Aplysinopsin analogs: Synthesis and anti-proliferative activity of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones

A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC₅₀ values of 4.4 and 5.2 μM, respectively, compared to 5-fluorouracil (IC₅₀ = 15.2 μM) against MCF-7 cells.     

Synthesis and biological activity of (24E)- and (24Z)-26-hydroxydesmosterol

Using 3β-hydroxychol-5-en-24-oic acid (4) as starting material, the diastereoisomeric allylic alcohols (24E)-26-hydroxydesmosterol (2) and (24Z)-26-hydroxydesmosterol (3) have been synthesised in six steps with 67% and 12% overall yield, respectively. Both of these isomers are found in newborn mouse brain where sterol synthesis is high. Unlike desmosterol (1), neither of these isomers is a ligand to the liver x receptors and thus represents a novel biological deactivation mechanism avoiding cholesterol synthesis.     

Synthesis and antifungal activity of benzofuran-5-ols

Benzofuran-5-ol derivatives were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species, and Cryptococcus neoformans. Among them tested, many benzofuran-5-ols showed good antifungal activity. The results suggest that benzofuran-5-ols would be promising antifungal agents.     

Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5-halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamides

We report herein the design and synthesis of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC₅₀’s: 0.45-5.08 μM) are more active than Sunitinib (IC₅₀’s: 1.35-6.61 μM), and the most active compound 1h (IC₅₀: 0.47-3.11 μM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.     

Facile syntheses for (5Z,9Z)-5,9-hexadecadienoic acid, (5Z,9Z)-5,9-nonadecadienoic acid, and (5Z,9Z)-5,9-eicosadienoic acid through a common synthetic route

The delta 5,9 fatty acids (5Z,9Z)-5,9-hexadecadienoic acid, (5Z,9Z)-5,9-nonadecadienoic acid, and (5Z,9Z)-5,9-eicosadienoic acid were synthesized for the first time in four steps (9-12% overall yield) starting from commercially available 2-(2-bromoethyl)-1,3-dioxolane. The synthetic approach provided enough material to corroborate the structure and stereochemistry of (5Z,9Z)-5,9-nonadecadienoic acid which was recently identified in the flowers of Malvaviscus arboreus (Malvaceae). The novel phospholipids 1-hexadecanoyl-2-[(5Z,9Z)-5,9-eicosadienoyl]-sn-glycer o-3-phosphocholine and 1-octadecanoyl-2-[(5Z,9Z)-5,9-eicosadienoyl]-sn- glycero-3-phosphocholine were also synthesized from commercially available L-alpha-phosphatidylcholine (egg yolk) and characterized by positive ion electrospray mass spectrometry. These are the first examples of unsymmetrical phospholipids with saturated fatty acids at the sn-1 position and delta 5,9 fatty acids at the sn-2 position.     

Synthesis and antiherpetic activity of (Z)- and (E)-isomers of 9-(3-phosphonomethoxyprop-1-en-yl)adenine

9-(3-Phosphonomethoxyprop-1-en-yl)adenine (Z)- and (E)-isomers were synthesized. The stereoselectivity of double bond formation was studied by variation of sulfonyl groups. The resulting phosphonates exhibited a moderate antiherpetic activity in a culture of Vero cells infected with herpes simplex type 1 virus. The Z-isomer was shown to be more effective inhibitor of virus reproduction in the case of both wild and acyclovir-resistant strain.     

Synthesis and study of (Z)-3-chlorophosphoenolpyruvate

(Z)-3-Chlorophosphoenolpyruvate has been synthesized by the reaction of 3,3-dichloropyruvic acid with trimethylphosphite, followed by deesterification. This compound is a competitive inhibitor of pyruvate kinase and phosphoenolpyruvate carboxylase. Pyruvate kinase is not inactivated upon prolonged incubation with the compound, but phosphoenolpyruvate carboxylase is slowly inactivated (t1/2 = 5 h). The compound is a substrate for both enzymes, being acted upon by pyruvate kinase approximately 0.1% as rapidly as phosphoenolpyruvate itself. In the case of phosphoenolpyruvate carboxylase, the compound is converted into a 3:1 mixture of chloropyruvate and chlorooxalacetate, at an overall rate that is about 25% the carboxylation rate for phosphoenolpyruvate.     

Synthesis and antileishmanial activity of 5-(5-nitroaryl)-2-substituted-thio-1,3,4-thiadiazoles

A series of novel 2-substituted-thio-1,3,4-thiadiazoles bearing a 5-nitroaryl moiety including nitrofuran, nitrothiophene or nitroimidazole at the 5-position and a bulky residue attached to the 2-position of the thiadiazole ring were synthesised as potential antileishmanial agents. The target compounds were evaluated against the promastigote form of Leishmania major using the tetrazolium bromide salt (MTT) colorimetric assay. All test compounds exhibited high activity against L. major promastigotes with 50% inhibitory concentrations (IC₅₀) ranging from 1.11 to 3.16 μM. The structure-activity relationship study indicated that the S-pendant group attached to the 2-position of the thiadiazole ring has a high flexibility for structural alteration therefore retaining good antileishmanial activity.     

Synthesis and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives

Starting from the key intermediate 5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole-2-thiol (4) or the oxadiazole analogue (5), the title compounds 9 and 10 are synthesized by a two-step process. Thioetherification reaction of 4 or 5 with an organic halide catalyzed by indium or indium tribromide first affords appropriate sulfide 7 or 8, which is then converted into title compounds 9 or 10 by hydrogen peroxide oxidation catalyzed by ammonium molybdate in ionic liquid [bmim]PF6. The structures are unequivocally confirmed by spectroscopic (IR, 1H and 13C NMR) data and elemental analyses. The structures of 8d and 10q are further established by X-ray crystallographic diffraction analysis. The compounds have been shown to be fungicidally active. Title compounds 10i and 10j can inhibit mycelia growth by approximately 50% (EC50) at 2.9-93.3 microg/mL in vitro against 10 kinds of fungi.     

Synthesis and analgesic activity of N-(N-acetyl-L-amino-acyl)-5-methoxytryptamines

5-Methoxytryptamine was acylated with N-acetyl-L-amino acids to give rise the corresponding N-(N-acetyl-L-amino acyl)-5-methoxytryptamines. The analgesic activity was evaluated by the tail flick test. Among the 6 compounds, the analgesic potency of N-(N-acetyl-tryptophanyl)-5-methoxytryptamine (5e) and N-(N-acetyl-glycyl)-5-methoxytryptamine (5a) are much more potent than that of melatonin.     

Synthesis and antifungal activity of a novel series of 13-(4-isopropylbenzyl)berberine derivatives

By replacing the methyl group of 13-(4-isopropylbenzyl)berberine 2 with various acyl, alkyl, and benzyl groups via the demethylated intermediate, 13-(4-isopropylbenzyl)berberrubine 4, a novel series of 9-O-alkyl-13-(4-isopropylbenzyl)berberine derivatives was synthesized and examined for antifungal activities against various human pathogenic fungi. The introduction of various alkyl groups led to enhanced antifungal activity but that of acyl groups resulted in decrease of the activity. Among them, 9-O-butyl-13-(4-isopropylbenzyl)berberine 6d exhibited the most potent antifungal activities against Cryptococcus neoformans, Candida species (MIC=0.25-1 μg/ml), and Aspergillus species (MIC=2-4 μg/ml). The compound was found to be relatively safe up to 900 mg/kg in oral administration to mice.     

Synthesis and antiviral activity of 3-(beta-D-ribofuranosyl)-1,2,4-oxadiazole-5-carboxamide

3-(beta-D-Ribofuranosyl)-1,2,4-oxadiazole-5-carboxamide (5) was prepared by condensation reaction of amidoxime 6 with monoethyl oxaloyl chloride followed by reaction with ammonia. The compound 5, however, did not exhibit any significant activity against herpes simplex virus type-I (HSV-I) and semliki forest virus (SFV).     

Synthesis and antitumor activity of 5-(9-acridinylamino)anisidine derivatives

A series of 5-(9-acridinylamino)anisidines were synthesized by condensing methoxy-substituted 1,3-phenylenediamines (10 and 11) with 9-chloroacridine derivatives to form 5-(9-acridinylamino)-m-anisidines (AMAs, 14a-e) and 5-(9-acridinylamino)-o-anisidines (AOAs, 15a-e). 5-(9-Acridinylamino)-p-anisidines (APAs, 17a-e) were synthesized by reacting 2-methoxy-5-nitroaniline (12) with 9-anilinoacridines, followed by reduction. The cytotoxic inhibition of growth of various human tumor cells in culture, inhibitory effects against topoisomerase II, and DNA interaction of these agents were studied. The structure-activity relationship studies revealed the following degree of potency: AOAs > AMAs > APAs. They also revealed that the newly synthesized derivatives bearing CONH(2)NH(2)NMe(2) and Me substituents at C4 and C5 positions of the acridine chromophore (i.e., AMA 14e, AOA 15e, and APA 17e) exhibited significant cytotoxicity against human tumor cell growth in vitro. AOA (15e) was the most potent among these derivatives, which resulted in 60% suppression of tumor volume at a dose of 20 mg/kg (Q2D x 9), intravenous injection on day 26 in nude mice bearing human breast carcinoma MX-1 xenografts.     

Synthesis of (Z)-(1-fluoro-2-hydroxymethylcyclopropylmethyl)purines

(Z)-(1-fluoro-2-hydroxymethylcyclopropylmethyl)purines were designed, synthesized and evaluated their antiviral activity against poliovirus, HSV, and HIV.     

Stereoselective synthesis and antifungal activity of (Z)-trans-3-azolyl-2-methylchromanone oxime ethers

A series of (Z)-trans-3-azolyl-2-methylchromanone oxime ethers were stereoselectively synthesized and tested for in vitro antifungal activity. Many of these derivatives exhibit high activity against Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, and Microsporum gypseum.     

Synthesis of (Z)-(1-Fluoro-2-hydroxymethyl-cyclopropylmethyl)purines

Abstract

(Z)-(1-fluoro-2-hydroxymethylcyclopropylmethyl)purines were designed, synthesized and evaluated their antiviral activity against poliovirus, HSV, and HIV.     

Synthesis, antibacterial activity, and quantitative structure-activity relationships of new (Z)-2-(nitroimidazolylmethylene)-3(2H)-benzofuranone derivatives

A new series of (Z)-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2H)-benzofuranones (11a-p) and (Z)-2-(1-methyl-4-nitroimidazole-5-ylmethylene)-3(2H)-benzofuranones (12a-m) were synthesized and assayed for their antibacterial activity against Gram-positive and Gram-negative bacteria. Most of the 5-nitroimidazole analogues (11a-p) showed a remarkable inhibition of a wide spectrum of Gram-positive bacteria (Staphylococcus aureus, Streptococcus epidermidis, MRSA, and Bacillus subtilis) and Gram-negative Klebsiella pneumoniae, whereas 4-nitroimidazole analogues (12a-m) were not effective against selected bacteria. The quantitative structure-activity relationship investigations were applied to find out the correlation between the experimentally evaluated activities with various parameters of the compounds studied. The QSAR models built in this work had reasonable predictive power and could be explained by the observed trends in activities.     

Synthesis and sulfatase inhibitory activities of (E)- and (Z)-4-hydroxytamoxifen sulfamates

We report the development of (E)- and (Z)-4-hydroxytamoxifen sulfamates as estrone sulfatase inhibitors, potential therapeutic agents for the treatment of breast cancer. Both compounds competitively inhibit estrone sulfatase isolated from rat liver with apparent Ki of 35.9 microM for (E)-4-hydroxytamoxifen sulfamate and an apparent Ki of > 500 microM for the (Z) isomer.     

Synthesis and biological activity of 2-(4,5-dihydroisoxazol-5-yl)-1,3,4-oxadiazoles

Acid hydrazides were coupled with acrylic acid derivatives and cyclodehydration gave 1,3,4-oxadiazoles. Lastly, in-situ nitrile oxide formation from aryl oximes treated with sodium hypochlorite, and subsequent 1,3-dipolar cycloaddition to the exomethylene moiety delivered 2-(4,5-dihydroisoxazol-5-yl)-1,3,4-oxadiazoles. This library was evaluated in a high-throughput screen at Dow AgroSciences. Several compounds were active against fungal pathogens and pest insects.