Structure–cytotoxic activity relationship of sesquilignan,morinol A

The cytotoxic activities of sesquilignans, (7S,8S,7′R,8′R)- and (7R,8R,7′S,8′S)-morinol A and (7S,8S,7′S,8′S)- and (7R,8R,7′R,8′R)-morinol B were compared, showing no significant difference between stereoisomers (IC₅₀ = 24–35 μM). As a next stage, the effect of substituents at 7, 7′, and 7″-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18 (IC₅₀ = 6–7 μM). In the research on the structure–activity relationship of 7″-position of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18, the most potent compounds were 7,7′,7″-phenyl derivative 18 (IC₅₀ = 6 μM) against HeLa cells. Against HL-60 cells, 7″-(4-nitrophenyl)-7,7′-phenyl derivative 33 and 7″-hexyl-7,7′-phenyl derivative 37 (IC₅₀ = 5 μM) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7′R,8′R)-morinol A. It was also confirmed that the 7′-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity.     

Four isoflavanones from the stem bark of Platycelphium voënse

From the stem bark of Platycelphium voënse (Leguminosae) four new isoflavanones were isolated and characterized as (S)-5,7-dihydroxy-2′,4′-dimethoxy-3′-(3″-methylbut-2″-enyl)-isoflavanone (trivial name platyisoflavanone A), (±)-5,7,2′-trihydroxy-4′-methoxy-3′-(3″-methylbut-2″-enyl)-isoflavanone (platyisoflavanone B), 5,7-dihydroxy-4′-methoxy-2″-(2?-hydroxyisopropyl)-dihydrofurano-[4″,5″:3′,2′]-isoflavanone (platyisoflavanone C) and 5,7,2′,3″-tetrahydroxy-2″,2″-dimethyldihydropyrano-[5″,6″:3′,4′]-isoflavanone (platyisoflavanone D). In addition, the known isoflavanones, sophoraisoflavanone A and glyasperin F; the isoflavone, formononetin; two flavones, kumatakenin and isokaempferide; as well as two triterpenes, betulin and β-amyrin were identified. The structures were elucidated on the basis of spectroscopic evidence. Platyisoflavanone A showed antibacterial activity against Mycobacterium tuberculosis in the microplate alamar blue assay (MABA) with MIC = 23.7 μM, but also showed cytotoxicity (IC₅₀ = 21.1 μM) in the vero cell test.     

Two new diphenyl ethers from Acanthopanax senticosus (Rupr. & Maxim.) Harms with PTP1B inhibitory activity

Bioassay-guided fractionation of an EtOAc-soluble extract of Acanthopanax senticosus (Rupr. & Maxim.) Harms yielded two new diphenyl ethers, 3-[3′-methoxy-4′-(4″-formyl-2″,6″-dimethoxy-phenoxy)-phenyl]-propenal (1) and 3-[3′,5′-dihydroxy-4′-(4″-hydroxymethyl-3″,5″-dimethoxy-phenoxy)-phenyl]-propenal (2), along with eight other known compounds (3–10). The structures of these new ethers were elucidated with spectroscopic and physico-chemical analyses. All of the isolates were evaluated for their in vitro inhibitory activity against PTP1B, VHR and PP1. The new compounds (1 and 2) inhibited PTP1B with IC₅₀ values ranging from 9.2 ± 1.4 to 12.6 ± 1.2 μM.     

Two new guaiane sesquiterpenes from Datura metel L. with anti-inflammatory activity

Chemical investigation of an acidic methanol extract of the whole plants of Datura metel resulted in the isolation of two new guainane sesquiterpenes, 1β,5α,7β-guaiane-4β,10α,11-triol (1) and 1α,5α,7α-11-guaiene-2α,3β,4α,10α,13-pentaol (2), along with eight known compounds: pterodontriol B (3), disciferitriol (4), scopolamine (5), kaempferol 3-O-β-d-glucosyl(1 → 2)-β-d-galactoside 7-O-β-d-glucoside (6), kaempferol 3-O-β-glucopyranosyl(1 → 2)-β-glucopyranoside-7-O-α-rhamnopyranoside (7), pinoresinol 4′′-O-β-d-glucopyranoside (8), (7R,8S,7′S,8′R)-4,9,4′,7′-tetrahydroxy-3,3′-dimethoxy-7,9′-epoxy-lignan-4-O-β-d-glucopyranoside (9), and (7S,8R,7′S,8′S)-4,9,4′,7′-tetrahydroxy-3,3′-dimethoxy-7,9′-epoxylignan-4-O-β-d-glucopyranoside (10). Their structures were elucidated by extensive spectroscopic methods, including 1D and 2D NMR and MS spectra. Compounds 2-4 and 6-10 were shown to have modest anti-inflammatory effects through inhibition of NO production in LPS-stimulated BV cells.     

Lignan glycosides from the Rhizomes of Smilax trinervula and their Biological activities

Phytochemical investigation of the rhizomes of Smilax trinervula led to isolation and structure elucidation of eight lignan glycosides, including five new lignans, namely, (7S, 8R, 8′R)-4, 4′, 9-trihydroxy-3, 3′, 5, 5′-tetramethoxy-7, 9′-epoxylignan-7′-one 4′-O-β-d-glucopyranoside (1), (7S, 8R, 8′R)-4, 4′, 9-trihydroxy-3, 3′, 5, 5′-tetramethoxy-7, 9′-epoxylignan-7′-one 4-O-β-d- glucopyranoside (2) (7S, 8R)-4, 9, 9′-trihydroxy-3, 3′, 5-trimethoxy-4′, 7-epoxy-8, 5′-neolignan 9′-O-β-d-glucopyranoside (3), (7R, 8R)-4, 9, 9′-trihydroxy-3, 5-dimethoxy-7.O.4′, 8.O.3′- neolignan 9′-O-β-d-glucopyranoside (4), and (7S, 8R)-4, 9, 9′-trihydroxy-3, 3′, 5-trimethoxy-8, 4′-oxy-neolignan 4-O-β-d-glucopyranoside (5), along with three known compounds (6-8). Their structures were established mainly on the basis of 1D and 2D NMR spectral data, ESI–MS and comparison with the literature. Compounds 1-8 were tested in vitro for their cytotoxic activity against four human tumor cell lines (SH-SY5Y, SGC-7901, HCT-116, Lovo). Compounds 3 and 5 exhibited cytotoxic activity against Lovo cells, with IC₅₀ value of 10.4 μM and 8.5 μM, respectively.     

3-Hydroxyisoflavanones from the stem bark of Dalbergia melanoxylon: Isolation,antimycobacterial evaluation and molecular docking studies

Two new 3-hydroxyisoflavanones, (S)-3,4′,5-trihydroxy-2′,7-dimethoxy-3′-prenylisoflavanone (trivial name kenusanone F 7-methyl ether) and (S)-3,5-dihydroxy-2′,7-dimethoxy-2″,2″-dimethylpyrano[5″,6″:3′,4′]isoflavanone (trivial name sophoronol-7-methyl ether) along with two known compounds (dalbergin and formononetin) were isolated from the stem bark of Dalbergia melanoxylon. The structures were elucidated using spectroscopic techniques. Kenusanone F 7-methyl ether showed activity against Mycobacterium tuberculosis, whereas both of the new compounds were inactive against the malaria parasite Plasmodium falciparum at 10 μg/ml. Docking studies showed that the new compounds kenusanone F 7-methyl ether and sophoronol-7-methyl ether have high affinity for the M. tuberculosis drug target INHA.     

Anti-hepatitis B virus lignans from the root of Streblus asper

Four new lignans, strebluslignanol F (1), (7′R,8′S,7″R,8″S)-erythro-strebluslignanol G (2), isomagnaldehyde (3) and isostrebluslignanaldehyde (4), along with 12 known lignans (5–16) were isolated from the ethyl acetate-soluble part of MeOH extract of the root of Streblus asper. Their structures were elucidated through various spectroscopic methods, including 1D NMR (¹H NMR, ¹³C NMR), 2D NMR (HMQC, HMBC and NOESY) and HRMS. The stereochemistry at the chiral centers was determined using CD spectra, as well as analyses of coupling constants and optical rotation data. The isolated lignans were evaluated for their anti-HBV activities in vitro using the HBV transfected HepG2.2.15 cell line. The most active lignans, (7′R,8′S,7″R,8″S)-erythro-strebluslignanol G, magnolol, isomagnolol and isolariciresinol, exhibited significant anti-HBV activities with IC₅₀ values of 1.58, 2.03, 10.34 and 3.67 μM, respectively, for HBsAg with no cytotoxicity, and of 3.24, 3.76, 8.83 and 14.67 μM, respectively, for HBeAg with no cytotoxicity. (7′R,8′S,7″R,8″S)-erythro-Strebluslignanol G and magnolol showed significant anti-HBV activities to inhibit the replication of HBV DNA with the IC₅₀ values of 9.02 and 8.67 μM, respectively.     

A new synthesis and an antiviral assessment of the 4′-fluoro derivative of 4′-deoxy-5′-noraristeromycin

A synthetic route to (1S,2S,3R,5S)-3-(6-amino-9H-purin-9-yl)-5-fluorocyclopentane-1,2-diol (that is, the 4′-fluoro derivative of 4′-deoxy-5′-noraristeromycin, 3) is described via a fluorinated cyclopentanol, which is in contrast to existing schemes where fluorination occurred once the purine ring was present. Compound 3 was assayed versus a number of viruses. A favorable response was observed towards measles (IC₅₀ of 1.2 μg/mL in the neutral red assay and 14 μg/mL by the visual assay) but this was accompanied by cytotoxicity in the CV-1 host cells (21–36 μg/mL). Among the viruses unaffected by 3 were human cytomegalovirus and the poxviruses (vaccinia and cowpox), which are three viruses that were inhibited by the 4′,4′-difluoro analog of 3 (that is, 2).     

Three new benzophenone glycosides with MAO-A inhibitory activity from Hypericum thasium Griseb.

Purification of n-BuOH fraction from 80% ethanol extract of Hypericum thasium Griseb. resulted in the isolation of three new compounds 3′,4,5′-trihydroxy-6-methoxy-2-O-α-l-arabinosylbenzophenone (1), 3′,4,5′,6-tetrahydroxy-2-O-α-l-arabinosylbenzophenone (2), and 3′,4-dihydroxy-5′-methoxy-2-O-α-l-arabinosyl-6-O-β-d-xylosylbenzophenone (3) along with a known flavonoid glycoside quercetin-3-O-α-l-arabinofuranoside (4). The structures of the new compounds were elucidated by 1D and 2D NMR analysis as well as HRESIMS. The isolated compounds (1–4), as well as quercetin, and kaempferol previously isolated from EtOAc fraction were screened against MAO-A inhibitory activity. When tested against the MAO-A quercetin and kaempferol displayed IC₅₀ values of 19.6, and 17.5 μM, respectively. The IC₅₀ values for MAO-A inhibition by compounds (1–4) were 310.3, 111.2, 726.0, and 534.1 μM, respectively. Standard inhibitor (clorgyline) exhibited MAO-A inhibition with an IC₅₀ value of 0.5 μM.     

Two new glycosides and one new neolignan from the roots of Cynanchum stauntonii

Three new compounds including one C₂₁-steroidal glycoside, one methylglycoside, and one neolignan, named as Deoxyamplexicogenin A-3-O-yl-4-O-(4-O-α-l-cymaropyranosoyl-β-d-digitoxopyranosoyl)-β-d-canaropyranoside (1), Methyl-O-α-l-cymaropyranosoyl-(1 → 4)-β-D-digitoxopyranoside (2), and (+)-(7S, 8R, 7′E)-5-hydroxy-3, 5′-dimethoxy-4′, 7-epoxy-8, 3′-neolign-7′-ene-9, 9′-diol 9′-ethyl ether (3), respectively, were isolated from the roots of Cynanchum stauntonii. The structure elucidations were achieved by in-depth spectroscopic examination, mainly including the experiments and analyses of multiple 1D- and 2D-NMR and HRESIMS and CD analysis and qualitative chemical tests. Cytotoxicity activities of compounds 1–3 were evaluated against five tumor cell lines (HCT-8, Bel-7402, BGC-823, A549, and A2780) in cell based assays where they were found to be inactive.     

A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents

A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4′-(4-bromophenyl)-1′-methyldispiro[acenaphthylene-1,2′-pyrrolidine-3′,2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.     

New aromatic compounds from the rhizomes of Homalomena occulta

Three new aromatic compounds, identified as 1-(3′,4′-methylenedioxy-phenyl)-10-(3″-hydroxyphenyl)-decane (1), 1-(3′,4′-methylenedioxy-phenyl)-12-(3″-hydroxyphenyl)-dodecane (2), and 1-(3′,4′-methylenedioxy-phenyl)-12-(3″-hydroxyphenyl)-6Z-dodecylene (3), along with six known compounds (4–9) were isolated from the 95% EtOH extract of Homalomena occulta. Their structures were elucidated by chemical and spectral methods Compounds 4–9 were isolated for the first time from this plant. Compounds 1–3 exhibited inhibitory activity against BACE1, with IC₅₀ values of 0.82–1.09 μmol/L.     

Distinct chemotypes of Tephrosia vogelii and implications for their use in pest control and soil enrichment

Tephrosia vogelii Hook. f. (Leguminosae) is being promoted as a pest control and soil enrichment agent for poorly-resourced small-scale farmers in southern and eastern Africa. This study examined plants being cultivated by farmers and found two chemotypes. Chemotype 1 (C1) contained rotenoids, including deguelin, rotenone, sarcolobine, tephrosin and α-toxicarol, required for pest control efficacy. Rotenoids were absent from chemotype 2 (C2), which was characterised by prenylated flavanones, including the previously unrecorded examples (2S)-5,7-dimethoxy-8-(3-hydroxy-3-methylbut-1Z-enyl)flavanone, (2S)-5,7-dimethoxy-8-(3-methylbut-1,3-dienyl)flavanone, (2S)-4′-hydroxy-5-methoxy-6″,6″-dimethylpyrano[2″,3″:7,8]flavanone, (2S)-5-methoxy-6″,6″-dimethyl-4″,5″-dihydrocyclopropa[4″,5″]furano[2″,3″:7,8]flavanone, (2S)-7-hydroxy-5-methoxy-8-prenylflavanone, and (2R,3R)-3-hydroxy-5-methoxy-6″,6″-dimethylpyrano[2″,3″:7,8]flavanone. The known compounds (2S)-5-methoxy-6″,6″-dimethylpyrano[2″,3″:7,8]flavanone (obovatin 5-methyl ether) and 5,7-dimethoxy-8-(3-hydroxy-3-methylbut-1Z-enyl)flavone (Z-tephrostachin) were also found in C2. This chemotype, although designated Tephrosia candida DC. in collections originating from the World Agroforestry Centre (ICRAF), was confirmed to be T. vogelii on the basis of morphological comparison with verified herbarium specimens and DNA sequence analysis. Sampling from 13 locations in Malawi where farmers cultivate Tephrosia species for insecticidal use indicated that almost 1 in 4 plants were T. vogelii C2, and so were unsuitable for this application. Leaf material sourced from a herbarium specimen of T. candida contained most of the flavanones found in T. vogelii C2, but no rotenoids. However, the profile of flavonol glycosides was different to that of T. vogelii C1 and C2, with 6-hydroxy-kaempferol 6-methyl ether as the predominant aglycone rather than kaempferol and quercetin. The structures of four unrecorded flavonol glycosides present in T. candida were determined using cryoprobe NMR spectroscopy and MS as the 3-O-α-rhamnopyranosyl(1 → 6)-β-galactopyranoside-7-O-α-rhamnopyranoside, 3-O-α-rhamnopyranosyl(1 → 2)[α-rhamnopyranosyl(1 → 6)]-β-galactopyranoside, 3-O-α-rhamnopyranosyl(1 → 2)[α-rhamnopyranosyl(1 → 6)]-β-galactopyranoside-7-O-α-rhamnopyranoside, and 3-O-α-rhamnopyranosyl(1 → 2)[(3-O-E-feruloyl)-α-rhamnopyranosyl(1 → 6)]-β-galactopyranosides of 6-hydroxykaempferol 6-methyl ether. Tentative structures for a further 37 flavonol glycosides of T. candida were assigned by LC–MS/MS. The correct chemotype of T. vogelii (i.e. C1) needs to be promoted for use by farmers in pest control applications.     

Acylated iridoid glycosides and acylated rhamnopyranoses from Gmelina arborea flowers

Nine acylated iridoid glycosides (1–9), five acylated rhamnopyranoses (10–14) and verbascoside (15) were isolated from Gmelina arborea flowers, including 5 new compounds (1, 2, and 10–12). The cytoprotective activity of 11 selected compounds (1–8, 10, 11, and 15) against CCl₄-induced cytotoxicity on liver was determined. Compounds 1, 2, 4, 7, 8 and 15 displayed hepatoprotective activity. 6-O-α-l-(2″, 3″-di-O-trans-p-hydroxycinnamoyl)rhamnopyranosylcatalpol (2) exhibited the most potent cytoprotective effect with an EC₅₀ value of 42.5 μM (SI = 19.3) compared with biphenyldimethylesterate (DDB, EC₅₀ = 277.3 μM, SI = 9.8) and bicylo-ethanol (EC₅₀ = 279.2 μM, SI = 12.2). Among the acylated iridoid glycosides, the compounds (2 and 8) containing phenolic hydroxy groups were more active than were those lacking them.     

Two polymethoxylated flavonoids with antioxidant activities and a rearranged clerodane diterpenoid from the leaf exudates of Microglossa pyrifolia

Three novel compounds; two polymethoxylated flavonoids, 5,7,4′-trihydroxy-3,8,3′,5′-tetramethoxyflavone (1), 5,7,3′-trihydroxy-3,8,4′,5′-trimethoxyflavone (2), and a clerodane diterpenoid; 8-acetoxyisochiliolide lactone (3) were characterized from the leaf exudates of Microglossa pyrifolia. In addition, three known polymethoxylated flavonoids including; 5,7,4′-trihydroxy-3,8,3′-trimethoxyflavone (4), 5,3′4′-trihydroxy-3,7,8-trimethoxyflavone (5), 5,3′4′-trihydroxy-7-methoxyflavanone (6) and a clerodane diterpenoid; 7,8-epoxyisocholiolide lactone (7) were identified. Their structures were determined on the basis of spectroscopic evidence. All the compounds did not exhibit antiplasmodial and antimicrobial activities at 47.6 μg/mL and were not cytotoxic at 5 μg/mL. Compound 6 exhibited modest antileishmanial activity with IC₅₀ value of 13.13 μg/mL with 5 and 7 showing activities with IC₅₀ values of 31.13 and 38.00 μg/mL, respectively, therefore inactive. The flavonoids (quercetin derivatives, 4 and 5) showed similar antioxidant activities, using 2,2-diphenylpicrylhydrazyl (DPPH) assay, with IC₅₀ values of 6.2 ± 0.3 μg/mL for 4 (17.3 μM) and 5 (17.8 μM) respectively. These activities were comparable to that of the standard quercetin (IC₅₀ value of 6.0 ± 0.2 μg/mL (19.9 μM)), irrespective of methylation of the characteristic hydroxyl groups expected to be responsible for activity and additional substitution at C-8 in ring A of the flavonoid ring. These studies revealed that the presence of an hydroxyl group at C-4′ positions and oxygenation at C-3 in flavone skeleton, appears to be necessary for good antioxidant activities as encountered in compounds 1, 4 and 5. Substantial reduction in antioxidant activity was shown by methoxylation of the 4′-OH as observed in compound 2 with an IC₅₀ value of 8.79 ± 0.3 μg/mL (24.4 μM).     

Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors

New oxazolinyl derivatives of [17(20)E]-pregna-5,17(20)-diene: 2′-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4′,5′-dihydro-1′,3′-oxazole 1 and 2′-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4′,4′-dimethyl-4′,5′-dihydro-1′,3′-oxazole 2 were evaluated as potential CYP17A1 inhibitors in comparison with 17-(pyridin-3-yl)androsta-5,16-dien-3β-ol 3 (abiraterone). Differential absorption spectra of human recombinant CYP17A1 in the presence of compound 1 (λ_max = 422 nm, λ_min = 386 nm) and compound 2 (λ_max = 416 nm) indicated significant differences in enzyme/inhibitors complexes. CYP17A1 activity was measured using electrochemical methods. Inhibitory activity of compound 1 was comparable with abiraterone 3 (IC₅₀ = 0.9 ± 0.1 μM, and IC₅₀ = 1.3 ± 0.1 μM, for compounds 1 and 3, respectively), while compound 2 was found to be weaker inhibitor (IC₅₀ = 13 ± 1 μM). Docking of aforementioned compounds to CYP17A1 revealed that steroid fragments of compound 1 and abiraterone 3 occupied close positions; oxazoline cycle of compound 1 was coordinated with heme iron similarly to pyridine cycle of abiraterone 3. Configuration of substituents at 17(20) double bond in preferred docked position corresponded to Z-isomers of compounds 1 and 2. Presence of 4′-substituents in oxazoline ring of compound 2 prevents coordination of oxazoline nitrogen with heme iron and worsens its docking score in comparison with compound 1. These data indicate that oxazolinyl derivative of [17(20)E]-pregna-5,17(20)-diene 1 (rather than 4′,4′-dimethyl derivative 2) may be considered as potential CYP17A1 inhibitor and template for development of new compounds affecting growth and proliferation of prostate cancer cells.     

Melanogenesis inhibitory activity of a 7-O-9′-linked neolignan from Alpinia galanga fruit

An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC₅₀ = 7.3 μg/mL). Through bioassay-guided separation of the extract, a new 7-O-9′-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2–15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC₅₀ = 2.5 μM), 1′S-1′-acetoxychavicol acetate (2, 5.0 μM), and 1′S-1′-acetoxyeugenol acetate (3, 5.6 μM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1′-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9′-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1′ (IC₅₀ = 1.9 μM) and 2′ (4.5 μM)] and racemic mixtures [(±)-1 (2.2 μM) and (±)-2 (4.4 μM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1–3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity.     

New coumestan and coumaronochromone derivatives from Dalbergia boehmii Taub. (Fabaceae)

Chemical investigation of leaves and heartwood of Dalbergia boehmii resulted in the isolation of two new phenolic compounds, designated dalbergestan (1) and dalbergichromone (2), along with eleven known compounds, carpachromene (3), proanthocyanidin A-2 (4); piceatannol (5); biochanin A (6); macckiain (7); homopterocarpin (8); angolensin (9); medicarpin (10); 2′,7-dihydroxy-4′,5′-dimethoxyisoflavone (11); 2′-methoxyformononetin (12); and genistein (13). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses including, IR, UV, 1D and 2D – NMR as well as HRMS data. Some of the isolated compounds were evaluated for their in vitro insulin secretion activity on isolated mice islets, leishmanicidal activity against L. major (DESTO) promastigotes and in vitro cytotoxicity on MCF-7 cell lines. All tested compounds were inactive on glucose-stimulated insulin secretion at stimulatory glucose (20.0 mM) from MIN6 cells. Compounds 3 (IC₅₀, 70.0 μg/ml), 6 (IC₅₀, 60.3 μg/ml), 7 (IC₅₀, 86.5 μg/ml) and 13 (IC₅₀, 62.6 μg/ml) exhibited low leishmanicidal activity while compound 12 (IC₅₀, 56.8 μg/ml) displayed a moderate activity. Compounds 3 and 5 were found to be active against MCF-7 at 50 μM with IC₅₀ value 33.2 ± 3.79 μg/ml and 42.64 ± 5.05 μg/ml respectively.     

Synthesis and biological evaluation of 3′,4′,5′-trimethoxychalcone analogues as inhibitors of nitric oxide production and tumor cell proliferation

A series of 23 3′,4′,5′-trimethoxychalcone analogues was synthesized and their inhibitory effects on nitric oxide (NO) production in LPS/IFN-γ-treated macrophages, and tumor cell proliferation has been investigated. 4-Hydroxy-3,3′,4′,5′-tetramethoxychalcone (7), 3,4-dihydroxy-3′,4′,5′-trimethoxychalcone (11), 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (14), and 3,3′,4′,5′-tetramethoxychalcone (15) were the most potent growth inhibitory agents on NO production, with an IC₅₀ value of 0.3, 1.5, 1.3 and 0.3 μM, respectively. The tumor cells proliferation assay results revealed that several compounds exhibited potent inhibition activity against different cancer cell lines. The chalcone 15 was the most potent anti-proliferative compound in the series with IC₅₀ values of 1.8 and 2.2 μM toward liver cancer Hep G2 and colon cancer Colon 205 cell lines, respectively. 2,3,3′,4′,5′-Pentamethoxychalcone (1), 3,3′,4,4′,5,5′-hexamethoxychalcone (3), 2,3′,4,4′,5,5′-hexamethoxychalcone (5), 2-hydroxy-3,3′,4′,5′-tetramethoxychalcone (10), 11 and 14 showed significant anti-proliferation actions in Hep G2 and Colon 205 cells with an IC₅₀ values ranging between 10 and 20 μM. Among the tested agents, compound 7 showed selective NO production inhibition (IC₅₀ = 0.3 μM), while has no effect on tumor cell proliferation (IC₅₀ >100 μM). 3,3′,4,4′,5′-Pentamethoxychalcone (2) showed selective anti-proliferation effect in Hep G2 cells, in addition to its potent NO inhibition, however has no such response in Colon 205 cells. In contrast, 3-formyl-3′,4′,5′-trimethoxychalcone (22) showed moderate growth inhibition in Colon 205 cells, while has no such effect on NO production and Hep G2 cells proliferation. These results provide insight into the correlation between some structural properties of 3′,4′,5′-trimethoxychalcones and their in vitro anti-inflammatory and anti-cancer differentiation activity.