclusion: Nanoencapsulation of AG 050-P implicated its potential development for clinical use in CCA treatment.

Induction of apoptosis in cholangiocarcinoma by an andrographolide analogue is mediated through topoisomerase II alpha inhibition

Cholangiocarcinoma (CCA), the common primary malignant tumor of bile duct epithelial cells, is unresponsive to most chemotherapeutic drugs. Diagnosis with CCA has a poor prognosis, and therefore urgently requires effective therapeutic agents. In the present study we investigated anti-cancer effects of andrographolide analogue 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) and its mechanism in human CCA cell line KKU-M213 derived from a Thai CCA patient. By 24h after exposure, the analogue 3A.1 exhibited a potent cytotoxic effect on KKU-M213 cells with an inhibition concentration 50 (IC50) of approximately 8.0µM. Analogue 3A.1 suppressed DNA topoisomerase II α (Topo II α) protein expression, arrested the cell cycle at sub G0/G1 phase, induced cleavage of DNA repair protein poly (ADP-ribose) polymerases-1 (PARP-1), and enhanced expression of tumor suppressor protein p53 and pro-apoptotic protein Bax. In addition, analogue 3A.1 induced caspase 3 activity and inhibited cyclin D1, CDK6, and COX-2 protein expression. These results suggest that andrographolide analogue 3A.1, a novel topo II inhibitor, has significant potential to be developed as a new anticancer agent for the treatment of CCA.

CONVERTIBLE FORMATION OF DIFFERENT GLYCOSIDE USING MOLECULAR IODINE

The observation of convertible formation between 2-deoxy-2-iodo-O-glycosides and 2,3-unsaturated glycoside was described. The selective formation of 2-deoxy-2-iodo-O-glycosides was found from the reaction of D -glucal with iodine in the excess alcohol acceptor or the addition of ceric ammonium nitrate as additive while the addition of a stoichiometric amount of alcohol in solvent favored 2,3-unsaturated glycosides formation.

One-pot synthesis of O-glycosyl triazoles by O-glycosylation-click reaction.

2,3-Unsaturated-glycosyl triazoles were synthesized in a simple one-pot process under mild condition via tandem O-glycosylation using iodine promoter and a mild CuAAC reaction. Thirty examples of a variety of O-glycosyl triazoles were obtained in good to excellent yields and α-anomeric selectivity.

One-pot three steps cascade synthesis of novel isoandrographolide analogues and their cytotoxic activity

An efficient one-pot synthesis of novel andrographolide analogues is reported from a naturally occurring and abundant andrographolide isolated from aerial parts of Andrographis paniculata. Reactions in the one-pot proceed through a cascade epoxide ring opening by aniline derivatives/intramolecular ring closing and oxa-conjugate addition-elimination reactions. This methodology produces a new series of 17-amino-8-epi-isoandrographolide analogues in fair to excellent yields with high stereoselectivity using an economic and environmental procedure without base or catalyst at room temperature. Twenty-five analogues were obtained and cytotoxicity of all new analogues were evaluated against six cancer cell lines to search for a new lead compound based on andrographolide structure.