Short Total Synthesis of (±)-Gelliusine E and 2,3'-Bis(indolyl)ethylamines via PTSA-Catalyzed Transindolylation.

A first and short total synthesis of the marine sponge 2,3'-bis(indolyl)ethylamine (2,3'-BIEA) alkaloid (±)-gelliusine E was performed in both a three-step divergent approach and a one-pot three-component approach with an overall yield of up to 58%. A key feature of the novel strategy is PTSA-catalyzed transindolylation of the readily synthesized 3,3'-BIEAs with tryptamine derivatives. The structure of the isolated natural product is revised as protonated (±)-gelliusine E (4'). By design, this modular route allows the rapid synthesis of other members of the 2,3'-BIEA family, for example, (±)-6,6'-bis-(debromo)-gelliusine F and analogues with step economy, operational simplicity, and reduced waste. Furthermore, their cytotoxicity in breast cancer cells was investigated.

Synthesis and biological evaluation of 1,6-bis-triazole-2,3,4-tri-O-benzyl-α-d-glucopyranosides as a novel α-glucosidase inhibitor in the treatment of Type 2 diabetes.

A novel series of 1,6-bis-triazole-benzyl-α-glucoside derivatives (7a-7ee) were designed, synthesized and evaluated for inhibitory activity against α-glucosidase. Most of the synthesized compounds exhibited good activity with IC50 ranging from 3.73 µM to 53.34 µM and are more potent than the standard drug acarbose (IC50 = 146.25 ± 0.40 µM). SARs study showed the ester and menthol moiety play an important role in the inhibitory activity. The molecular docking model of the potent compounds 7f, 7z, 7cc and 7dd showed good binding energy and interacts well with amino acid residues around the active site of the enzyme, which confirmed the in vitro activity results.

Synthesis and cytotoxic activity of new 7-acetoxy-12-amino-14-deoxy andrographolide analogues.

Two new series of 19-silylether- and 19-formyl-7-acetyl-12-amino-14-deoxyandrographolide analogues were designed and synthesized from natural andrographolide via key step reactions including allylic hydroxylation, tandem CAE reaction and one pot formylation. Evaluation of their cytotoxicity against eight cancer cells line found 6e exhibited the highest activity on MCF-7 cancer cell (IC50 2.93) and comparable to the drug elipticin. Replacement of silylether at C-19 with formyl group exhibited selective activity on P-388 cell line. Computational studies revealed the amino group at C-12 and O-acetoxy at C-7 position play significant roles in cytotoxicity against MCF-7 cancer cells. Cytotoxicity of these two series highlights the importance of 12-substituted-14-deoxyandrographolide scaffold and these types of compounds could be employed in future developments against breast cancer.

New class of alkynyl glycoside analogues as tyrosinase inhibitors.

A new series of alkynyl glycoside analogues were designed and synthesized from cheap and a commercially available sugar by introduction of various alkynyl and alkyl groups at C-1 and C-6 positions of the sugar ring. The inhibitory abilities of alkynyl glycosides were investigated in vitro on mushroom tyrosinase for the catalysis of l-Tyrosine and l-DOPA as substrates and comparing with arbutin and kojic acid. Non-terminal alkyne compound 2d showed excellent tyrosinase inhibitory activity (IC50 54.0 µM) against l-Tyrosine comparable to arbutin (IC50 1.46 mM) while 2b exhibited potent activities (IC50 34.3 µM) against L-DOPA higher than kojic acid (IC50 0.11 mM) and arbutin (IC50 13.3 mM). Kinetic studies revealed that compound 2d was a non-competitive inhibitor with the best Ki value of 21 µM and formed an irreversible receptor complex with mushroom tyrosinase. The SARs results showed that the type of alkyne and alkyl groups at position C-6 on sugar and the stereoisomer played an important role in determining their inhibitory activities. The potent activity of alkynyl glycosides identified in this study highlight the importance of this scaffold and these compounds are very modestly potent to the development of new class for tyrosinase inhibitor.

Design and synthesis of C-12 dithiocarbamate andrographolide analogues as an anticancer agent.

A series of 21 new analogues of C-12 dithiocarbamate andrographolide was designed and synthesized from natural andrographolide isolated from a common Thai plant, Andrographis paniculata. The reaction used to manipulate the andrographolide scaffold was conducted in one pot under mild reaction conditions. This avoided toxic catalysts and gave nearly quantitative yields of new analogues, generally without by-products and can be easily scaled -up for industrial processing. All new analogues were evaluated against nine cancer cell lines, some analogues exhibited greater selective cytotoxic activity to MCF-7 cancer cell than that of the parent andrographolide and cancer drugs.

One-Pot Approach for the Synthesis of Bis-indole-1,4-disubstituted-1,2,3-triazoles.

A new strategy for the synthesis of bis-indoletriazoles was developed using a sequential one-pot four-step procedure via I2 and H2SO4-SiO2 catalyzed Friedel-Crafts reactions of indole with aldehyde followed by N-alkylation with propargyl bromide, azidation, and copper(I)-catalyzed azide alkyne cycloaddition (CuAAC). The reaction proceeded smoothly at room temperature in a short time, and a series of bis-indoletriazoles were obtained in good to excellent yields proving the generality of this one-pot methodology.

Synthetic analogues of durantoside I from Citharexylum spinosum L. and their cytotoxic activity.

New iridoid glycoside derivatives from durantoside I, the latter from the dried flowers and leaves of Citharexylum spinosum, were synthesized by variously modifying a sugar moiety by silylation or acetylation and/or removal of cinnamate group at C-7 position and subsequent screening for comparative cytotoxicity against several cancer cell lines. Addition of alkylsilane to durantoside I and removal of cinnamate group were most effective in improving cytotoxicity.

Synthesis of 14-deoxy-11,12-didehydroandrographolide analogues as potential cytotoxic agents for cholangiocarcinoma.

A series of 14-deoxy-11,12-didehydroandrographolide analogues were synthesized from naturally occurring andrographolide and their cytotoxicity evaluated against nine cancer cell lines including cholangiocarcinoma. Analogues 5a and 5b exhibited the most potent cytotoxicity with ED50s of 3.37 and 3.08 µM on KKU-M213 cell lines and 2.93 and 3.27 µM on KKU-100 cell lines, respectively. Selective cytotoxicity on cholangiocarcinoma cell lines identified in this study highlight the importance of structural modification in the development of drugs for this cancer.

Synthesis and evaluation of 6-(3-[(18)F]fluoro-2-hydroxypropyl)-substituted 2-pyridylbenzothiophenes and 2-pyridylbenzothiazoles as potential PET tracers for imaging Aß plaques.

3-[(18)F]Fluoro-2-hydroxypropyl substituted compounds were synthesized and evaluated as novel (18)F-labeled PET tracers for imaging Aß plaque in a living brain. All compounds exhibited high binding affinities toward the synthetic Aß1-42 aggregate and/or Alzheimer's disease brain homogenate. In the microPET study with normal mice, the 3-[(18)F]fluoro-2-hydroxypropyl substituted compounds resulted in fast brain washout by reducing the lipophilicities of the compounds. Intriguingly, (S)-configured PET tracers, (S)-[(18)F]1b and (S)-[(18)F]1c, exhibited a 2.8 and 4.0-fold faster brain washout rate at a peak/30 min in the mouse brain than the corresponding (R)-configured PET tracers despite there being no meaningful difference in binding affinities toward Aß plaque. A further evaluation of (S)-[(18)F]1c with healthy rhesus monkeys also revealed excellent clearance from the frontal cortex with ratios of 7.0, 16.0, 30.0 and 49.0 at a peak/30, 60, 90, and 120 min, respectively. These results suggest that (S)-[(18)F]1c may be a potential PET tracer for imaging Aß plaque in a living brain.

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.

Metal- and solvent-free synthesis of aniline- and phenol-based triarylmethanes via Brönsted acidic ionic liquid catalyzed Friedel-Crafts reaction.

A beneficial, scalable and efficient methodology for the synthesis of aniline-based triarylmethanes has been established through the double Friedel-Crafts reaction of commercial aldehydes and primary, secondary or tertiary anilines using Brönsted acidic ionic liquid as a powerful catalyst, namely [bsmim][NTf2]. This protocol was successfully performed under metal- and solvent-free conditions with a broad range of substrates, giving the corresponding aniline-based triarylmethane products in good to excellent yields (up to 99%). In addition, alternative aromatic nucleophiles such as phenols and electron-rich arenes were also studied using this useful approach to achieve a diversity of triarylmethane derivatives in high to excellent yields.

One-pot synthesis of substituted-amino triazole-glycosides.

This work combined three classes of compounds in the same molecule "amino triazole-glycoside" and developed a convenient method for the synthesis of this type of compound via a one-pot two step reaction. Alkylation of amine derivatives with propargyl bromide to give propargylamine was performed in the first step subsequently followed by a 'click' reaction with various ß-azido-glycosides in the presence of CuI in aqueous solution to provide ß-amino triazole-glycosides. Thirty-two examples of glycosides were obtained in moderate to good yield using this one-pot procedure.

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.

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.

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 ß-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.

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.