Synthesis and Anti‐tumor Evaluation of B‐ring Modified Caged Xanthone Analogues of Gambogic Acid

Gambogic acid (GA, 1 ), the most prominent member of Garcinia natural products, has been reported to be a promising anti‐tumor agent. Previous studies have suggested that the planar B ring and the unique 4‐oxa‐tricyclo[4.3.1.0^3,7]dec‐2‐one caged motif were essential for anti‐tumor activity. To further explore the structure‐activity relationship (SAR) of caged Garcinia xanthones, two new series of B‐ring modified caged GA analogues 13a – 13e and 15a – 15e were synthesized utilizing a Claisen/Diel‐Alder cascade reaction. Subsequently, these compounds were evaluated for their in vitro anti‐tumor activities against A549, MCF‐7, SMMC‐7721 and BGC‐823 cancer cell lines by MTT assay. Among them, 13b – 13e exhibited micromolar inhibition against several cancer cell lines, being approximately 2–4 fold less potent in comparison to GA. SAR analysis revealed that the peripheral gem‐dimethyl groups are essential for maintaining anti‐tumor activity and substituent group on C1 position of B‐ring has a significant effect on potency, while modifications at C‐2, C‐3 and C‐4 positions are relatively tolerated. These findings will enhance our understanding of the SAR of Garcinia xanthones and lead to the development of simplified analogues as potential anti‐tumor agents.     

Synthesis and biological evaluations of mono‐ and bis‐ferrocene uracil derivatives

Mono‐ ( 3a – 3e and 4a – 4e ) and bis‐ferrocene ( 5a – 5e and 6a – 6e ) conjugated 5‐substituted uracil derivatives that are bridged by 1,2,3‐triazole linker were synthesized. The impact of ferrocene unit and spacer between ferrocene and triazole on radical scavenging potency was observed. Bis‐ferrocenyl uracil derivatives exhibited better antiproliferative activities than their mono‐ferrocenyl analogs. Bis‐ferrocenyl methyl‐ ( 5b ) and halogen‐substituted ( 5e , 6c , and 6d ) uracil derivatives showed pronounced and selective cytostatic activities on colon adenocarcinoma (CaCo‐2) and Burkitt lymphoma (Raji) cells, with higher potency and selectivity than the reference drug 5‐fluorouracil. Generation of reactive oxygen species (ROS) in CaCo‐2 and Raji cells when treated with compounds 5b , 5e , and 6d was observed. Bis‐ferrocenyl 5‐chlorouracil 6c induced significant disruption in mitochondrial membrane potential that is accompanied by activation of apoptosis in CaCo‐2, Raji, and acute lymphoblastic leukemia (CCRF‐CEM) cells, while 6d caused mitochondrial dysfunction and apoptosis induction in CaCo‐2 and Raji cells. Potent antiproliferative activity of 6c and 6d could be associated with mitochondrial membrane potential disruption accompanied by apoptosis induction. Our findings highlighted 6c and 6d with potent and selective antiproliferative activity on CaCo‐2, Raji, and CCRF‐CEM cells that may be associated with targeting cancer cell mitochondria, as a molecular target.     

Cyclic Voltammetric Study of Some Anti‐Chagas‐Active 1,4‐Dioxidoquinoxalin‐2‐yl Ketone Derivatives

The electrochemical properties of 24 1,4‐dioxidoquinoxalin‐2‐yl ketone derivatives with varying degrees of anti‐Chagas activity were investigated in the aprotic solvent dimethylformamide (DMF) by cyclic voltammetry and first‐derivative cyclic voltammetry. For this group of compounds, the first reduction in DMF was either reversible or quasireversible and consistent with reduction of the N‐oxide functionality to form the radical anion. The second reduction process for these compounds was irreversible under the conditions used. The reduction potentials correlated well with molecular structure. Substitution in the 3‐, 6‐, and 7‐ positions of the quinoxaline ring by electron‐withdrawing substituents directly affected the ease of reduction and improved the biological activities of these compounds, whereas substitution by electron‐donating groups had the opposite effect. The electrochemical results, when combined with previous work on their mechanism of action against Chagas disease and their measured anti‐Chagas activities, indicated that the quinoxaline 1,4‐dioxide system serves as a promising starting point for chemical modifications aimed at improving the T. cruzi activity via a possible bioreduction mechanism.     

Regenerable Antioxidants—Introduction of Chalcogen Substituents into Tocopherols

To improve the radical‐trapping capacity of the natural antioxidants, alkylthio‐, alkylseleno‐, and alkyltelluro groups were introduced into all vacant aromatic positions in β‐, γ‐ and δ‐tocopherol. Reaction of the tocopherols with electrophilic chalcogen reagents generated by persulfate oxidation of dialkyl dichalcogenides provided convenient but low‐yielding access to many sulfur and selenium derivatives, but failed in the case of tellurium. An approach based on lithiation of the appropriate bromo‐tocopherol, insertion of chalcogen into the carbon‐lithium bond, air‐oxidation to a dichalcogenide, and final borohydride reduction/alkylation turned out to be generally applicable to the synthesis of all chalcogen derivatives. Whereas alkylthio‐ and alkylseleno analogues were generally poorer quenchers of lipid peroxyl radicals than the corresponding parents, all tellurium compounds showed a substantially improved radical‐trapping activity. Introduction of alkyltelluro groups into the tocopherol scaffold also caused a dramatic increase in the regenerability of the antioxidant. In a two‐phase lipid peroxidation system containing N‐acetylcysteine as a water‐soluble co‐antioxidant the inhibition time was up to six‐fold higher than that recorded for the natural antioxidants.     

4‐Hydroxy‐3‐carboxycoumarin as an efficient building block for new ruthenium(II) complexes: synthesis,characterization, antibacterial,antioxidant and anti‐inflammatory activities

A new 4‐hydroxy‐3‐carboxycoumarin ligand and its ruthenium(II) complexes ( 1 – 5 ) have been synthesized, characterized and screened for their in vitro antibacterial activity against a range of Gram‐positive and Gram‐negative bacteria. In addition, compounds 1 – 5 were investigated for antioxidant activities using superoxide radical, 2,2‐diphenyl‐1‐picrylhydrazyl radical and hydroxyl radical scavenging assays, in which most of them displayed significant antioxidant activities. Furthermore, compounds 1 – 5 were evaluated for anti‐inflammatory activity using indirect haemolytic and lipoxygenase inhibition assays and revealed good activity. The new complexes were characterized using spectroscopic methods in addition to elemental analysis.     

Synthesis and Antibacterial Activity of Some New 2,5‐Disubstituted‐1,3,4‐oxadiazole Derivatives

Synthesis of some new oxadiazole derivatives starting from 1,2,3-benzo[d]triazole-1-acetic hydrazide (1) is described. The target compounds 2-(N-substituted-aminocarbonylmethylthio)-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (4a—4i) and 2-[2-(N-substituted-aminocarbonyl)ethylthio]-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (5a—5i) were obtained in good yields via cyclisation of 1 and subjected to antibacterial activity test against pathogenic bacteria. The halogen containing mono- and di-substituted derivatives showed excellent antibacterial activity compared to other analogues.     

Structure‐cytotoxicity relationship for apoptotic inducers organotin(IV) derivatives of mandelic acid and L‐proline and their mixed ligand complexes having enhanced cytotoxicity

Structure‐cytotoxicity relationship of di?/tri‐organotin(IV) derivatives of mandelic acid ( 1 – 4 ), L‐proline ( 5 – 7, 15, 16 ), and mixed ligand complexes of latter with 1,10‐phenanthroline ( 8 – 14 ) investigated on the basis of MTT assay against human cancer cell lines, viz. MCF‐7 (mammary cancer), HepG2 (liver cancer) and PC‐3 (prostate cancer) in vitro indicated that all complexes except methyl‐ and octyl‐ analogues displayed potential cytotoxicity. The most active one is dibutyltin(IV) mandelate ( 2 ) exhibiting IC₅₀ 2.03 ± 0.40, 0.98 ± 0.23 and 3.86 ± 1.68 μM against MCF‐7, HepG2 and PC‐3, respectively, which is ≈ 15 and 2.5 times against MCF‐7, 20 and 5 times against HepG2 and 5 and ≈ 3 times against PC‐3 more cytotoxic than cis‐platin and 5‐fluorouracil, respectively. Diorganotin(IV) derivatives of mandelic acid are more cytotoxic than triorganotin analogues. Organotin(IV) derivatives of L‐proline (except Bu₃Sn(Pro) 16 ) are less cytotoxic than those of mandelic acid but their cytotoxicity is enhanced by complexion with 1,10‐phenanthroline. This may be due to the structural planarity and extended π system of 1,10‐phenanthroline which facilitates their transportation across the cell membrane and enhances the possibility of DNA intercalation over the planar L‐proline ring, and eventually, their DNA binding affinity so as to interfere with the cellular functions of DNA leading to apoptosis. Various biophysical experiments such as DNA fragmentation, acridine orange and comet assays, and flow cytometry assay using annexin V–fluorescein isothiocyanate (FITC) and propidium iodide (PI) have been carried out in order to ascertain their mode of action. The observed results indicated that the major cause of cancer cell death is apoptosis, but a minor role played by necrosis cannot be excluded. It is concluded on the basis of the observed results that the nature and number of organic groups bonded to tin as well as the nature of counter anions play an important role in determining the cytotoxicity of organotin(IV) compounds.     

Synthesis and catalytic performance of ferrocene‐based compounds as burning rate catalysts

To overcome migration problems of ferrocene‐based burning rate catalysts and to enhance burning rate of ammonium perchlorate (AP)‐based propellants, eleven ferrocene‐based compounds ( 1 – 11 ) were synthesized by the condensation reaction of ferrocenecarbonyl chloride with corresponding amines and alcohols. The synthesis of 1 – 11 was confirmed using ¹H NMR, Fourier transform infrared and UV–visible spectroscopy. Their electrochemical properties were analyzed using cyclic voltammetry. The compounds showed redox behavior due to the presence of ferrocene. Their catalytic behavior in the thermal decomposition of AP was investigated using thermogravimetry (TG) and differential TG (DTG). In the presence of 5 wt% 1 – 11 , the thermal decomposition temperature of AP was significantly decreased. TG and DTG analyses showed that 1 – 11 had a good catalytic effect in the thermal decomposition of AP. Anti‐migration studies showed that migration of 1 – 11 was slower than that of 2,2‐bis(ethylferrocenyl)propane (catocene) and ferrocene. The effect of the presence of polar elements like oxygen and nitrogen on anti‐migration behavior of small ferrocene‐based compounds was also investigated. Oxygen‐containing compounds showed better anti‐migration behavior than nitrogen‐containing compounds.     

Anti‐tumor platinum (IV) complexes bearing the anti‐inflammatory drug naproxen in the axial position

The role of inflammation in cancer generation is gaining importance in the field of cancer research. The chemo‐anti‐inflammatory strategy that involves using non‐steroidal anti‐inflammatory drug compounds as effective anti‐tumor agents is being acceded globally. In the present study, seven new Pt (IV) complexes based on cisplatin, carboplatin and oxaliplatin scaffold bearing the anti‐inflammatory drug naproxen in the axial position were synthesized and characterized by elemental analysis, ESI‐MS, Fourier transform‐infrared, ¹H‐ and ¹⁹⁵Pt‐NMR spectroscopy. The reduction behavior in the presence of ascorbic acid was studied using high‐performance liquid chromatography. The cytotoxicity against two human breast cell lines and the anti‐inflammatory properties were evaluated. All the complexes are able to promote a comparable activity, with average three‐ and 13‐fold more cytotoxic than cisplatin against MCF7 and MDA‐MB‐231 cell lines, respectively. The complexes show remarkable anti‐inflammatory effects, which indicated their potential in treating cancer associated with inflammation and reducing side‐effects of chemotherapy.     

One‐Pot Regioselective Synthesis of Novel Oximino Ester‐Containing 1‐Aryl‐4‐chloro‐3‐oxypyrazoles as Potential Fungicides

A novel, functional‐group‐tolerant, and highly regioselective one‐pot synthesis of six 4‐chloro‐1‐aryl‐3‐oxypyrazoles, 8a – 8f , containing an oximino ester moiety has been developed. Their structures were characterized by ¹H‐ and ¹³C‐NMR, IR, MS, and elemental analyses. The regioselectivity of the reaction was also determined by single‐crystal X‐ray diffraction analysis of product 8d . The reaction pathway, proposed with the aid of DFT calculations, likely proceeds via a DMF‐catalyzed mechanism, which involves an electrophilic attack by SOCl₂ and two nucleophilic substitutions by benzyl bromide (BnBr) and Cl^?, respectively, as the key steps. A preliminary in vitro bioassay indicated that most compounds exhibited good fungicidal activities against Sclerotinia sclerotiorum and Gibberella zeae. Especially, 8d and 8e displayed higher or similar fungicidal activities compared with pyraclostrobin at the concentration of 10 μg/ml.     

Design and Synthesis of 2‐(5‐Phenylindol‐3‐yl)benzimidazole Derivatives with Antiproliferative Effects towards Triple‐Negative Breast Cancer Cells by Activation of ROS‐Mediated Mitochondria Dysfunction

Benzimidazole derivatives are widely studied because of their broad‐spectrum biological activity, such as antitumor properties and excellent fluorescence performance. Herein, two types of 2‐(5‐phenylindol‐3‐yl)benzimidazole derivatives ( 1 a – 1 h and 2 a – 2 e ) were rationally designed and synthesized. When these compounds were investigated in vitro anti‐screening assays, we found that all of them possessed antitumor effect, in particular compound 1 b , which showed an outstanding antiproliferative effect on MDA‐MB‐231 cells (IC₅₀≈2.6 μm ). A study of the drug action mechanisms in cells showed that the antitumor activity of the compounds is proportional to their lipophilicity and cellular uptake; the tested compounds all entered the lysosome of MDA‐MB‐231 cells and caused changes in the levels of reactive oxygen species (ROS), and then caused mitochondrial damage. Apparent differences in the ROS levels for each compound suggest that the lethality of these compounds towards MDA‐MB‐231 cells is closely related to the ROS levels. Taken together, this study not only provides a theoretical basis for 2‐(5‐phenylindol‐3‐yl)benzimidazole anticarcinogens but also offers new thinking on the rational design of next‐generation antitumor benzimidazole derivatives.     

Synthesis,anti‐proliferative activity,SAR, and kinase inhibition studies of thiazol‐2‐yl‐ substituted sulfonamide derivatives

A series of novel thiazol‐2‐yl substituted‐1‐sulfonamide derivatives were synthesized from anilines. This involved the coupling of sulfonyl chlorides with thiazol amine to obtain the final compounds 7a – 7j and 8a – 8j . All synthesized compounds were screened for anticancer activity against MCF‐7, HeLa, A‐549, and Du‐145 cancer cell lines by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Preliminary bioassay suggests that most of the compounds show anti‐proliferation to different degrees, with doxorubicin used as positive control. The synthesized compounds show IC₅₀ values in the range 2.74–8.17 μM in the different cell lines. The compounds 7d , 7e , 8a , 8d , and 8e were active compared to doxorubicin. The compounds having butyl and pantyl chains were more active than their lower and higher carbon chains and also their ring counterparts.     

Flavonoids Isolated from Heat‐Processed Epimedium koreanum and Their Anti‐HIV‐1 Activities

Systematic phytochemical investigation on heat‐processed Epimedium koreanum led to the isolation of 13 flavonoids, including five new prenyl‐flavonol glycosides, koreanosides A–E ( 1 – 5 , resp.). Their structures were elucidated on the basis of detailed analysis of the 1D‐ and 2D‐NMR spectroscopic data and chemical reactions. Apigenin ( 11 ) exhibited moderate anti‐HIV‐1 activity with an EC₅₀ value of 12.8±3.27 μg/ml.     

Synthesis,Characterization and Migration of Ionic Polyferrocenyl Compounds of 5‐Ferrocenyl‐1H‐tetrazole and Their Effects During Combustion

Eighteen ionic polyferrocenyl compounds with 5‐ferrocenyl‐1H‐tetrazolate as anion and mono‐ and dinuclear ferrocenyl‐alkylammonium as cations were synthesized and characterized by ¹H NMR, ¹³C NMR, FT‐IR, and UV/Vis spectroscopy, and elemental analysis. Molecular structures of three compounds were further confirmed by single‐crystal X‐ray diffraction. Their thermal stability was evaluated by TG and DSC and found that they are of high thermal stability. The cyclic voltammetry analysis suggested that each of the compounds exhibits only an irreversible redox wave of the ferrocene units in the molecule. Both migration and volatility test results showed that, on comparison with those of Catocene, all tested compounds exhibit much more excellent anti‐migration ability and most of the tested compounds have lower volatility. Their effects on the thermal disintegration of ammonium perchlorate (AP), 1,3,5‐trinitro‐1,3,5‐triazacyclohexane (RDX), and 1,2,5,7‐tetranitro‐1,3,5,7‐tetraazacyclooctane (HMX) were measured by DSC. The results revealed that most of the compounds exhibit significant catalytic effects on the thermal degradation of AP and RDX. Particularly, most of the compounds containing one ferrocene unit in their cations show higher activity than that of Catocene. These compounds can be used as alternatives to Catocene in the composite solid propellants.     

Synthesis and ABTS Radical,MMP‐1 Inhibitory Activity of CAPE Analogues

In the photoaging process of skin, the ultraviolet (UV)‐induced reactive oxygen species (ROS) is the key regulator of matrix metalloproteinase (MMPs) expression. In this study, a series of Caffeic acid phenethyl ester (CAPE) analogues were synthesized by conjugating the group VI elements (selenium, sulfur, oxygen)‐containing aliphatic alcohols to polyphenolic acids. Their biological activities were evaluated by in vitro testing of their radical scavenging activity the of ABTS [2,2′‐azinobis‐(3‐ethyl‐benzothiazoline‐6‐sulfonic acid)] radical and inhibitory effect against the matrix metalloproteinase‐1 (MMP‐1) activity of collagen degradation and cytotoxicity of a human dermal fibroblast skin cell. Our results suggest these compounds displayed moderate anti‐free radical, potent MMP‐1 inhibitory, and low cytotoxic activities.     

Diastereoselective Electrophilic Amination of Chiral 1‐Benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one for the Asymmetric Syntheses of α‐Substituted α,β‐Diaminopropanoic Acids

The chiral compounds (R)‐ and (S)‐1‐benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one ((R)‐ and (S)‐ 1 ), derived from (R)‐ and (S)‐asparagine, respectively, were used as convenient starting materials for the preparation of the enantiomerically pure α‐alkylated (alkyl=Me, Et, Bn) α,β‐diamino acids (R)‐ and (S)‐ 11 – 13 . The chiral lithium enolates of (R)‐ and (S)‐ 1 were first alkylated, and the resulting diasteroisomeric products 5 – 7 were aminated with ‘di(tert‐butyl) azodicarboxylate’ (DBAD), giving rise to the diastereoisomerically pure (≥98%) compounds 8 – 10 . The target compounds (R)‐ and (S)‐ 11 – 13 could then be obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.     

The first crystal structures of six‐ and seven‐membered tellurium‐ and nitrogen‐containing (Te—N) heterocycles: 2H‐1,4‐benzotellurazin‐3(4H)‐one and 2,3‐dihydro‐1,5‐benzotellurazepin‐4(5H)‐one

There is a paucity of data concerning the structures of six‐ and seven‐membered tellurium‐ and nitrogen‐containing (Te—N) heterocycles. The title compounds, C₈H₇NOTe, (I), and C₉H₉NOTe, (II), represent the first structurally characterized members of their respective classes. Both crystallize with two independent molecules in the asymmetric unit. When compared to their sulfur analogs, they exhibit slightly greater deviations from planarity to accommodate the larger chalcogenide atom, with (II) adopting a pronounced twist‐boat conformation. The C—Te—C angles of 85.49 (15) and 85.89 (15)° for the two independent molecules of (I) were found to be somewhat smaller than those of 97.4 (2) and 97.77 (19)° for the two independent molecules of (II). The C—Te bond lengths [2.109 (4)–2.158 (5) Å] are in good agreement with those predicted by the covalent radii. Intermolecular N—H...O hydrogen bonding in (I) forms centrosymmetric R₂²(8) dimers, while that in (II) forms chains. In addition, intermolecular Te...O contacts [3.159 (3)–3.200 (3) Å] exist in (I).     

Facile Synthesis,Single‐Crystal Structure,and Biological Evaluation of Novel Pyrazolo[5,1‐d][1,2,5]triazepin‐4‐ones

A facile ring‐enlargement reaction of 2,6‐diphenyl‐4H‐pyrazolo[5,1‐c][1,4]oxazin‐4‐one is described, generating the pyrazolo[5,1‐d][1,2,5]triazepin‐4‐ones in good yields. Structures of the prepared compounds were determined on the basis of IR, ¹H‐ and ¹³C‐NMR, and HR‐MS data. Moreover, the molecular structure was confirmed by the X‐ray crystal‐structure analysis of one compound that was prone to crystallization. Preliminary biological evaluation showed that the compounds 2e – 2h promote the viability and inhibit the apoptosis of vascular endothelial cells at low concentration.     

Three New, 1‐Oxygenated ent‐8,9‐Secokaurane Diterpenes from Croton kongensis

Three new ent‐8,9‐secokaurane diterpenes, kongensins A–C ( 1 – 3 ), were isolated from the aerial parts of Croton kongensis, together with two known compounds, rabdoumbrosanin ( 4 ) and (7α,14β)‐7,14‐dihydroxy‐ent‐kaur‐16‐en‐15‐one ( 5 ). The structures of the new compounds were elucidated by HR‐MS as well as in‐depth 1D‐ and 2D‐NMR analyses. Compounds 1 – 3 showed an unusual oxygenation pattern, with an AcO or OH group at C(1), in combination with a Δ⁸⁽¹⁴⁾ unsaturation ( 1 ) or an 8,14‐epoxide function ( 2, 3 ).     

Design,Synthesis and Antitumor Activity of Asymmetric Bis(s‐triazole Schiff‐base)s Bearing Functionalized Side‐Chain

1‐Amino‐2‐pyrid‐3‐yl‐5‐(2‐benzoylethylthio)‐s‐triazole ( 1 ) was condensed with 1‐amino‐3‐mercapto‐5‐ [(un)substituted phenyl]‐s‐triazoles and subsequently substituted with chloroacetic acid to afford bis‐s‐triazole sulfanylacetic acid mono‐Schiff bases ( 3a – 3e ), which were condensed with 9‐formylanthracene to produce asymmetric bis(s‐triazole Schiff base) sulfanylacetic acids ( 4a – 4e ). The structures of new synthesized compounds were characterized by elemental analysis and spectral data, and their in vitro antitumor activity against L1210, CHO and HL60 cell lines was evaluted via the respective IC₅₀ values by methylthiazole trazolium (MTT) assay.