Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41

A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (?)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (?)-gossypol, oligopeptide derivative of (?)-gossypol and taurine derivative of (?)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (?)-gossypol.     

Cytotoxic benzil and coumestan derivatives from Tephrosia calophylla

A benzil, calophione A, 1-(6′-Hydroxy-1′,3′-benzodioxol-5′-yl)-2-(6″-hydroxy-2″-isopropenyl-2″,3″-dihydro-benzofuran-5″-yl)-ethane-1,2-dione and three coumestan derivatives, tephcalostan B, C and D were isolated from the roots of Tephrosia calophylla. Their structures were deduced from spectroscopic data, including 2D NMR ¹H-¹H COSY and ¹³C-¹H COSY experiments. Compounds were evaluated for cytotoxicity against RAW (mouse macrophage cells) and HT-29 (colon cancer cells) cancer cell lines and antiprotozoal activity against various parasitic protozoa. Calophione A exhibited significant cytotoxicity with IC₅₀ of 5.00 (RAW) and 2.90 μM (HT-29), respectively.     

Identification of a naturally‐occurring 8‐[α‐D‐glucopyranosyl‐(1→6)‐β‐D‐glucopyranosyl]daidzein from cultivated kudzu root

Introduction – Kudzu root (Radix puerariae) is a rich source of isoflavones that are effective in preventing osteoporosis, heart disease and symptoms associated with menopause. The major isoflavonoids in kudzu root extracts were reported as puerarin, daidzin and daidzein. Recently, an unknown isoflavonoid (compound 1) was detected from one‐year‐old kudzu root cultivated in Vietnam. Objective – To identify a novel compound 1 in kudzu root extract and determine the structure of the compound by ESI⁺ TOF MS‐MS, ¹H‐, ¹³C‐NMR and enzymatic hydrolysis. Methodology – Samples were prepared by extraction of one‐year‐old kudzu root with 50% ethanol and the isoflavonoids were purified using recycling preparative HPLC. Unknown compound 1 was detected using UV‐light at 254 nm in TLC and HPLC analyses. The molecular weight of 1 was determined using a TOF mass spectrometer equipped with an electrospray ion source. The structure of 1 was determined from the ¹³C and ¹H NMR spectra recorded at 100.40 and 400.0 MHz, respectively. Results – ESI⁺ TOF MS‐MS analysis shows that 1 is a puerarin diglycoside. The interglycosidic linkage of diglycoside determined by ¹H‐, ¹³C‐NMR, and enzymatic hydrolysis suggests that 1 has a glucosyl residue linked to puerarin by an α‐1,6‐glycosidic bond. This compound is the first naturally‐occurring 8‐[α‐D ‐glucopyranosyl‐(1→6)‐β‐D ‐glucopyranosyl]daidzein in kudzu root. The concentration of glucosyl‐α‐1,6‐puerarin in kudzu root was 2.3 mg/g as determined by HPLC. Conclusion – The results indicate that puerarin diglycoside is one of the major isoflavonoids in kudzu root and has a significant impact on the preparation of highly water‐soluble glycosylated puerarin. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis, double stranded DNA-binding and photocleavage studies of a functionalized ruthenium(II) complex with 7,7′-methylenedioxyphenyldipyrido[3,2-a:2′,3′-c]-phenazine

A new Ru(II) complex [Ru(phen)₂(mdpz)]²⁺ (phen = 1,10-phenanthroline, mdpz = 7,7′-methylenedioxyphenyl-dipyrido-[3,2-a:2′,3′-c]phenazine) has been synthesized and characterized in detail by elemental analysis, mass spectrometry and ¹H NMR spectroscopy. The interaction of the complex with calf thymus DNA was investigated by spectroscopic and viscosity measurements. The results suggest that the complex binds to DNA via an intercalative mode and serves as a molecular “light switch” for DNA. Moreover, the complex has been found to promote the photocleavage of plasmid DNA pBR322 under irradiation at 365 nm. The mechanism studies reveal that singlet oxygen (¹O₂) plays a significant role in the photocleavage.     

Synthesis and characterization of 2-quinoxalinol Schiff-base metal complexes

The reaction of uranyl acetate with (2,2′-(1E,1′E)-(2-benzyl-3-hydroxyquinoxaline-6,7-diyl)bis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene) diphenol) (H₂L1) at room temperature in methanol and chloroform yields the UO₂L1 complex. Crystals were grown through solvent diffusion of the ligand-metal complex in dimethyl formamide with diethyl ether to prepare: UO₂L1 · DMF (1). Complexes with 2,2′-(1E,1′E)-(2-benzyl-3-hydroxyquinoxaline-6,7-diyl)bis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene)dibenzene-1,4-diol (H₂L2) and 2,2′-(1E,1′E)-(2-hydroxy-3-isopropylquinoxaline-6,7-diyl)bis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene)diphenol (H₂L3) were also prepared, and crystals of the uranyl complexes (UO₂L2 · DMF (2) and (3)) grown from DMF/ether. A fourth complex UO₂L4 · H₂O (4) was prepared through layering a solution of the tetra-tert-butyl substituted 2-quinoxalinol salen ligand H₂L4 in acetone with an aqueous solution containing uranyl acetate. The complexes exhibit a symmetric core featuring a slightly distorted bicapped pentagonal geometry around the uranium center with two oxo-groups and two imine groups from the ligand chelating the ligand and the fifth site in the coordination plane of the ligand occupied by a solvent molecule. These compounds have been characterized using solution (NMR and UV-Vis) and solid-state (IR, X-ray crystallography) techniques. Complexes of H₂L4 with early transition metals; Mn²⁺, Co²⁺, Ni²⁺, and Cu²⁺ are also prepared and characterized for comparison of solution and spectroscopic characteristics.     

Inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 macrophage cells by lignans isolated from Euonymus alatus leaves and twigs

The 80% methanolic extract of Euonymus alatus leaves and twigs afforded three new lignans, (−)-threo-4,9,4′,9′-tetrahydroxy-3,7,3′,5′-tetramethoxy-8-O-8′-neolignan (1), (−)-threo-4,9,4′,9′-tetrahydroxy-3,5,7,3′-tetramethoxy-8-O-8′-neolignan (2), (7R,8R,7′R)-(+)-lyoniresinol (3), together with seventeen known lignans (4-20). The structures of 1-20 were elucidated by extensive 1D and 2D spectroscopic methods including ¹H NMR, ¹³C NMR, ¹H-¹H COSY, HMQC, HMBC and NOESY. All the isolated compounds except for dilignans (19 and 20) significantly inhibited nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells.     

Synthesis and anti-H5N1 activity of chiral gossypol derivatives and its analogs implicated by a viral entry blocking mechanism

A series of chiral gossypol derivatives and its analogs were synthesized and tested in vitro for their anti-H₅N₁ activity. Interestingly, (+)-gossypol derivatives and its analogs were more active against H₅N₁ than the corresponding (?)-gossypol derivatives and its analogs. Through a simple chemical modification with amino acids, less active chiral gossypol could be converted into more active derivatives, and most of chiral gossypol derivatives were more potent against H₅N₁ than 1-adamantylamine. With regard to the mechanism of action, chiral gossypol derivatives and its analogs might impair the virus entry step of cell infection, likely targeting to HA2 protein.     

Antidiabetic activity of phenolic compounds from Pecan bark in streptozotocin-induced diabetic rats

The n-butanol fraction (BF) of bark of Pecan tree, Carya illinoinensis (Wangenh) K. Koch (Juglandaceae) afforded two new flavonol methyl ether: caryatin-3′ sulfate (6) and caryatin-3′ methyl ether-7-O-β-d-glucoside (7) while five known phenolics (1–5) were isolated from its ethyl acetate fraction (EAF). The structures of isolated compounds were established based on 1D and 2D NMR spectroscopy. The isolated compounds were investigated for their hypoglycaemic, antioxidant as well as the aldose reductase (AR) inhibitory effect in lenses of streptozocin diabetic rats. All the isolated compounds showed significant hypoglycaemic and antioxidant activities, except 5 and 6. A marked AR-inhibitory effect was identified for compounds 2, 3 and 7.     

Phialomyces macrosporus: Chemical Constituents,Antimicrobial Activity and Complete NMR Assignments for the 7,7′‐Biphyscion

Five known secondary metabolites, chrysophanol ( 1 ), 7,7′‐biphyscion ( 2 ), secalonic acid D ( 3 ), mannitol ( 4 ) and trehalose ( 5 ) were isolated for the first time from the extracts of the fungus Phialomyces macrosporus. Their structures were elucidated by NMR methods (1D and 2D NMR analysis), optical activity and ESI‐MS. Complete ¹H and ¹³C assignments were performed for compound 2 . The antimicrobial activity was evaluated by serial microdilution assay for compounds 2 and 3 and results showed that compound 3 exhibited a significant growth inhibition at concentrations of 15.6 mg/ml (S. aureus and S. choleraesius) and 0.97 mg/mL (B. subtilis), comparable to the positive control.     

Novel 2′-hydroxylfurylchalcones: synthesis and biological activity

Twelve novel 2′-hydroxylfurylchalcones have been synthesized by Claisen-Schmidt condensation with galactosylisomaltol, a reagent prepared from lactose. The procedures are environmentally benign and economical. All the compounds are identified by IR, ¹H NMR and ¹³C NMR spectroscopy and by mass spectrometry. Preliminary bioassays indicate that all the title compounds show moderately high herbicidal activities against the height and/or the fresh weight of the seedlings of cucumber, rape, amaranth, wheat, sorghum and Chinese sprangletop at 7.5 g of active ingredient per hm². However, the compounds exhibit weak fungicidal activities against cucumber powdery mildew, and no activities against rice blast, cucumber grey mould and cucumber downy mildew. The structure-activity relationships are discussed. The present work demonstrates that 2′-hydroxylfurylchalcones could be used as potential lead compounds for further study of novel herbicides.     

The (+)- and (−)-gossypols potently inhibit human and rat 11β-hydroxysteroid dehydrogenase type 2

Gossypol has been proven to be a very effective male contraceptive. However, clinical trials showed that the major side effect of gossypol was hypokalemia. Gossypol occurs naturally as enantiomeric mixtures of (+)-gossypol and (−)-gossypol. The (−)-gossypol is found to be the active component of antifertility. 11β-Hydroxysteroid dehydrogenase 2 (11βHSD2) has been demonstrated to be a mineralocorticoid receptor (MR) protector by inactivating active glucocorticoids including corticosterone (CORT) in rats, and therefore mutation or suppression of 11βHSD2 causes hypokalemia and hypertension. In the present study, the potency of gossypol enantiomers was tested for the inhibition of 11βHSD1 and 2 in rat and human. Both (+) and (−)-gossypols showed a potent inhibition of 11βHSD2 with the half maximal inhibitory concentration (IC₅₀) of 0.61 and 1.33 μM for (+) and (−)-gossypols, respectively in rats and 1.05 and 1.90 μM for (+) and (−)-gossypols, respectively in human. The potency of gossypol to inhibit 11βHSD1 was far less; the IC₅₀ was ≥100 μM for racemic gossypol. The gossypol-induced hypokalemia is likely associated with its potent inhibition of kidney 11βHSD2.     

Synthesis of some imidazolyl-thioacetyl-pyrazolinone derivatives and their antinociceptive and anticancer activities

In this study, some 4-(1,5-diarylimidazol-2-yl)thioacetyl-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one derivatives were prepared by reacting 4-(2-chloroacetyl)-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one and 2-mercapto-1, 5-diarylimidazole derivatives. The antinociceptive and anticancer activities of the compounds obtained were investigated. It was observed that some of the compounds, 2a, 2d, 2g, and 2j, showed remarkable antinociceptive activity, and one of the compounds, 2i, showed weak anticancer activity.     

Synthesis and bioactivity of 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-oxa(thia)diazol-2-amines

A series of new N′-[N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)thiocarbamoyl]-2-[(1-aryl-1H-tetrazol-5-yl)sulfanyl]acetohydrazides 5a–5e were synthesized rapidly in high yields from 2-(1-aryl-1H-tetrazol-5-ylsulfanyl)acetohydrazides 3a–3e and 2,3,4-tri-O-acetyl-β-d-xylopyranosyl isothiocyanate 4, then 5a–5e were converted to a series of new 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-oxadiazole-2-amines 6a–6e and 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-thiadiazole-2-amines 7a–7e, respectively under mercuric acetate/alcohol system or acetic anhydride/phosphoric acid system, then deacetylated in the solution of CH₃ONa/CH₃OH. All of the novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The structures of compounds 2e, 3e, 5a and 5c have been determined by X-ray diffraction analysis. Some of the synthesized compounds displayed PTP1B inhibition and microorganism inhibition.     

Nucleophilic N1 → N3 Rearrangement of 5′-O-Trityl-O2,3′-Cycloanhydrothymidine

Abstract

5′-O-Trityl-O²,3′-cycloanhydrothymidine (1) heated at 150°C in the presence of O,O-diethyl phosphate or O,O-diethyl phosphorothioate anions undergoes rearrangement into N³-isomer (2); its structure was established by both advanced NMR methods and X-ray crystallographic studies. The most probable mechanism of 1→2 rearrangement relies upon reversibility of glycosidic bond cleavage process.     

Design,synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives

Novel N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives were designed, synthesized and their chemical structures were confirmed by ¹H NMR, ¹³C NMR and Mass spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including K562, Colo-205 and MDA-MB 231 by MTT assay. The screening results showed that five compounds (16b, 16d, 16i, 16p and 16q) exhibited potent cytotoxic activities with IC₅₀ values between 20 and 40 μM. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Design and synthesis of antimicrobial,anticoagulant, and anticholinesterase hybrid molecules from 4-methylumbelliferone

We designed and synthesized new series of diverse triazoles, isoxazoles, isoxazolines, and aziridines linked 4-methylumbelliferone 1 using intermolecular 1,3-dipolar cycloaddition reactions. Structures of these compounds were established on the basis of ¹H NMR, ¹³C NMR, and ESI-HRMS. All prepared compounds were evaluated for their antimicrobial, anticoagulant, and anticholinesterase activities. Interestingly, among the tested molecules, some of the analogs displayed better activities than the parent 4-methylumbelliferone 1 such as 6a and 6d for their antifungal properties. Moreover, compounds 4, 5, 6, and 7 showed the importance of the added fragments to 4-methylumbelliferone 1 via the linker methylene to have good activity.     

Structural elucidation of 4'-epiadriamycin by nuclear magnetic resonance spectroscopy and comparison with adriamycin and daunomycin using quantum mechanical and restrained molecular dynamics approach

The structural and electronic properties of 4′-epiadriamycin, adriamycin, and daunomycin have been studied using density functional theory (DFT) employing B3LYP exchange correlation. The chemical shifts of ¹H and ¹³C resonances in nuclear magnetic resonance spectra have been calculated using Gauge-Invariant Atomic Orbital (GIAO) method as implemented in Gaussian 98 and compared with experimental spectra recorded at 500 MHz. ¹³C resonances of drugs have been assigned for the first time. A restrained molecular dynamics approach was used to get the optimized solution structure of drugs using inter-proton distance constraints obtained from 2D NOESY spectra. The glycosidic angle C7-O7-C1′-C2′ is found to show considerable flexibility by adopting 156°-161° (I), 142°-143° (II), and 38°-78° (III) conformations, of which the biological relevant structure appears to be the conformer II. The observed different conformations of the three drugs are correlated to the differential anticancer activity and the available biochemical evidence exhibited by these drugs.     

Versatile coordination behavior of N,N-di(alkyl/aryl)-N′-benzoylthiourea ligands: Synthesis, crystal structure and cytotoxicity of palladium(II) complexes

The synthesis and characterization of Pd(II) complexes with the general formula cis-[Pd(L-O,S)₂] (HL = N,N-diethyl-N′-benzoylthiourea, N,N-diisobutyl-N′-benzoylthiourea or N,N-dibenzyl-N′-benzoylthiourea) and trans-[PdCl₂(HL-S)₂] (HL = N,N-diphenyl-N′-benzoylthiourea, N,N-di-n-butyl-N′-benzoylthiourea or N,N-diisopropyl-N′-benzoylthiourea) are reported. These complexes were formed from the reaction between PdCl₂ and N,N-di(alky/aryl)-N′-benzoylthiourea in acetonitrile with the formulation dependent on the nature of HL. The new Pd(II) complexes have been characterized by analytical and spectral (FT-IR, UV-Vis, ¹H NMR and ¹³C NMR, Mass) techniques. The molecular structures of two of the complexes (1 and 5) have been conformed by X-ray crystallography. Complex 1 shows cytotoxicity against human breast cancer cells.     

Two new lignans with their biological activities in Portulaca oleracea L.

Two new lignans, identified as 6,7-dihydroxy-4-(4′’-hydroxy-3′’-methoxyphenyl)-2-naphthoic acid, named Oleralignan C (1), and 4-(3,4-dihydroxyphenyl)-6-hydroxy-7-methoxy-2-naphthoic acid, named Oleralignan D (2), were obtained from Portulaca oleracea L. The structures were determined by spectroscopic methods, including UHPLC-ESI-QTOFMS, ¹D and ²D NMR. Both Oleralignan C (1) and Oleralignan D (2) inhibited the inflammatory factors, IL-1β and TNF-α in RAW 264.7 cells induced by lipopolysaccharide (LPS). Both compounds also could clear 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals indicating their antioxidant potential.     

Design of vanadium mixed-ligand complexes as potential anti-protozoa agents

In the search for new therapeutic tools against Chagas’ disease (American Trypanosomiasis) four novel mixed-ligand vanadyl complexes, [V^IVO(L²-2H)(L¹)], including a bidentate polypyridyl DNA intercalator (L¹) and a tridentate salycylaldehyde semicarbazone derivative (L²) as ligands were synthesized, characterized by a combination of techniques, and in vitro evaluated. EPR suggest a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and the polypyridyl ligand coordinated in an equatorial/axial mode. Both complexes including dipyrido[3,2-a: 2′,3′-c]phenazine (dppz) as polypyridyl coligand showed IC₅₀ values in the μM range against Dm28c strain (epimastigotes) of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal reference drug Nifurtimox. To get an insight into the trypanocidal mechanism of action of these compounds, DNA was evaluated as a potential parasite target and EPR, and ⁵¹V NMR experiments were also carried out upon aging aerated solutions of the complexes. Data obtained by electrophoretic analysis suggest that the mechanism of action of these complexes could include DNA interactions.