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.     

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.     

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.     

Transition metal complexes (M = Cu, Ni and Mn) of Schiff-base ligands: Syntheses, crystal structures, and inhibitory bioactivities against urease and xanthine oxidase

Six new transition metal complexes (M = Cu(II), Ni(II) and Mn(III)) of tridentate (H₂L¹, HL²) and/or bidentate (HL³, HL⁴) Schiff-base ligands, obtained from the condensation of salicylaldehyde with glycine, N-(2-aminoethyl)morpholine, 4-(2-aminoethyl)phenylic acid and 4-(2-aminoethyl)benzsulfamide, respectively, were synthesized and structurally determined by single-crystal X-ray analysis. Complexes 1-6 were evaluated for their effect on the jack bean urease and xanthine oxidase (XO). Copper(II) complexes 1-3 (IC₅₀ = 0.43-2.25 μM) showed potent inhibitory activity against jack bean urease, comparable with acetohydroxamicacid (IC₅₀ = 42.12 μM), which is a positive reference. And these copper(II) complexes (IC₅₀ = 10.26-15.82 μM) also exhibited strong ability to inhibit activity of XO, comparable to allopurinol (IC₅₀ = 10.37 μM), which was used as a positive reference. Nickel(II) and manganese(III) complexes 4-6 showed weak inhibitory activity to jack bean urease (IC₅₀ = 4.36-8.25 μM) and no ability to inhibit XO (IC₅₀ > 100 μM).     

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.     

3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile): A new highly active compound against epimastigote and trypomastigote form of Trypanosoma cruzi

We have synthesized the Morita-Baylis-Hillman adduct (MBHA) 3-hydroxy-2-methylene-3-(4-nitrophenyl)-propanenitrile (3) in quantitative yield and evaluated on Trypanosoma cruzi epimastigote and bloodstream trypomastigote forms. Compound 3 strongly inhibited epimastigote growth, with IC₅₀/72 h of 28.5 μM and also caused intense trypomastigotes lysis, with an IC₅₀/24 h of 25.5 μM. Ultrastructural analysis showed significant morphological changes on both parasite forms treated with 3, including increase of cell volume and rounding of cell body as well as intense intracellular disorganization. Morphological changes indicative of apoptosis, autophagy or necrosis were observed in most affected cells. Docking calculations of 1, 2 and 3 pointed out the possibility of T. cruzi Farnesyl Pyrophosphate Synthase (TcFPPS) enzyme inhibition in 3 mechanism of action.     

Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles as novel selective cyclooxygenase-2 (COX-2) inhibitors

A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All compounds were evaluated by cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles 3a-e showed IC₅₀ values ranging from 0.42 to 8.1 mM for COX-1 and 2.0 to 200 μM for COX-2. Most potent compound 3c (IC₅₀ (COX-2) = 2.0 μM) was further used in molecular modeling docking studies.     

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.     

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.     

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.     

Synthesis and antitumor activity of new d-seco and d-homo androstane derivatives

Starting from 3β-hydroxy-17-oxo-16,17-secoandrost-5-ene-16-nitrile (1), the new 16,17-secoandrostane derivatives 4-9 were synthesized. On the other hand, 3β-hydroxy-17-oxa-d-homoandrost-5-ene-16-one (10) yielded the new d-homo derivatives 12, 13 and 15. In vitro antiproliferative activity of selected compounds against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER−, MDA-MB-231, prostate cancer AR−, PC-3, and normal fetal lung fibroblasts, MRC-5) was evaluated. Compounds 3 and 12 showed strong antiproliferative activity against PC-3 cells, the IC₅₀ values being 2 μM and 0.55 μM, respectively. Compounds 6 (10 μM) and 14 (9 μM) showed moderate activity against MDA-MB-231 cells. The synthesized compounds 1-3, 5-8, 10 and 12-15 were not toxic to normal fetal lung fibroblasts cells, MRC-5.     

Antiplasmodial and antitumor activity of dihydroartemisinin analogs derived via the aza-Michael addition reaction

A series of dihydroartemisinin derivatives were synthesized via an aza-Michael addition reaction to a dihydroartemisinin-based acrylate and were evaluated for antiplasmodial and antitumor activity. The target compounds showed excellent antiplasmodial activity, with dihydroartemisinin derivatives 5, 7, 9 and 13 exhibiting IC₅₀ values of ?10 nM against both D10 and Dd2 strains of Plasmodium falciparum. Derivative 4d was the most active against the HeLa cancer cell line, with an IC₅₀ of 0.37 μM and the highest tumor specificity.     

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.     

The first iron(III) complexes with cyclin-dependent kinase inhibitors: Magnetic, spectroscopic (IR, ES+ MS, NMR, Fe Mössbauer), theoretical, and biological activity studies

The first Fe^III complexes 1-6 with cyclin-dependent kinase (CDK) inhibitors of the type [Fe(L_n)Cl₃]·nH₂O (n = 0 for 1, 1 for 2, 2 for 3-6; L₁-L₆ = C2- and phenyl-substituted CDK inhibitors derived from 6-benzylamino-9-isopropylpurine), have been synthesized and characterized by elemental analysis, IR, ⁵⁷Fe Mössbauer, ¹H and ¹³C NMR, and ES+ mass spectroscopies, conductivity and magnetic susceptibility measurements, and thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The study revealed that the compounds are mononuclear, tetrahedral high-spin (S = 5/2) Fe^III complexes with an admixture of an S = 3/2 spin state originating probably from five-coordinated Fe^III ions either connecting with a bidentate coordination mode of the CDK inhibitor ligand or relating to the possibility that one crystal water molecule enters the coordination sphere of the central atom in a portion of molecules of the appropriate complex. Nearly spin-only value of the effective magnetic moment (5.82 μ_eff/μ_B) was determined for compound 1 due to absence of crystal water molecule(s) in the structure of the complex. Based on NMR data and DFT calculations, we assume that the appropriate organic ligand is coordinated to the Fe^III ion through the N7 atom of a purine moiety. The cytotoxicity of the complexes was tested in vitro against selected human cancer cell lines (G-361, HOS, K-562 and MCF-7) along with the ability to inhibit the CDK2/cyclinE kinase. The best cytotoxicity (IC₅₀: 4-23 μM) and inhibition activity (IC₅₀: 0.02-0.09 μM) results have been achieved in the case of complexes 2-4, and complexes 3, 4 and 6, respectively. In addition, the X-ray structure of 2-chloro-6-benzylamino-9-isopropylpurine, i.e. a precursor for the preparation of L₁, L₄ and L₅, is also described.     

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.     

Pregnane alkaloids from Pachysandra axillaris

Nine new pregnane alkaloids, pachysamines J-R (1-9), together with seven known ones, were isolated from Pachysandra axillaris. The chemical structures of the new alkaloids were elucidated by spectroscopic methods. All the compounds were evaluated for their inhibitory activities against HL-60, SMMC-7721, A-549, SK-BR-3, and PANC-1 cell lines. Compound 15 possessed moderate activities against A-549, SK-BR-3, and PANC-1 cells, with the IC₅₀ values of 11.17, 4.17, and 10.76 μM, respectively. Besides, compound 11 showed cytotoxicities against A-549 cell, with the IC₅₀ values as 24.94 μM.     

Synthesis and antitumor activity of novel ribonucleosides with C-5 OH replaced by a diaminopyrimidinyl group

A series of novel ribonucleosides with C-5 OH replaced by a diaminopyrimidinyl group were synthesized by successively nucleophilic substitutions of 5′-deoxy-5′-amino-ribonucleosides with 2,4-dichloropyrimidine and then with various fatty amines under microwave irradiation. Their anticancer activities in vitro were preliminarily evaluated. Compounds 7a and 8a only exhibited anticancer activity against A549 cell line with the IC₅₀ values of 10.73 and 10.99 μM, respectively. In addition, 7h and 8h showed potent activities against both A549 and Hela cell lines with the IC₅₀ values of 12.71, 8.55 and 8.44, 5.55 μM, respectively.     

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.     

Remarkable photocytotoxicity in hypoxic HeLa cells by a dipyridophenazine copper(II) Schiff base thiolate

Copper(II) complexes [Cu(satp)(L)] (1-3) of a Schiff base thiolate (salicylidene-2-aminothiophenol, H₂satp) and phenanthroline bases (L), viz. 1,10-phenanthroline (phen in 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3), were prepared, characterized and their anaerobic DNA photocleavage activity and hypoxic photocytotoxicity studied. The redox active complexes show the Cu(II)-Cu(I) couple near − 0.5 V for 1 and near 0.0 V vs. SCE (saturated calomel electrode) for 2 and 3. The one-electron paramagnetic complexes (~ 1.85 μ_B) are avid DNA binders giving K_b values within 1.0 × 10⁵ − 8.0 × 10⁵ M^− 1. Thermal melting and viscosity data along with molecular docking calculations suggest DNA groove and/or partial intercalative binding of the complexes. The complexes show anaerobic DNA cleavage activity in red light under argon via type-I pathway, while DNA photocleavage in air proceeds via hydroxyl radical pathway. The DFT (density functional theory) calculations reveal a thyil radical pathway for the anaerobic DNA photocleavage activity and suggest the possibility of generation of a transient copper(I) species due to bond breakage between the copper and sulfur to generate the thyil radical. An oxidation of the copper(I) species is likely by oxygen in an aerobic medium or by the buffer medium in an anaerobic condition. Complex 3 exhibits significant photocytotoxicity in HeLa cells (IC₅₀ = 8.3(± 1.0) μM) in visible light, while showing lower dark toxicity (IC₅₀ = 17.2(± 1.0) μM). A significant reduction in the dark toxicity is observed under hypoxic cellular conditions (IC₅₀ = 30.0(± 1.0) μM in dark), while retaining its photocytotoxicity (IC₅₀ = 8.0(± 1.0) μM).