Synthesis and biological activity of hydroxy substituted phenyl-benzo[d]thiazole analogues for antityrosinase activity in B16 cells

In this study, we synthesized hydroxy and/or alkoxy substituted phenyl-benzo[d]thiazole derivatives using substituted benzaldehydes and 2-aminothiophenol in MeOH. The structures of these compounds were established by ¹H and ¹³C NMR and mass spectral analyzes. All synthesized compounds were evaluated for their mushroom tyrosinase inhibition activity. Out the 12 generated compounds, 2a and 2d exhibited much higher tyrosinase inhibition activity (45.36-73.07% and 49.94-94.17% at 0.01-20 μM, respectively) than kojic acid (9.29-50.80% at 1.25-20 μM), a positive control.The cytotoxicity of 2a and 2d was evaluated using B16 cells and the compounds were found to be nontoxic. Compounds 2a and 2d were also demonstrated to be potent mushroom tyrosinase inhibitors, displaying IC₅₀ values of 1.14 ± 0.48 and 0.01 ± 0.0002 μM, respectively, compared with kojic acid, which has an IC₅₀ value of 18.45 ± 0.17 μM. We also predicted the tertiary structure of tyrosinase, simulated the docking with compounds 2a and 2d and confirmed that the compounds strongly interact with mushroom tyrosinase residues. Kinetic plots showed that 2a and 2d are competitive tyrosinase inhibitors. Substitutions with a hydroxy group at R³ or both R³ and R¹ of the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase. We further found that compounds 2a and 2d inhibit melanin production and tyrosinase activity in B16 cells. These results may assist in the development of new potent tyrosinase inhibitors against hyperpigmentation.     

Cytotoxic and antioxidant activities of diterpenes and sterols from the Vietnamese soft coral Lobophytum compactum

Two new diterpenes, lobocompactols A (1) and B (2), and five known compounds (3-7) were isolated from the methanol extract of the soft coral Lobophytum compactum using combined chromatographic methods and identified based on NMR and MS data. Each compound was evaluated for cytotoxic activity against A549 (lung) and HL-60 (acute promyelocytic leukemia) human cancer cell lines. Among them, compound 5 exhibited strong cytotoxic activity against the A549 cell line with an IC₅₀ of 4.97 ± 0.06 μM. Compounds 3, 4, and 7 showed moderate activity with IC₅₀ values of 23.03 ± 0.76, 31.13 ± 0.08, and 36.45 ± 0.01 μM, respectively. The cytotoxicity of 5 on the A549 cells was comparable to that of the positive control, mitoxantrone (MX). All compounds exhibited moderate cytotoxicity against the HL-60 cell line, with IC₅₀ values ranging from 17.80 ± 1.43 to 59.06 ± 2.31 μM. Their antioxidant activity was also measured using oxygen radical absorbance capacity method, compounds 1 and 2 exhibiting moderate peroxyl radical scavenging activity of 1.4 and 1.3 μM Trolox equivalents, respectively, at a concentration of 5 μM.     

New halogenated phenylcoumarins as tyrosinase inhibitors

With the aim to find out structural features for the tyrosinase inhibitory activity, in the present communication we report the synthesis and pharmacological evaluation of a new series of phenylcoumarin derivatives with different number of hydroxyl or ether groups and bromo substituent in the scaffold. The synthesized compounds 5-12 were evaluated as mushroom tyrosinase inhibitors showing, two of them, lower IC₅₀ than the umbelliferone. Compound 12 (IC₅₀ = 215 μM) is the best tyrosinase inhibitor of this series.     

Synthesis and topoisomerase II inhibitory and cytotoxic activity of oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives

In order to find potential anticancer drug candidate targeting topoisomerases enzyme, we have designed and synthesized oxiranylmethoxy- and thiiranylmethoxy-retrochalcone derivatives and evaluated their pharmacological activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds prepared compound 25 showed comparable or better cytotoxic activity against cancer cell lines tested. Compound 25 inhibited MCF7 (IC₅₀: 0.49 ± 0.21 μM) and HCT15 (IC₅₀: 0.23 ± 0.02 μM) carcinoma cell growth more efficiently than references. In the topoisomerases inhibition test, all the compounds were inactive to topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially, compound 25 inhibited topoisomerase II activity with comparable extent to etoposide at 100 μM concentrations. Correlation between cytotoxicity and topoisomerase II inhibitory activity implies that compound 25 can be a possible lead compound for anticancer drug impeding the topoisomerase II function.     

Antioxidant, anti-inflammatory and anti-hyperglycaemic activities of heterocyclic homoprostanoid derivatives

A series of 19 heterocyclic homoprostanoids were synthesized from easily available oleic and ricinoleic acids and evaluated for their possible antioxidant, anti-inflammatory and anti-hyperlipidaemic activities. Compounds with thioxo- and oxoimidazole ring (1) and (2) have shown potent antioxidant activity with IC₅₀ values 0.23 ± 0.09 and 0.41 ± 0.01 mM comparable with standard ascorbic acid. Compound (3) with a quinoxaline ring showed maximum inhibition of BSA denaturation at 1 mM concentration and comparable with standard diclofenac. Incorporation of electron withdrawing substitutions like chloro- and nitro-groups in the quinoxaline ring has resulted in an increase anti-inflammatory activity. Test compounds (3), (3a) and (3c) showed modest inhibition of DPP-IV in vitro. However, the unsubstituted quinoxaline (3) and substituted quinoxalines (3b and 3c) reduced plasma glucose levels indicating the presence of hypoglycemic activity.     

1,2,3,4,6-penta-O-galloyl-β-d-glucose: A cholinesterase inhibitor from Terminalia chebula

The search for a novel pharmacotherapy from medicinal plants for neurodegenerative disorders has significantly advanced. Therefore, the present study was performed to evaluate the anticholinesterase activities of one hundred medicinal plants in Korea, where Terminalia chebula (T. chebula) fruits showed significant acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitions. Further bioassay monitored phytochemical exploration led to the isolation of 1,2,3,4,6-penta-O-galloyl-β-d-glucose (compound 1), which showed significant AChE and BChE inhibitory effects with IC₅₀ values of 29.9 ± 0.3 µM and 27.6 ± 0.2 µM, respectively. The inhibitory effect of compound 1 towards acetylcholinesterase was also evaluated using TLC and compared with tacrine as the positive control; the positive effect was confirmed. Furthermore, compound 1 also displayed strong antioxidant activity by the FRAP assay (IC₅₀ = 4.6 ± 0.2 µM). In conclusion, compound 1 may prove to be a potential natural anti-Alzheimer source based on noteworthy AChE and BChE inhibitions, and strong antioxidant activity.     

Amides derived from heteroaromatic amines and selected steryl hemiesters

The current interest of the team has been focused on investigation of novel amides with potential cytotoxicity. The presented series of compounds was synthesized from selected steryl hemiesters and heteroaromatic amines. The synthetic protocol was designed in a simple and economic way, and divided into several general methodologies applicable to the compounds synthesized. The cytotoxicity was tested on cells derived from human T-lymphoblastic leukemia, breast adenocarcinoma and cervical cancer, and compared with tests on normal human fibroblasts. Most of the lanosterol-based compounds (3–5 and 7–10) showed medium to good cytotoxicity, while only two derivatives of cholesterol (18 and 19) showed medium cytotoxicity on human T-lymphoblastic leukemia cell line. The compounds 8 and 9 displayed the reasonable cytotoxicity among this series of amides, tested on the cell lines of T-lymphoblastic leukemia [14.5 ± 0.4 μM (8) and 18.5 ± 3.9 μM (9)], breast adenocarcinoma [19.5 ± 2.1 μM (8) and 23.1 ± 4.0 μM (9)] and cervical cancer [24.8 ± 5.3 μM (8) and 29.1 ± 4.7 μM (9)]. Only the compound 8 was adequately less active on normal human fibroblasts (40.4 ± 11.1 μM).     

Evaluation of in vitro cytotoxicity and hepatotoxicity of platinum(II) and palladium(II) oxalato complexes with adenine derivatives as carrier ligands

In vitro antitumour activity of the [Pt(ox)(L_n)₂] (1-7) and [Pd(ox)(L_n)₂] (8-14) oxalato (ox) complexes involving N6-benzyl-9-isopropyladenine-based N-donor carrier ligands (L_n) against ovarian carcinoma (A2780), cisplatin resistant ovarian carcinoma (A2780cis), malignant melanoma (G-361), lung carcinoma (A549), cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines was studied. Some of the tested complexes were even several times more cytotoxic as compared with cisplatin employed as a positive control. The improved cytotoxic effect was demonstrated for the platinum(II) complexes 3 (IC₅₀ = 3.2 ± 1.0 μM and 3.2 ± 0.6 μM) and 5 (IC₅₀ = 4.0 ± 1.0 μM and 4.1 ± 1.4 μM) against A2780 and A2780cis, as compared with 11.5 ± 1.6 μM, and 30.3 ± 6.1 μM determined for cisplatin, respectively. The significant in vitro cytotoxicity against MCF7 (IC₅₀ = 8.2 ± 3.8 μM for 12) and A2780 (IC₅₀ = 5.4 ± 1.2 μM for 14) was evaluated for the palladium(II) oxalato complexes, which again exceeded cisplatin, whose IC₅₀ equalled 19.6 ± 4.3 μM against the MCF7 cells. Selected complexes were also screened for their in vitro cytotoxic effect in primary cultures of human hepatocytes and they were found to be non-hepatotoxic.     

Synthesis, DNA binding, photo-induced DNA cleavage, cytotoxicity and apoptosis studies of copper(II) complexes

Two new Cu(II) complexes, [Cu(acac)(dpq)Cl] () and [Cu(acac)(dppz)Cl] () (acac = acetylacetonate, dpq = dipyrido[3,2-d:20,30-f]quinoxaline, dppz = dipyrido[3,2-a:20,30-c] phenazine), have been synthesized and their DNA binding, photo-induced DNA cleavage activity and cell cytotoxicity are studied. The complexes show good binding propensity to calf thymus DNA in the order: 2(dppz) > 1(dpq). Furthermore, two complexes exhibit efficient DNA cleavage activity on natural light or UV-A (365 nm) irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The photo-induced DNA cleavage activity of the dppz complex 2 is found to be more efficient than its dpq analogue. In vitro study of the photocytotoxicity of two complexes on HeLa cells indicate that both of them have the potential to act as effective anticancer drugs, with IC₅₀ values of 5.25 ± 0.83 μM (1) and 4.40 ± 0.52 μM (2) in the natural light, and 2.57 ± 0.92 μM (1) and 2.18 ± 0.52 μM (2) in UV-A light. In addition, to detect an apoptotic HeLa body, cells were stained with Hoechst 33342 dye.     

Structure-activity relationships and DNA binding properties of apoptosis inducing cytotoxic rhodium(III) polypyridyl complexes containing the cyclic thioether [9]aneS3

The Rh(III) polypyridyl complexes of the type [RhCl(pp)([9]aneS₃)]²⁺ [(pp) = 2,2′-bipyridine (bpy), 2,2′-bipyrimidine (bpm),1,10-phenanthroline (phen), pyrazino[2,3-f]quinoxaline (tap), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq), dipyrido[2,3-a:2′,3′-c]phenazine (dppz)] 2-7 have been prepared in a stepwise manner by treatment of RhCl₃ · 3H₂O with the appropriate polypyridyl ligand (pp) followed by 1,4,7-trithiacyclononane. Interactions of the polypyridyl complexes with DNA were investigated by CD and UV/visible spectroscopy and by gel electrophoresis. The dpq complex 6 cleaves DNA exiguously in the dark, but UV irradiation is required to induce nuclease activity for the bpy complex 2. Whereas 2 [IC₅₀ values: 12.8 (±0.2) and 4.4 (±0.1) μM] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC₅₀ values: 36.3 (±6.0) and 72.2 (±8.0)], the activity of complexes in the series 4/6/7 correlates directly with the size of the polypyridyl ligand, as documented by their respective IC₅₀ values of 72.2 (±8.0), 20.9 (±2.8) and 7.4 (±2.2) towards HT-29 cells. Complexes of the nitrogen-rich ligands bpm (3) [IC₅₀ values: 1.7 (±0.5) and 1.9 (±0.1) μM] and tap (5) [IC₅₀ values: 11.5 (±0.6) and 7.6 (±4.8) μM] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1 h incubation demonstrates that unspecific necrosis is negligible for the most active compounds 3 and 7. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72 h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved.     

Design of novel N-phenylnicotinamides as selective cyclooxygenase-1 inhibitors

A series of N-phenylnicotinamides (1-40) were designed and evaluated in vitro for their COX inhibitory activities. Most of the synthesized compounds were proved to be potent and selective inhibitors of COX-1. Compound 28 showed the most potent COX-1 inhibitory activity (COX-1 IC₅₀ = 0.68 ± 0.07 μM) and good selectivity (COX-2 IC₅₀ >100 μM). This compound may be useful as a lead compound for superior COX-1 inhibitors. On the basis of the biological results, structure-activity relationships for the COX-1-inhibitory activities of the synthesized N-phenylnicotinamides were discussed concisely.     

Platinum(II) oxalato complexes with adenine-based carrier ligands showing significant in vitro antitumor activity

[Pt(L)₂(ox)] (1), [Pt(2-OMeL)₂(ox)] (2), [Pt(3-OMeL)₂(ox)] (3), [Pt(2,3-diOMeL)₂(ox)] (4), [Pt(2,4-diOMeL)₂(ox)] (5), [Pt(3,4-diOMeL)₂(ox)] (6) and [Pt(3,5-diOMeL)₂(ox)]·4H₂O (7) platinum(II) oxalato (ox) complexes were synthesized using the reaction of potassium bis(oxalato)platinate(II) dihydrate with 2-chloro-N6-(benzyl)-9-isopropyladenine or its benzyl-substituted analogues (nL). The complexes 1-7, which represent the first platinum(II) oxalato complexes involving adenine-based ligands, were fully characterized by various physical methods including multinuclear and two dimensional NMR spectroscopy. A single-crystal X-ray analysis of [Pt(2,4-diOMeL)₂(ox)]·2DMF (5·2DMF; DMF = N,N′-dimethylformamide), proved the slightly distorted square-planar geometry in the vicinity of the Pt(II) ion with one bidentate-coordinated oxalate dianion and two adenine derivatives (nL) coordinated to the Pt(II) centre through the N7 atom of an adenine moiety, thereby giving a PtN₂O₂ donor set. In vitro cytotoxicity of the prepared complexes was tested by an MTT assay against osteosarcoma (HOS) and breast adenocarcinoma (MCF7) human cancer cell lines. The best results were achieved for the complexes 2 and 5 in the case of both cell lines, whose IC₅₀ values equalled 3.6 ± 1.0, and 4.3 ± 2.1 μM (for 2), and 5.4 ± 3.8, and 3.6 ± 2.1 μM (for 5), respectively. The IC₅₀ equals 9.2 ± 1.5 μM against MCF7 cells in the case of 1. The in vitro cytotoxicity of the mentioned complexes significantly exceeded commercially used platinum-based anticancer drugs cisplatin (34.2 ± 6.4 μM and 19.6 ± 4.3 μM) and oxaliplatin (> 50.0 μM for both cancer cell lines).     

Synthesis, characterization, X-ray structure and in vitro antimycobacterial and antitumoral activities of Ru(II) phosphine/diimine complexes containing the "SpymMe2" ligand, SpymMe2=4,6-dimethyl-2-mercaptopyrimidine

The reaction of cis-[RuCl₂(dppb)(N-N)], dppb = 1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe₂, 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe₂)(dppb)(N-N)]PF₆, N-N = bipy (1) and Me-bipy (2), bipy = 2,2′-bipyridine and Me-bipy = 4,4′-dimethyl-2,2′-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl₂(dppb)(N-N)], N-N = bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe₂. The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC₅₀ values for the antitumor activity were determined. Compounds 1-4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25 μg/mL, compared to the free ligands (MIC of 25 to >50 μg/mL) and the drugs used to treat tuberculosis. Complexes 1 and 2 also showed promising antitumor activity, with IC₅₀ values of 0.46 ± 0.02 and 0.43 ± 0.08 μM, respectively, against MDA-MB-231 breast tumor cells.     

Antibacterial and antioxidant activities of four kaempferol methyl ethers isolated from Dodonaea viscosa Jacq. var. angustifolia leaf extracts

Fractionation of dichloromethane and acetone fractions obtained by serial extraction from the leaf powder of Dodonaea viscosa Jacq. var. angustifolia (Sapindaceae) resulted in the isolation of four kaempferol methyl ethers. The compounds were identified by spectral data (¹H NMR, ¹³C NMR and MS) as: 3, 5, 7-trihydroxy-4'-methoxyflavone (1); 5, 7, 4'-trihydroxy-3, 6-dimethoxyflavone (2); 5, 7-dihydroxy-3, 6, 4'-trimethoxyflavone (santin) (3); and 5-hydroxy -3, 7, 4'-trimethoxyflavone (4) together with 3,4',5,7-tetrahydroxy flavone (kaempferol) (5). Antioxidant potential of the compounds was evaluated using a DPPH spectrophotometric assay, while antibacterial activity was determined using a serial dilution microplate technique. The isolates demonstrated varying degrees of antioxidant and antibacterial activities. Of all the compounds investigated, compounds 1 and 5 demonstrated some antioxidant activity (EC₅₀ = 75.49 ± 1.76 µM and 35.06 ± 0.85 respectively) but lower than l-ascorbic acid (EC₅₀ = 13.55 ± 0.28 µM) used as a standard antioxidant agent. The minimum inhibitory concentration (MIC) of isolated compounds against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa varied from 16 µg/ml to more than 250 µg/ml. Some structure activity relationships could be established for these compounds.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Unusual stilbenoids and a stilbenolignan from seeds of Syagrus romanzoffiana

Stilbenoids, syagrusins A-B (1-2), and a stilbenolignan, 5-hydroxyaiphanol (3), along with three known phenylpropanoids (4-6), were isolated from seeds of Syagrus romanzoffiana. Compounds 1 and 2 possess unusual 1,4,4a,9a-tetrahydrofluoren-9-one and bicyclo[3.3.0]octanedione skeletons, respectively, whereas compound 3 is a stilbenolignan belonging to a very rare structural class of plant secondary metabolites. Their structures were elucidated by spectroscopic analyses. Compounds 1-3 exhibited moderate inhibitory activity against α-glucosidase with IC₅₀ values of 16.9 μM (1), 23.7 μM (2) and 12.8 μM (3), respectively.     

α-Glucosidase inhibition and antihyperglycemic activity of prenylated xanthones from Garcinia mangostana

An ethanol extract of the fruit case of Garcinia mangostan, whose most abundant chemical species are xanthones, showed potent α-glucosidase inhibitory activity (IC₅₀ = 3.2 μg/ml). A series of isolated xanthones (1-16) demonstrated modest to high inhibition of α-glucosidase with IC₅₀ values of 1.5-63.5 μM. In particular, one hitherto unknown xanthone 16 has a very rare 2-oxoethyl group on C-8. Kinetic enzymatic assays with a p-nitrophenyl glucopyranoside indicated that one of them, compound (9) exhibited the highest activity (K_i = 1.4 μM) and mixed inhibition. Using, a physiologically relevant substrate, maltose, as substrate, many compounds (6, 9, 14, and 15) also showed potent inhibition which ranged between 17.5 and 53.5 μM and thus compared favorably with deoxynojirimycin (IC₅₀ = 68.8 μM). Finally, the actual pharmacological potential of the ethanol extract was demonstrated by showing that it could elicit reduction of postprandial blood glucose levels. Furthermore, the most active α-glucosidase inhibitors (6, 9, and 14) were proven to be present in high quantities in the native seedcase by a HPLC chromatogram.     

Sesquiterpene lactones from the endemic Cape Verdean Artemisia gorgonum

Leaves and flowers of Artemisia gorgonum (Asteraceae) collected in Fogo, Cape Verde islands, were phytochemically investigated and resulted in isolation and characterization of three guaianolides 1, 2, 5, and a secoguainolide 4, in addition to eight known guaianolides 6-11 and two known germacranolides 12, 13. Structures were elucidated by 1D and 2D NMR experiments. Careful examination of the ¹³C NMR spectrum led to revision of the structure of a previously described guaianolide from 2 to 3. Most compounds exhibited mild antiplasmodial activities, ridentin (13) being the most interesting with an IC₅₀ of 3.8 ± 0.7 μg ml⁻¹ against Plasmodium falciparum FcB1 and weak cytotoxicity in a vero cell line (IC₅₀ 71.0 ± 3.9 μg ml⁻¹).     

Phenolic compounds with NF-κB inhibitory effects from the fungus Phellinus baumii

Chemical investigation of the fungus Phellinus baumii has resulted in characterization of five previously undescribed hispidin derivatives, phellibaumins A-E (1-5), as well as two pairs of new non-equivalent epimeric benzyl dihydroflavones, methylphelligrin A (9), epi-methylphelligrin A (10), methylphelligrin B (11), and epi-methylphelligrin B (12), together with five known compounds, interfungin B (6), phelligridin H (7), phelligridimer A (8), phelligrin A (13), and epi-phelligrin A (14). Phellibaumin A (1) was a novel hispidin derivative with a unique 3,4-dihydroxybenzofuran unit. These compounds exhibited NF-κB inhibitory activity with IC₅₀ values of 52.96 μM (1), 41.40 μM (2), 52.92 μM (5), 36.44 μM (9 and 10), and 22.46 μM (11 and 12), respectively.