Conjugates of 3α-methoxyserrat-14-en-21β-ol (PJ-1) and 3β-methoxyserrat-14-en-21β-ol (PJ-2) as cancer chemopreventive agents

3α-Methoxyserrat-14-en-21β-ol (PJ-1) and 3β-methoxyserrat-14-en-21β-ol (PJ-2) were conjugated with well-known phenolic compounds, narigenin, hesperetin, genistein, and daidzein (1-8). Other conjugates of PJ-2-3,5-dihydroxy-4-methoxybenzoic acid (9), PJ-2-pyrogallol (10), and derivatives of PJ-1, PJ-2-3,3-dimethyl-succinates (11, 12), PJ-1, PJ-2-succinates (13, 14), PJ-2-glycine (15), PJ-2-piperidine acetic acid (16), and PJ-1 epoxy-3,3-dimethyl-succinate (17) were tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effects of 11 (IC₅₀ = 251), 12 (IC₅₀ = 248), and 17 (IC₅₀ = 230 mol ratio/32 pmol/TPA), were 2-fold stronger than those of the other compounds such as oleanolic acid (IC₅₀ = 449). Compounds 10, 11, and 17 inhibited mouse skin tumor promotion in an in vivo two-stage carcinogenesis model. The in vivo two-stage mouse-skin carcinogenesis test employed 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.     

Synthesis and structure of new bicopper(II) complexes bridged by N-(2- aminopropyl)-N'-(2-oxidophenyl)oxamide: the effects of terminal ligands on structures, anticancer activities and DNA-binding properties

A novel dissymmetrical N,N′-bis(substituted)oxamide ligand, N-(2-aminopropyl)-N′-(2-oxido- phenyl)oxamide (H₃apopoxd) (L), and its three bicopper(II) complexes, [Cu₂(apopoxd)(bpy)]- (ClO₄)·H₂O (1), [Cu₂(apopoxd)(dabt)](ClO₄)·2H₂O (2), and [Cu₂(apopoxd)(phen)₂](ClO₄) (3) (bpy = 2,2′-bipyridine; dabt = 2,2′-diamino-4,4′-bithiazole; phen = 1,10-phenanthroline) have been synthesized and characterized. The crystal structures of the three bicopper(II) complexes have been determined by X-ray single-crystal diffraction. In complexes 1 and 2, the cis-apopoxd³⁻ ligands bridge two copper(II) ions in square-planar geometries with the corresponding separations of 5.1868(3) and 5.2016(4) Å, respectively. While in complex 3, the apopoxd³⁻ ligand adopting a trans conformation bridges the two copper(II) ions in distorted square-pyramid environments with a Cu···Cu distance of 5.2508(7) Å. The anticancer activities and DNA-binding properties of L and the three complexes were investigated.     

Mycobacterium tuberculosis and cholinesterase inhibitors from Voacanga globosa

Globospiramine (1), a new spirobisindole alkaloid possessing an Aspidosperma-Aspidosperma skeleton, together with deoxyvobtusine (2), deoxyvobtusine lactone (3), vobtusine lactone (4) and lupeol (5), were isolated and identified from Voacanga globosa through a bioassay-guided purification. The gross structure and absolute stereochemistry of 1 were established by circular dichroism spectroscopy, HR-MS and unambiguous NMR spectroscopic experiments. In addition, a new biogenetic pathway for the formation of the spiro-Aspidosperma-Aspidosperma skeleton is proposed. Alkaloid 1 showed potent antituberculosis activity against Mycobacterium tuberculosis H₃₇Rv as evidenced in microplate Alamar blue assay (MIC = 4 μg/mL) and low-oxygen recovery assay (LORA (MIC = 5.2 μg/mL). The bisindole alkaloids also exhibited promising activity against acetylcholinesterase and, especially butyrylcholinesterase, with deoxyvobtusine (2) (IC₅₀ = 6.2 μM) as the most strongly inhibiting compound. This study extends the variety of alkaloid structural platforms which exhibit antimycobacterial and anticholinesterase activity.     

Co(III), Ni(II), Zn(II) and Cd(II) complexes with 2-acetyl-2-thiazoline thiosemicarbazone: Synthesis, characterization, X-ray structures and antibacterial activity

The new ligand 2-acetyl-2-thiazoline thiosemicarbazone (HATtsc) and the complexes [Co(ATtsc)₂]₂[CoCl₄]·2H₂O (1), [Co(ATtsc)₂]NO₃·H₂O (2), [Ni(HATtsc)₂](NO₃)₂ (3), [ZnCl₂(HATtsc)]·CH₃CN (4), [{CdCl(HATtsc)}₂(μ-Cl)₂]·2H₂O (5) and [{Cd(NO₃)(HATtsc)}₂(μ-NO₃)₂] (6) were isolated and characterized by a variety of physico-chemical techniques and X-ray diffraction. The structure of HATtsc in 1 and 2 presented a thiolate form while in 3-6 the thione form was present, as it was in free ligand. In addition, we studied the antibacterial activity of the ligand and complexes 2-6 against some representative bacteria. Cd(II) complexes were more active against Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Bacillus subtilis than organic ligand. Conversely, Cd(II) compounds seemed to interfere in the cell separation of B. subtilis.     

Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with novel 3-pyridinesulfonamide derivatives

A series of novel 3-pyridinesulfonamide derivatives (2-5, 9-11 and 13-15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed K_Is in the range of 0.089-251 μM, whereas toward hCA II, K_Is = 50.5-487 nM. Isozyme hCA IX was inhibited with K_Is in the range of 5.2-18.3 nM, while hCA XII with K_Is = 6.0-16.4 nM, and hCA XIV with K_Is = 76.4-152.0 nM. All of the new compounds 2-5, 9-11 and 13-15 showed excellent hCA IX inhibitory efficacy, with K_Is = 5.2-18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (K_Is = 24-50 nM).     

Synthesis, evaluation against Leishmania amazonensis and cytotoxicity assays in macrophages of sixteen new congeners Morita-Baylis-Hillman adducts

We report the design, synthesis, in vitro evaluation against Leishmania amazonensis (IC₅₀), cytotoxicity assays in macrophages (CC₅₀), and selectivity index (SICC₅₀/IC₅₀) of sixteen new congeners aromatic Morita-Baylis-Hillman adducts 1-16. The 1-16 were prepared in good to excellent yields (58%-97%) from the “one pot” Morita-Baylis-Hillman Reaction between the aldehydes 29-36 and the acrylates 27 or 28 under DABCO as promoter. The MBHA 2-[Hydroxy(2-nitrophenyl)propyl] propanoate (1, IC₅₀ = 7.52 μg/mL or 28.38 μM; CC₅₀ = 35.77 μg/mL or 134.98 μM; SI = 4.75) and 2-[Hydroxy(2-nitrophenyl)hydroxyethyl] propanoate (9, IC₅₀ = 5.48 μg/mL or 20.52 μM; CC₅₀ = 29.81 μg/mL or 111.64c μM and, SI = 5.43) were the most effective and safe evaluated compounds.     

Synthesis, biological evaluation, and docking studies of gigantol analogs as calmodulin inhibitors

Several analogs of gigantol (1) were synthesized to evaluate their effect on the complexes Ca²⁺-calmodulin (CaM) and Ca²⁺-CaM-CaM sensitive phosphodiesterase 1 (PDE1). The compounds belong to four structural groups including, 1,2-diphenylethanes (2-11), diphenylmethanes (13-15), 1,3-diphenylpropenones (16-18), and 1,3-diphenylpropanes (20-22). In vitro enzymatic studies showed that all compounds except 11 inhibited the complex Ca²⁺-CaM-PDE1 with IC₅₀ values ranging from 9 to 146 μM. On the other hand, all analogs but 11, 12 and 15 quenched the extrinsic fluorescence of the CaM biosensor hCaM-M124C-mBBr to different extent, then revealing different affinities to CaM; their affinity constants (K_m) values were in the range of 3-80 μM. Molecular modeling studies indicated that all these compounds bound to CaM at the same site that the classical inhibitors trifluoperazine (TFP) and chlorpromazine (CPZ). Some of these analogs could be worthy candidates for developing new anti-tumor, local anesthetics, antidepressants, antipsychotic, or smooth muscle relaxant drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis. In addition they could be valuable tools for the study of Ca²⁺-CaM functions.     

Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives

Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4′,3′:-1,2]pyrimido[4,5-b]quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4′,3′:1,2]-pyrimidoquinoline (5a,b, 10), imidazolo[3′,2′:1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline (12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD₅₀ values in the low micromolar to nanomolar concentration range.     

Synthesis and biological activity of 7H-benzo[4,5]indolo[2,3-b]-quinoxaline derivatives

New 7-(2-aminoethyl)-7H-benzo[4,5]indolo[2,3-b]quinoxalines (13-20) were synthesized with high yields starting from 3H-benzo[e]indole-1,2-dione. These compounds were screened for the cytotoxicity, anti-viral activity, interferon inducing ability and DNA affinity compared with the corresponding 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives (1-12). It was shown, that compounds 13-20 bind to DNA stronger (lg К_a = 6.23-6.87) than compounds 1-12 (lg К_a = 5.57-5.89). Anti-viral activity is significantly reduced with annulations of benzene ring in Indoloquinoxaline moiety 13-20.     

Synthesis, anti-inflammatory activity and COX-1/COX-2 inhibition of novel substituted cyclic imides. Part 1: Molecular docking study

A group of cyclic imides (1-13) was designed for evaluation as selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model. Compounds 5b, 6b, 11b, 11c, 12b and 12c were proved to be potent COX-2 inhibitors with IC₅₀ range of 0.1-1.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 5b as a highly potent (IC₅₀ = 0.1 μM), and an extremely selective [COX-2 (SI) = 400] comparable to celecoxib [COX-2 (SI) > 333.3], COX-2 inhibitor that showed superior anti-inflammatory activity (ED₅₀ = 104 mg/kg) relative to diclofenac (ED₅₀ = 114 mg/kg). A Virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Molecular modeling (docking) study showed that the CH₃O substituents of 5b inserted deep inside the 2°-pocket of the COX-2 active site, where the O-atoms of such group underwent a H-bonding interaction with His⁹⁰ (2.43, 2.83 Å), Arg⁵¹³ (2.89 Å) and Tyr³⁵⁵ (3.34 Å). Docking study of the synthesized compound 5b into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.     

Synthesis, cellular uptake, apopotosis, cytotoxicity, cell cycle arrest, interaction with DNA and antioxidant activity of ruthenium(II) complexes

A new ligand and two ruthenium(II) complexes [Ru(bpy)₂(DNPIP)](ClO₄)₂1 and [Ru(bpy)₂(DAPIP)](ClO₄)₂2 were synthesized and characterized. The DNA-binding constants for complexes 1 and 2 were determined to be 2.24 (±0.30) × 10⁵ M⁻¹ (s = 1.29) and 6.34 (±0.32) × 10⁴ M⁻¹ (s = 2.84). The photocleavage of pBR322 DNA by Ru(II) complexes was investigated. The cytotoxicity of complexes 1 and 2 were assessed against three tumor cell lines. The apoptosis and cellular uptake were studied. The retardation assay of pGL 3 plasmid DNA was explored. The cell cycle arrest was analysized by flow cytometry. The antioxidant activities of the ligand and complexes were also investigated.     

Synthesis and selective human monoamine oxidase inhibition of 3-carbonyl, 3-acyl, and 3-carboxyhydrazido coumarin derivatives

Several 3-carbonyl (1-26), 3-acyl (27-52), and 3-carboxyhydrazido (53-58) coumarins have been synthesized in high yields (72-99%) and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory activity. Different substituents on the coumarin nucleus were evaluated for their effect on biological activity and isoform selectivity. Substitution at position C7 of the 3-ethyl ester coumarin ring, or the introduction of a hydrazido substituent at C3, were important to obtain highly potent and selective hMAO-B inhibitors with IC₅₀ values in the nanomolar range. Some derivatives were also submitted to a stability test and showed no chemical cleavage in vitro.     

Bismuth heterocycles based on a diphenyl sulfone scaffold: synthesis and substituent effect on the antifungal activity against Saccharomyces cerevisiae

A series of heterocyclic organobismuth(III) compounds 2 [ClBi(5-R-C₆H₃-2-SO₂C₆H₄-1'-): R = Me, Ph, MeO, Cl, H, t-Bu, CF₃, F, Me₂N] was synthesized in order to study the relative importance of structure and specific substitutions in relation to their lipophilicity and antifungal activity against the yeast Saccharomyces cerevisiae. A clear structure-activity relationship between the size of the inhibition zone and the value of ClogP was found for 2. These results suggest that the higher the lipophilicity, the lower the antifungal activity. Thus, 2e (R = H) and 2h (R = F), which had ClogP values of 1.18 and 1.45, respectively, were most active. In contrast, 2b (R = Ph) and 2f (R = t-Bu) had ClogP values of 3.06 and 3.00, respectively, and exhibited no antifungal activity. Compound 6b ClBi[5-(OH)C₆H₃-2-SO₂-5′-(OH)C₆H₃-1'-] had an estimated ClogP value of 0.81 but exhibited only low activity in spite of its low ClogP value, suggesting that such a considerable decrease in lipophilicity lowers inhibition activity. Bismuth carboxylate 7b derived from p-nitrobenzoic acid and 2e exhibited inhibition activity comparable to those of 2e and 2h despite its higher lipophilicity (ClogP = 2.68).     

Cytotoxic and protective DNA damage of three new diterpenoids from the brown alga Dictoyota dichotoma

Three new diterpenes Amijiol acetate (3), dolabellane, Dolabellatrienol (4), and dolastane, Amijiol-7, 10-diacetate (9) were isolated together with the previously described Pachydictyol A (1), Isopachydictyol A (2), 8β-hydroxypachydictyol A (5), Amijiol (6), Isodictyohemiacetal (7) and Dictyol C (8) from the Red Sea brown alga Dictyota dichotoma var. implexa. The structures and relative stereochemistry of the new diterpenoids were proposed on the basis of their spectral data. Compounds 3 and 9 have potent activity against DNA damage, cytotoxicity against WI-38, HepG2, and MCF-7 cell lines, and antioxidant using ABTS and erythrocytes hemolysis.     

Synthesis, characterization, antiproliferative and anti-metastatic properties of two ruthenium-DMSO complexes containing 2,2'-biimidazole

Two new ruthenium complexes, trans,cis,cis-[RuCl₂(DMSO)₂(H₂biim)] (1) and mer-[RuCl₃(DMSO)(H₂biim)] (2) (DMSO = dimethyl sulfoxide and H₂biim = 2,2′-biimidazole), have been synthesized and fully characterized by single-crystal X-ray analysis. The less stable complex 2 is more cytotoxic against the four human cancer cell lines tested than 1. Further studies show that 1 and 2 exhibit cell growth inhibition by triggering G0/G1 cell cycle arrest and mitochondria-mediated apoptosis. Additionally, complex 2 exerts potent inhibitory effects on the adhesion and migration of human cancer cells comparable to that of NAMI-A ([ImH][trans-[RuCl₄(Im)(DMSO-S)], Im = imidazole). Target validation studies show that cyclin-dependent kinases (CDKs), other than DNA, are more likely to be targets of 1 and 2.     

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

Tetrabenazine (TBZ) ((±)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (±)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (K_i = 4.47 nM) was 8000-fold more potent than (−)-1 (K_i = 36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: K_i = 3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington’s disease and other hyperkinetic disorders.     

Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles 14a-d, 15a-d, 17a, 17b, 18a-d, 19a, and 19b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 2-[3-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) inhibited ALK5 phosphorylation with an IC₅₀ value of 0.013 μM and showed 80% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. part 3

A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT_1A/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT_1A and SERT with K_i ranging from 28,3 to 642 nM and 42,4 nM-1,8 μM, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 8i as an antagonist of 5-HT_1A presynaptic receptors in the inducible hypothermia test in mice.     

Design, synthesis and biological evaluation of novel 4-thiazolidinones containing indolin-2-one moiety as potential antitumor agent

A series of novel 4-thiazolidinone and indolin-2-one hybrid derivatives 5a-5s and 10a-10s have been designed and synthesized and their cytotoxic activities were evaluated in vitro against three human cancer cell lines including HT-29 (human colon cancer), H460 (human lung cancer), MDA-MB-231 (human breast cancer) by MTT assay. Several potent target compounds (5m, 5p, 5s, 10a, 10c-10g, 10m, 10p) were further evaluated against one cancer cell line SMMC-7721 (human liver cancer) and one normal cell line WI-38 (human fetal lung fibroblasts). Most of the prepared compounds exhibited significant antitumor activities against different human cancer cell lines. Compound 10c (IC₅₀ = 0.025 μM, 0.075 μM, 0.77 μM, 1.95 μM) was 52, 36, 4.8 and 3.3 times more active than Sunitinib (IC₅₀ = 1.3 μM, 2.7 μM, 3.7 μM, 6.47 μM) against HT-29, H460, MDA-MB-231 and SMMC-7721 cancer cell line, respectively.