Leishmanicidal and trypanocidal activities of 2-aminocyclohexanol and 1,2-cyclohexanediamine derivatives

A number of aminoalcohols, diamines and other related cycloanalogues of sphingosine have been synthesized and assayed in vitro against three Leishmania spp. and Trypanosoma cruzi. Most of the compounds were potent parasiticides, with IC50 values in the microM or lower range and potencies higher than those of pentamidine and benznidazol, the common therapeutic agents against these parasitoses.     

Leishmanicidal effects of piperine, its derivatives, and analogues on Leishmania amazonensis

Leishmaniasis is a tropical disease caused by protozoan parasites of the genus Leishmania which affects 12 million people worldwide. The discovery of drugs for the treatment of leishmaniasis is a pressing concern in global health programs. The aim of this study aim was to evaluate the leishmanicidal effect of piperine and its derivatives/analogues on Leishmania amazonensis. Our results showed that piperine and phenylamide are active against promastigotes and amastigotes in infected macrophages. Both drugs induced mitochondrial swelling, loose kinetoplast DNA, and led to loss of mitochondrial membrane potential. The promastigote cell cycle was also affected with an increase in the G1 phase cells and a decrease in the S-phase cells, respectively, after piperine and phenylamide treatment. Lipid analysis of promastigotes showed that piperine reduced triglyceride, diacylglycerol, and monoacylglycerol contents, whereas phenylamide only reduced diacylglycerol levels. Both drugs were deemed non toxic to macrophages at 50 μM as assessed by XTT (sodium 2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt), Trypan blue exclusion, and phagocytosis assays, whereas low toxicity was noted at concentrations higher than 150 μM. None of the drugs induced nitric oxide (NO) production. By contrast, piperine reduced NO production in activated macrophages. The isobologram analysis showed that piperine and phenylamide acted synergistically on the parasites suggesting that they affect different target mechanisms. These results indicate that piperine and its phenylamide analogue are candidates for development of drugs for cutaneous leishmaniasis treatment.     

Leishmanicidal activity of combretastatin analogues and heteroanalogues.

We have investigated the in vitro leishmanicidal activity of representative members from series II-V of combretastatin analogues and heteroanalogues. Most of them exhibited different degrees of activity against various strains of Leishmania spp. The diaryl(heteroaryl)ethane system or the more complex fused heterocyclic stilbenoids, constitute useful skeletal bases to support some kind of antiparasitic activity. Particularly, the incorporation of 2-furyl substituents led to potent antileishmanial compounds, which have been selected for in vivo testing on murine models.     

Synthesis, in vitro antimalarial activities and cytotoxicities of amino-artemisinin-ferrocene derivatives

Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC₅₀ values of 2.79?nM against Pf K1 and 3.2?nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells.     

Antiprotozoal and cytotoxic naphthalene derivatives from Diospyros assimilis

Chemical investigation of the roots of Diospyros assimilis had led to the isolation and characterization of six naphthalene derivatives, two 2-naphthaldehyes, namely 4-hydroxy-3,5-dimethoxy-2-naphthaldehyde 1, 4-hydroxy-5-methoxy-2-naphthaldehye 2, its related isomer 5-hydroxy-4-methoxy-2-naphthaldehyde 3 and three commonly occurring naphthoquinones, diospyrin 4, 8'-hydroxyisodiospyrin 5 and the simple monomer, plumbagin 6. Their chemical structures were established by detailed NMR investigations including 1H and 13C NMR, HSQC, HMBC and NOESY experiments. In addition, the naphthalene derivatives 1-5 were evaluated for their in vitro antiprotozoal activity against protozoan parasites belonging to the genera Trypanosoma, Leishmania and Plasmodium. Among the tested compounds, naphthaldehyde 1 showed moderate inhibition of the growth of the parasites, T. brucei, T. cruzi, L. donovani with IC50 values of 19.82, 12.28 and 38.78 microM and displayed cytotoxicity towards rat skeletal myoblasts (L-6 cells) with IC50 of 174.94 microM, while 2 and 3 were found to be comparatively less active to 1. The dimeric quinones 4 and 5 exhibited good activity against T. brucei and L. donovani with IC50 of 1.12 and 8.82 microM and 12.94 and 16.66 microM respectively.     

Synthesis and cytotoxicities of icogenin analogues with disaccharide residues

For further structure–activity relationships (SAR) research of furostan saponin, two icogenin analogues: (25R)-22-O-methyl-furost-5-en-3β,26-diol-3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranoside 1 and (25R)-22-O-methyl-furost-5-en-3β,26-diol-3-O-α-l-rhamnopyranosyl-(1 → 2)-α-d-glucopyranoside 2, with valuable disaccharide moieties, were synthesized from diosgenin through eight steps. Both of the analogues behaved the similar cytotoxic activities with icogenin, towards nine types of human tumor cells herein.     

Insecticidal activities of a Diospyros kaki root-isolated constituent and its derivatives against Nilaparvata lugens and Laodelphax striatellus

Diospyros kaki root-derived materials were examined for insecticidal properties against Nilaparvata lugens and Laodelphax striatellus. Based on the LD₅₀ values, the chloroform fraction of D. kaki extracts showed the most activity against N. lugens (3.78 μg/female) and L. striatellus (7.32 μg/female). The active constituent of the chloroform fraction was isolated by various chromatographic methods and was identified as 5-hydroxy-2-methyl-1,4-naphthoquinone by spectroscopic analyses. To establish the structure–activity relationships, the insecticidal effects of 5-hydroxy-2-methyl-1,4-naphthoquinone and its derivatives against N. lugens and L. striatellus were determined using micro-topical application bioassays. On the basis of LD₅₀ values, 5-hydroxy-1,4-naphthoquinone was the most effective against N. lugens (0.072 μg/female) and L. striatellus (0.183 μg/female). 2-Bromo-1,4-naphthoquinone, 2-hydroxy-1,4-naphthoquinone, and 5-hydroxy-2-methyl-1,4-naphthoquinone also had potent insecticidal activities against N. lugens and L. striatellus. In contrast, no insecticidal activity was observed with 2-methoxy-1,4-naphthoquinone or 2-methyl-1,4-naphthoquinone. These results indicate that the functional group (bromo- and hydroxyl-) at the C-2 position of the 1,4-naphthoquinone skeleton and the change in position of the hydroxyl group play important roles in insecticidal activity. Therefore, naturally occurring D. kaki root-derived 5-hydroxy-2-methyl-1,4-naphthoquinone and its derivatives may be suitable as insecticides.     

Synthesis and cytotoxicities of dioscin derivatives with decorated chacotriosyl residues

Two series of dioscin derivatives (4a-o and 5a-o) with selected modifications at the 6' and 4' positions of the chacotriosyl residue, respectively, were synthesized. All the 6'-N-acyl-dioscin derivatives did not show considerable inhibitory activities at 10 microM, while most of the 4'-O-(2-N-acyl)ethyl-dioscin derivatives behaved as potent as dioscin, against the growth of tumor cells.     

Pyrimidine homonucleoside analogues from 2,5-anhydroaldose derivatives

3,4-Di-O-acetyl-2,5-anhydro-D-xylose diisobutyl dithioacetal (1) reacts with bromine to give a monobromo derivative which, on condensation with 2,4-diethoxy-pyrimidine or its 5-methyl analogue, affords the protected nucleoside derivatives 4 and 11, respectively; ammonolysis of 4 gave the cytosine “homonucleoside” 7, and hydrolysis of 11 gave the thymine “homonucleoside” 12. The same type of “homonucleoside” may be produced by cyclization of the sugar chain in a suitable acyclic-sugar nucleoside, as in the conversion of 1-S-ethyl-1-thio-1-(uracil-1-yl)-D-xylitol (16, obtained from tetra-O-acetyl-D-xylose diethyl dithioacetal, 9), by the action of one molar equivalent of p-toluenesulfonyl chloride, into a homonucleoside isolated as its diacetate 17; acyclic-sugar derivatives not susceptible to such cyclization afford instead the 5-p-toluenesulfonates, as exemplified by the conversion of the D-arabino analogue (13) of 16 into the 5′-ester 14. When cyclohexene is used to remove the excess of bromine in the preparation of nucleoside analogues from dithioacetals, the alkylsulfenyl bromide produced may react, by way of its cyclohexene adduct, with the hoterocyclic base to give cyclohexane-base adducts, for example, compounds 6 and 10.     

Synthesis,antimalarial activities and cytotoxicities of amino-artemisinin-1,2-disubstituted ferrocene hybrids

Artemisinin-ferrocene conjugates incorporating a 1,2-disubstituted ferrocene analogous to that embedded in ferroquine but attached via a piperazine linker to C10 of the artemisinin were prepared from the piperazine artemisinin derivative, and activities were evaluated against asexual blood stages of chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf). The most active was the morpholino derivative 5 with IC₅₀ of 0.86?nM against Pf K1 and 1.4?nM against Pf W2. The resistance indices were superior to those of current clinical artemisinins. Notably, the compounds were active against Pf NF54 early and late blood stage gametocytes – these exerted >86% inhibition at 1?µM against both stages; they are thus appreciably more active than methylene blue (～57% inhibition at 1?µM) against late stage gametocytes. The data portends transmission blocking activity. Cytotoxicity was determined against human embryonic kidney cells (Hek293), while human malignant melanoma cells (A375) were used to assess their antitumor activity.     

Chromone derivatives from Halenia elliptica and their anti-HBV activities

Nine water-soluble chromone derivatives, including chromone-2-carboxylic acids, 2-methylchromones and their structural hybrids, were isolated from aerial tissues of Halenia elliptica (Gentianaceae), six of which were previously unknown. Their structures were elucidated by comprehensive mass, 1D and 2D NMR spectroscopic analyses and chemical derivatization. Two unstable structural hybrids of chromone-2-carboxylic acids and 2-methylchromones, viz. 3-acetyl-8-hydroxy-4H-1-benzopyran-4-one-2-carboxylic acid (halenic acid C) and 2-(8-hydroxy-2-methyl-4H-1-benzopyran-4-one-3-yl)-2-oxoacetic acid (halenichromone A), were isomers and were interconvertible. The proposed mechanism of their acid-catalyzed isomerization in aqueous solvent is described. In addition, 2-methylchromones, 8-hydroxy-2-methyl-4H-1-benzopyran-4-one, and 8-methoxy-2-methyl-4H-1-benzopyran-4-one, were found to exhibit a strong inhibitory effect towards hepatitis B virus (HBV) in vitro without showing significant cytotoxicity.     

Norbergenin derivatives from the stem bark of Diospyros sanza-minika (Ebenaceae) and their radical scavenging activity

Three new norbergenin derivatives, 11-O-p-hydroxybenzoylnorbergenin, 4-O-(3′-methylgalloyl)norbergenin and 4-O-syringoylnorbergenin were isolated from the stem bark of Diospyros sanza-minika, along with three known compounds: norbergenin, 4-O-galloylnorbergenin and quercitol. Their structures were established on the basis of 1D and 2D NMR experiments and mass spectrometry. Some of the above compounds showed radical scavenging properties in a DPPH solution assay.     

Semisynthesis and cytotoxic activities of andrographolide analogues

Andrographolide 1, a diterpenoid lactone of the plant Andrographis paniculata, known to possess antitumour activity in in vitro and in vivo breast cancer models was subjected to semisynthesis leading to the preparation of a number of novel compounds. These compounds exhibited in vitro antitumour activity with moderate to excellent growth inhibition against MCF-7 (breast) and HCT-116 (colon) cancer cells. Compounds 3,19-(2-chlorobenzylidene)andrographolide(5), 3,19-(3-chlorobenzylidene)andrographolide(6), 3,19-(3-fluorobenzylidene)andrographolide(7), 3,19-(4-fluorobenzylidene)andrographolide(8), 3,19-(2-fluorobenzylidene)andrographolide(10), 3,19-(2-chloro-5-nitrobenzylidene)andrographolide (21), 3,19-(4-chlorobenzylidene)andrographolide(30) and 3,19-(2-chloro-4-fluorobenzylidene) andrographolide(31) were also screened against 60 NCI (National Cancer Institute, USA) human tumour cell lines derived from nine cancer cell types.     

Semisynthesis and cytotoxic activities of andrographolide analogues

Andrographolide 1, a diterpenoid lactone of the plant Andrographis paniculata, known to possess antitumour activity in in vitro and in vivo breast cancer models was subjected to semisynthesis leading to the preparation of a number of novel compounds. These compounds exhibited in vitro antitumour activity with moderate to excellent growth inhibition against MCF-7 (breast) and HCT-116 (colon) cancer cells. Compounds 3,19-(2-chlorobenzylidene)andrographolide(5), 3,19-(3-chlorobenzylidene)andrographolide(6), 3,19-(3-fluorobenzylidene) andrographolide(7), 3,19-(4-fluorobenzylidene)andrographolide(8), 3,19-(2-fluorobenzylidene)andrographolide(10), 3,19-(2-chloro-5-nitrobenzylidene)andrographolide (21), 3,19-(4-chlorobenzylidene)andrographolide(30) and 3,19-(2-chloro-4-fluorobenzylidene) andrographolide(31) were also screened against 60 NCI (National Cancer Institute, USA) human tumour cell lines derived from nine cancer cell types.     

Synthesis and biological activities of glycosphingolipid analogues from marine sponge Aplysinella rhax

A novel glycosphingolipid, beta-D-GalNAcp(1-->4)[alpha-D- Fucp(1-->3)]-beta-D-GlcNAcp(1-->)Cer (1), isolated from the marine sponge Aplysinella rhax, has a unique structure, with D-fucose and N-acetyl-D-galactosamine attached to a reducing-end N-acetyl-D-glucosamine through an alpha1-->3 and beta1-->4 linkage, respectively. We synthesized glycolipid analogues carrying a 2-branched fatty alkyl residue or a 2-trimethylsilyl ethyl residue in place of ceramide (2 and 3), non-natural type trisaccharide analogue containing an L-fucose residue (4), and other analogues (5 and 6). Among these prepared compounds, 2 showed the most potent nitric oxide (NO) production inhibitory activity against LPS-activated J774.1 cells. In addition, their structure-activity relationships were established.     

Synthesis and biological activities of isogranulatimide analogues

The synthesis of new isogranulatimide analogues, their inhibitory activities toward the Checkpoint 1 kinase (Chk1), and their in vitro cytotoxicities toward four tumor cell lines (one murine L1210 leukemia, and three human cell lines: DU145 prostate carcinoma, A549 non-small cell lung carcinoma, and HT29 colon carcinoma) are described. The affinity for DNA of some representative compounds and their ability to induce DNA cleavage mediated by topoisomerase I have been examined. In some of the newly synthesized compounds, the imidazole heterocycle of isogranulatimide is replaced by a pyrrole and/or the indole unit is replaced by a 7-azaindole. Compounds in which a sugar part is attached to the 7-azaindole moiety have also been prepared. Some of the newly synthesized compounds are more potent Chk1 inhibitors than granulatimide. The selectivity of two potent Chk1 inhibitors 24 and 26 has been evaluated using various kinases. The strongest inhibitory properties are found toward Chk1.     

Lignan from calyces of Diospyros kaki

From Diospyros kaki calyces, a new lignan was isolated. Its structure was elucidated as (?)-divanillyltetrahydrofuran ferulate by spectroscopic methods and was established by total synthesis.     

Aminooxy analogues of spermine and their monoacetyl derivatives

Convenient methods of synthesis of 1-aminooxy-3,8-diaza-11-aminoundecane, its earlier unknown N ¹-and N ¹¹-acetyl derivatives, and also 1,10-bis(aminooxy)-3,8-diazadecane are suggested. It is shown that it is possible to selectively delete the acid-labile ethoxyethylidene protection of aminooxy group by hydrosulfates in the presence of N-tert-butyloxycarbonyl group.