Inhibitory activity of four demethoxy fluorinated anthracycline analogs against five human-tumor cell lines

Four anthracycline analogs synthesized in our laboratory were evaluated in comparison with adriamycin (doxorubicin) for their growth-inhibitory effect against five human-tumor cell lines, including lung carcinoma, colon adenocarcinoma, breast adenocarcinoma, melanoma, and glioblastoma. The compounds included 4-demethoxy-7-O-(2,6-dideoxy-2-fluoro--l-talopyranosyl)daunomycinone (2), its 3′,4′-diacetate (1), its 14-bromo derivative 3, and its 14-hydroxy analog, namely 4-demethoxy-7-O-(2,6-dideoxy-2-fluoro-α-l-talopyranosyl)adriamycinone (4). Compounds 1, 2, and 3 showed moderate cytotoxic effect in most of the cell lines, while compound 4 had a strong effect, comparable to or better than that of adriamycin in most of the cell lines.     

Terpenoids with vasorelaxant effects from the Chinese liverwort Scapania carinthiaca

Four new diterpenoids scapanacins A–D (1–4) including one kaurane and three clerodane derivatives, along with eleven known compounds (9–15), were isolated from the Chinese liverwort Scapania carinthiaca J.B. Jack ex Lindb. Their structures were determined based on extensive spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Vasorelaxant activity assays of the clerodane-type diterpenoids 2, and 4–8 revealed that they relaxed 3^rd-order rat mesenteric arterioles pre-contracted with norepinephrine (NE). Further assays with scapanacin D (4) confirmed that the vasodilatation was mediated through inhibition of Ca²⁺ influx via voltage-dependent Ca²⁺ channels (VDCs), and this Ca²⁺ channel blocking effect was also confirmed by inhibiting the extracellular Ca²⁺ influx in MOVAS cells. Besides, very little decrease of the relaxant activity caused by 4 on endothelium-denuded mesenteric arterioles with NE also suggested the vasodilatation was mainly produced by inhibiting Ca²⁺-induced contraction of smooth muscle. In addition, cytotoxicity testing showed that compounds 1 and 9 with α,β-unsaturated ketone exhibited inhibitory activities against a small panel of human cancer cell lines.     

Vasodilatation effect of farnesylacetones,active constituents of Sargassum siliquastrum,on the basilar and carotid arteries of rabbits

Two farnesylacetones, 311 and 312, major active constituents of Sargassum siliquastrum collected from the coast of the East Sea in Korea, showed a moderate vasodilatation effect on the basilar arteries of rabbits. Therefore, treatment with farnesylacetones 311 and 312 may selectively accelerate cerebral blood flow through dilatation of the basilar artery.     

Synthesis,properties, and reactions of α- and β-D-glucopyranosyl esters of some tripeptides

The 2,3,4,6-tetra-O-benzyl-1-O-(N-benzyloxycarbonyltripeptidyl)-D-glucopyranoses 1, 8, and 13 were synthesised from 2,3,4,6-tetra-O-benzyl-α-D-glucopyranose and the active esters of the appropriate N-protected tripeptides (Gly-Gly-Gly-, L-Phe-Gly-Gly-, and Gly-Gly-L-Phe-) in the presence of imidazole; the anomeric mixtures were resolved and the α and β anomers characterised. The β anomer of 13, containing the L and D enantiomers (ratio ≈ 3:1) of Gly-Gly-Phe- as the aglycon, could be resolved by column chromatography into the pure isomeric forms. Catalytic hydrogenolysis of the β anomers, in the presence and absence of a strong acid, yielded the free 1-esters 2β, 9β, and 14β, which were characterised as the monooxalate or trifluoroacetate salts and as free bases. Similarly, the α anomers afforded 2α, 9α, and 14α, whereas omission of the strong acid led to accompanying 1→2 acyl migration, to give the 2-O-acyl derivatives. All of the compounds prepared were converted into the N-acetyl and/or peracetylated derivatives. The 1-esters 2β and 9β, both in the charged and uncharged form, and the trifluoroacetate salt of 14β, are susceptible to cleavage by β-D-glucosidase; the enzyme had no effect on the uncharged form of 14β. This difference between 14β and its salt is discussed in conformational terms.     

Lignans from the fruit of Schisandra sphenanthera,and their inhibition of HSV-2 and adenovirus

The systematic isolation of the EtOAc extract from Schisandra sphenanthera fruit was performed during a search for HSV-2 and adenovirus inhibitors. Sixteen lignans were obtained, with compound 1 representing a new and rare type of lignan in the genus Schisandra. Their structures were elucidated by spectroscopy and comparison with literature data. Among all the lignans tested for their antiviral activities, compound 14 was the most active against HSV-2 with a selectivity index value up to 29.83. Moreover, the new compound 1, and the known ones (4, 6, 7, 10 and 14) also exhibited moderate inhibition of HSV-2 and adenovirus. To the best of our knowledge, this is the first report that these lignans from Schisandra genus were shown to have modest activity against HSV-2 and adenovirus. Meanwhile, structure–activity relationships of some lignans for the inhibitory activity against HSV-2 and adenovirus were discussed in this study.     

Inhibitory constituents of the heartwood of Dalbergia odorifera on nitric oxide production in RAW 264.7 macrophages

Two new isoflavanones (1 and 13), along with 25 known compounds (2–12, 14–27), were isolated from the EtOAc-soluble fraction of the heartwood of Dalbergia odorifera by following their potential to inhibit the LPS-induced nitric oxide production in RAW 264.7 cells. The structures of the isolated compounds were established by spectroscopic data such as ¹D, ²D NMR and MS spectrometry. Among the isolated compounds, (2S)-pinocembrin (26), showed the most potent inhibitory effect with IC₅₀ value of 18.1 μM.     

7-Dehydroagapanthagenin and 8(14)-dehydroagapanthagenin,two new spirostan sapogenins from Agapanthus africanus

Besides sitosterol, yuccagenin (1a) and agapanthagenin (2a), the two new spirostan sapogenins 7-dehydroagapanthagenin (3a) and 8(14)-dehydroagapanthagenin (4a) have been isolated from the rhizomes of Agapanthus africanus and their structures determined.     

Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents

In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60 mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6 h at a dosage of 4.0 mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.     

Regioselective and efficient enzymatic synthesis of antimicrobial andrographolide derivatives

Labdane diterpene andrographolide (1) is a major constituent of Andrographis paniculata and known to exhibit wide spectrum of biological activities. In this study, regioselective monoesters of (1) have been synthesized by using Amano lipase AK (Pseudomonas fluorescens) as a biocatalyst. Amano lipase AK was able to execute highly efficient esterification of hydroxyl group attached to C-14 carbon of (1) in presence of acyl donors. Among the various synthesized derivatives including two novel compounds such as andrographolide-14-propionate (3) and andrographolide-14-caproate (5) displayed antimicrobial activity against Staphylococcus aureus with low minimal inhibitory concentration (MIC) 4?µg/mL and 16?µg/mL respectively. Furthermore, they have shown low hemolysis activity at their respective MIC and increase in the permeability of the bacterial cell membrane as delineated by FITC uptake and SEM imaging studies.     

Anticancer and antifungal activity of copper(II) complexes of quinolin-2(1H)-one-derived Schiff bases

The condensation of substituted aromatic aldehydes with 7-amino-4-methyl-quinolin-2(1H)-one (1) has lead to the isolation of quinolin-2(1H)-one derived Schiff bases (2-14). The copper(II) complexes (2a-14a) of the ligands were also prepared, and together with their corresponding free ligands were fully characterised by elemental analyses, spectral methods (IR, ¹H and ¹³C NMR, AAS, UV-Vis), magnetic and conductance measurements. The bidentate ligands coordinated to the copper(II) ion through the deprotonated phenolic oxygen and the azomethine nitrogen of the ligands in almost all cases. X-ray crystal structures of two of the complexes, 5a and 8a, confirmed the bidentate coordination mode. All of the compounds were investigated for their antimicrobial activities against the fungus, Candida albicans, and against Gram-positive and Gram-negative bacteria. The compounds were found to have excellent anti-Candida activity but were inactive against Staphylococcus aureus and Escherichia coli. Selected compounds (2-8 and 2a-8a) were also screened for their in vitro anticancer potential using the human hepatic carcinoma cell line, Hep-G₂. Several derivatives were shown to be active comparable to that of cisplatin.     

Biotransformation of ent-pimaradienoic acid by cell cultures of Aspergillus niger

Microbial transformation stands out among the many possible semi-synthetic strategies employed to increase the variety of chemical structures that can be applied in the search for novel bioactive compounds. In this paper we obtained ent-pimaradienoic acid (1, PA, ent-pimara-8(14),15-dien-19-oic acid) derivatives by fungal biotransformation using Aspergillus niger strains. To assess the ability of such compounds to inhibit vascular smooth muscle contraction, we also investigated their spasmolytic effect, along with another five PA derivatives previously obtained in our laboratory, on aortic rings isolated from male Wistar rats. The microbial transformation experiments were conducted at 30 °C using submerged shaken liquid culture (120 rpm) for 10 days. One known compound, 7α-hydroxy ent-pimara-8(14),15-dien-19-oic acid (2), and three new derivatives, 1β-hydroxy ent-pimara-6,8(14),15-trien-19-oic acid (3), 1α,6β,14β-trihydroxy ent-pimara-7,15-dien-19-oic acid (4), and 1α,6β,7α,11α-tetrahydroxy ent-pimara-8(14),15-dien-19-oic acid (5), were isolated and identified on the basis of spectroscopic analyses and computational studies. The compounds obtained through biotransformation (2–5) did not display a significant antispasmodic activity (values ranging from 0% to 16.8% of inhibition); however the previously obtained diterpene, methyl 7α-hydroxy ent-pimara-8(14),15-dien-19-oate (8), showed to be very effective (82.5% of inhibition). In addition, our biological results highlight the importance to study the antispasmodic potential of a large number of novel diterpenes, to conduct further structure–activity relationship investigations.     

Cytotoxic biotransformed products from andrographolide by Rhizopus stolonifer ATCC 12939

Biotransformation of andrographolide (1) by Rhizopus stolonifer ATCC 12939 was investigated. Ten bioconversion products were isolated and identified. Their structures were elucidated by high resolution mass spectroscopy (HR-MS), extensive NMR techniques, including ¹H NMR, ¹³C NMR, DEPT, ¹H–¹H correlation spectroscopy (COSY), two dimensional nuclear Overhauser effect correlation spectroscopy (NOESY), heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond coherence (HMBC). Their structures were identified to be 12(R),13(R)-12-hydroxyandrographolide (2), 12(S),13(S)-12-hydroxyandrographolide (3), isoandrographolide (4), 3-dehydro-isoandrographolide (5), 14-deoxy-11,12-didehydroandrographolide (6), 3-oxo-14-deoxy-11,12-didehydroandrographolide (7), 3-dehydroandrographolide (8), 14-deoxyandrographolide (9), 3-dehydro-14-deoxyandrographolide (10) and 3-dehydro-14-deoxyandrographolide-19-oic acid (11). Among them, compounds 5 and 11 are novel compounds. The biosynthetic pathways of andrographolide by R. stolonifer were proposed. Most of the products showed potential antiproliferative activities against human breast cancer (MCF-7), human colon cancer (HCT-116) and human leukemia (HL-60) cell lines, and their structure–activity relationships (SAR) were discussed in detail.     

Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities

Five flavonols (3, 5, and 9–11) were isolated from Rhodiola rosea, and compared with commercially available flavonoids (1, 2, 4, 6–8, and 12–14) to facilitate analysis of their structure–activity relationship (SAR). All compounds (1–14) showed neuraminidase inhibitory activities with IC₅₀ values ranging from 0.8 to 56.9 μM. The in vitro anti-influenza virus activities of flavonoids 1–6, 8–12, and 14 were evaluated using two influenza viral strains, H1N1 (A/PR/8/34) and H9N2 (A/Chicken/Korea/MS96/96), testing their ability to reduce virus-induced cytopathic effect (CPE) in MDCK cells. We found that the activity of these compounds ranged from 30.2 to 99.1 μM against H1N1- and 18.5 to 133.6 μM against H9N2-induced CPE. Of compounds 1–14, gossypetin (6) exhibited the most potent inhibitory activity, with IC₅₀ values of 0.8 and 2.6 μM on neuraminidases from Clostridium perfringens and recombinant influenza virus A (rvH1N1), respectively. In contrast, kaempferol (3) exhibited the highest activity against two influenza viruses, H1N1 and H9N2 with EC₅₀ values of 30.2 and 18.5 μM, respectively. Activity depended on the position and number of hydroxy groups on the flavonoids backbone. In kinetic studies, all isolated compounds behaved as noncompetitive inhibitors.     

Assignment of configuration at quaternary centres in pairs of 3-C Hydroxymethyl and 3-C methyl branched chain 1,2:4,6-diacetalated aldohexopyranose derivatives using 13C-N.M.R. spectoscopy

The configuration at the C-3 quaternary carbon atoms in two pairs (1 and 2, 3 and 4) of 3-C-hydroxymethyl, branched-chain, 1,2:4,6-diacetalated aldohexo-pyranoses have been determined from their ¹³ C-n.m.r. spectra. The stereochemical assignments were achieved by comparison of the spectra with those of the Z (13) and E isomers (14) of 4-tert-butyl-l-hydroxymethylcyclohexanol and with those of the corresponding diacetalated gluco- and allo-pyranoses (5, 6, 9, and 10). The spectra of 13 and 14 showed that an axial hydroxyl group shielded the α, β, and μ ring carbon atoms more than an axial hydroxymethyl group and that the carbon atom in the latter group was shielded relative to that in an equatorial hydroxymethyl group The spectra of 5, 6, 9, and 10 indicated the effect of an axial HO-3 on the shifts of the carbon atoms in the 1,2-O-alkylidene groups. The stereochemistry of an isomeric pair of 1,2:4,6-di-O-alkylidene-3-C-methyl-aldohexopyranoses (11 and 12) has also been determined.     

Biotransformation of isoimperatorin by Cunninghamella blakesleana AS 3.970

The biotransformation of isoimperatorin (1) by Cunninghamella blakesleana AS 3.970 yielded 6 novel products, 14-hydroxyl-isoimperatorin (2), 11-carbonyl-14-hydroxyl isoimperatorin (3), 11-carbonyl-14-hydroxyl-12,13-dihydrogen-iso-imperatorin (4), 14-hydroxyl-12,13-dihydrogenisoimperatorin (5), isoimperatorin-14-O-β-d-mannoside (6) and isoimperatorin-14-O-β-d-glucoside (7), respectively. The chemical structures of these metabolites were elucidated based on extensive spectral data including 2D NMR and HRMS. The hydroxylation, hydrogenation, carbonylation and glycosylation reactions of 1 by C. blakesleana AS 3.970 were observed in the present study. In addition, anti-osteoporosis activities of substrate and all transformed products were evaluated by using MC3T3-E1 cells. Our results suggested that hydroxylation or glycosylation of C-14 would enhance anti-osteoporosis activity significantly.     

Iridoid glucosides from the leaves of Vitex negundo var. cannabifolia

Five new iridoid glucosides, cannabifolisides A–E (1 – 5), together with nine analogues (6 – 14), were isolated from the leaves of Vitex negundo var. cannabifolia. Their structures were elucidated by spectroscopic data (NMR, UV, IR, and MS) analyses and comparison of their spectroscopic and physical data with the literature values. The protective effect of isolated compounds on human gastric epithelial cells were evaluated by measuring the enhanced cell viability of GES-1 cell insulted by TCA. Among these, compounds 4, 6, 8, 10, 12, and 14 remarkably increased the cell viability in a concentration-depend manner.     

Design,synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α₁-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α₁/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.     

Cytotoxic and antimalarial constituents from aerial parts of Sphaeranthus indicus

Two new eudesmanolide type sesquiterpenes, indicusalactone (1) and (⿿)⿿-⿿oxyfrullanolide (2), along with twelve known compounds (3⿿14), were isolated from the aerial parts of Sphaeranthus indicus. The structures of these compounds were established on the basis of their 1D and 2D NMR spectroscopic data. Compounds 1⿿4 and 12⿿14 showed antimalarial activity against Plasmodium falciparum with IC₅₀ values ranging from 2.32 to 6.47μg/mL. In addition, compounds 2⿿5 showed cytotoxicity against cancer cell lines, KB, NCI-H187 and MCF-7 with IC₅₀ values within the range 1.23⿿46.19 μg/mL.     

Synthesis of prumycin and related compounds

Prumycin (1) and related compounds have been synthesized from benzyl 2-(benzyloxycarbonyl)amino-2-deoxy-5,6-O-isopropylidene-β-d-glucofuranoside (4). Benzoylation of 4, followed by deisopropylidenation, gave benzyl 3-O-benzoyl-2-(benzyloxycarbonyl)amino-2-deoxy-β-d-glucofuranoside (6), which was converted, via oxidative cleavage at C-5–C-6 and subsequent reduction, into the related benzyl β-d-xylofuranoside derivative (7). Benzylation of 3-O-benzoyl-2-(benzyloxycarbonyl)-amino-2-deoxy-d-xylopyranose (8), derived from 7 by hydrolysis, afforded the corresponding derivatives (9, 11) of β- and α-d-xylopyranoside, and compound 7 as a minor product. Treatment of benzyl 3-O-benzoyl-2-(benzyloxycarbonyl)amino-2-deoxy-4-O-mesyl-β-d-xylopyranoside 10, formed by mesylation of 9, with sodium azide in N,N-dimethylformamide gave benzyl 4-azido-3-O-benzoyl-2-(benzyloxy-carbonyl)amino-2,4-dideoxy-α-l-arabinopyranoside (13), which was debenzoylated to compound 14. Selective reduction of the azide group in 14, and condensation of the 4-amine with N-[N-(benzyloxycarbonyl)-d-alaninoyloxy]succinimide, gave the corresponding derivative (15) of 1. Reductive removal of the protecting groups of 15 afforded 1. Prumycin analogs were also synthesized from compound 14. Evidence in support of the structures assigned to the new derivatives is presented.     

Guaianolides and elemanolides from Vernonia anthelmintica

Two new guaianolides, (1R,4R,5S,6R,7R,8S)-8,15-dihydroxyguaia-10(14),11(13)-dien-12,6-olide (1) and (1R,4R,5S,6R,7R,8S,11S)-8,15-dihydroxyguaia-10(14)-en-6,12-olide (2), and two known elemanolides, (4S,5R,6R,7R,8S,10R,11S)-11,13-dihydrovernolepin (3) and (5R,6R,7R,8S,10R,11S)-melitensin (4) were isolated from the aerial parts of Vernonia anthelmintica Willd. The structures of these compounds were determined on the basis of IR, UV, MS, 1D-NMR and 2D-NMR, and their absolute configurations were deduced using the CD exciton chirality method and single-crystal X-ray diffraction. The possible biosynthetic relationships of compounds 1–4 are postulated. Compounds 1–4 were evaluated for their cytotoxicity against HL-60 and SMMC-7721 cell lines.