Quinolinesulfonamides: Interaction between bovine serum albumin,molecular docking analysis,and antiproliferative activity against human breast carcinoma cells

The complex formation of bovine serum albumin (BSA) with library of all seven regioisomeric quinolinesulfonamides (QSAs) under physiological condition is studied in this paper. The fluorescence quenching mechanism of BSA by QSAs was discussed and the association constants, as well as the number of binding sites, were calculated. In addition, a molecular docking study of the tested sulfamoylquinolines on the active site of serum albumin is performed. The experimental data and molecular docking studies reveal that sulfamoylquinolines bind in the large hydrophobic cavity of subdomain IB, and in the hydrophobic pockets of BSA subdomains IIA and IIIA by hydrophobic interactions with tryptophanyl (Trp-213) and tyrosyl residues. Moreover, the antiproliferative activity of QSAs against two human breast cancer cell lines (human adenocarcinoma (MCF-7) and human ductal carcinoma (MDA-MB-231)) and a human normal fibroblast is also studied in this paper. The antiproliferative activity of the tested QSAs was comparable to those of cisplatin. The returned data indicate that some of the tested quinolinesulfamoyl derivatives display significant cytotoxic activity.     

Nanoencapsulation of hydroxytyrosol in chitosan crosslinked with sodium bisulfate tandem ultrasonication: Techno-characterization,release and antiproliferative properties

This research includes production of chitosan nanocapsules through ionic gelation with sodium bisulfate for nanoencapsulation of hydroxytyrosol (HT) using ultrasonication in tandem. The resulting nanocapsules encapsulating HT were analyzed for particle size, ζ-potential, packaging characteristics, FESEM, ATR-FTIR, XRD, DSC, in vitro release, antioxidant potential and antiproliferative properties. The nanocapsules (size 119.50–365.21 nm) were spherical to irregular shaped with positive ζ-potential (17.50–18.09 mV). The encapsulation efficiency of 5 mg/g HT (HTS1) and 20 mg/g HT (HTS2) was 77.13% and 56.30%, respectively. The nanocapsules were amorphous in nature with 12.34% to 15.48% crystallinity and crystallite size between 20 nm and 27 nm. Formation of nanocapsules resulted in increasing the glass transition temperature. HTS2 delivered 67.12% HT (HTS1 58.89%) at the end of the simulated gastrointestinal digestion. The nanoencapsulated HT showed higher antioxidant and antiproliferative (against A549 and MDA-MB-231 cancer cell lines) properties than the free HT.     

Synthesis and biological evaluation of glycosides containing triazene-chalcones

By combining triazenes with chalcones, we designed and synthesized 12 novel glycosides. The antiproliferative activity of all products was screened using an MTT assay against MGC803 cells and PC-3 cells. Compound \(\mathbf{2b}_{6}\) displayed more potent antiproliferative activity than dacarbazine. Furthermore, we explored the preliminary structure activity relationship of all target compounds. The derivatives in this work might serve as bioactive fragments and lead compounds for developing more potent cytotoxic agents.     

Antioxidative and antiproliferative activities of novel pyrido[1,2-<Emphasis Type="Italic">a</Emphasis>]benzimidazoles

A series of pyrido[1,2-a]benzimidazoles has been designed, and novel examples are synthesized and evaluated for their potential antiproliferative activity against four human tumour cell lines—cervical (HeLa), colorectal (SW620), breast (MCF-7) and hepatocellular carcinoma (HepG2). In addition, their antioxidative potency has been evaluated by in vitro spectrophotometric assays. Preliminary structure–activity relationships among the synthesized compounds are discussed. Evaluation of their antioxidative capacity has shown that two compounds (25 and 26) possess promising reducing characteristics and free radical scavenging activity. Selective antiproliferative effect in the single-digit micromolar range was observed for compound 25 on MCF-7 \((\hbox {IC}_{50} = 6\,{\upmu }\hbox {M})\) and HeLa \((\hbox {IC}_{50} = 8\,{\upmu }\hbox {M})\) cell lines, comparable to the standards 5-fluorouracil and cisplatin. The combination of the radical scavenging activity and antiproliferative activity of compound 25 positions this compound as a potential lead candidate for further optimization.     

Bis‐4,9‐diazapyrenium dications: synthesis of the methylenedibenzyl‐analogue,interactions with nucleotides,DNA, RNA. The antitumour activity of all till now prepared analogues

Novel bis‐4,9‐diazapyrenium dication has shown reversible pH dependent formation of 4,9‐ diazapyrenium pseudobase in water characteristic for most 4,9‐diazapyrenium derivatives. The compound has formed non‐covalent complexes with nucleotides in water, whose stability is controlled dominantly by aromatic stacking interactions. No cooperativity between two 4,9‐diazapyrenium subunits was observed in binding of nucleotides. Novel bis‐4,9‐diazapyrenium dication formed mono‐intercalative complexes with studied double stranded DNA and RNA. Additional interactions of non‐intercalated part were found to depend significantly on the polynucleotide secondary structure, yielding strong DNA over RNA preference. Appearance of ICD band of 3 was found to be specific for DNA polynucleotides and together with observed destabilisation of double stranded RNA is attributed to the aggregation of compound in one of the RNA grooves. All bis‐4,9‐diazapyrenium dications prepared till now have shown considerable antiproliferative activity against five human tumour cell lines, which suggested mechanism of action by interacting with cell DNA. Copyright © 2007 John Wiley & Sons, Ltd.     

Microwave-assisted synthesis of a novel class of imidazolylthiazolidin-4-ones and evaluation of its biological activities

The synthesis and biological activity of a hitherto unknown class of compounds, the imidazolylthiazolidin-4-ones, are described. A two-step procedure has been elaborated starting from our previously described 2-aminoimidazoles. The application of microwave irradiation has been proven to be beneficial for the condensation of the imine with mercaptoacetic acid leading to the formation of imidazolylthiazolidin-4-ones. None of the compounds showed antiviral activity at subtoxic concentrations. Several compounds displayed a moderate cytostatic activity. These data form the basis for further improvement of the potential antiproliferative activity of this class of compounds.     

Targeting and deep-penetrating delivery strategy for stented coronary artery by magnetic guidance and ultrasound stimulation

Stent placement is an effective treatment for atherosclerosis, but is suffered from in-stent restenosis (ISR) caused by stent mechanical damage. Conventional ISR treatment such as drug-eluting stents (DES) is challenged by the low therapeutic efficacy and severe complications, unchangeable drug dosage for individuals, and limited drug penetration in the vascular tissue. We hypothesize that magnetic targeting and deep-penetrating delivery strategy by magnetic guidance and ultrasound stimulation might be an effective approach for ISR treatment. In the present study, antiproliferative drug (paclitaxel, PTX) loaded poly (lactide-co-glycolide) (PLGA) nanoparticles (PLGA-PTX) were embedded within the shells of the magnetic nanoparticle coated microbubbles (MMB-PLGA-PTX). Once being targeted to the stent under a magnetic field, a low intensity focused ultrasound (LIFU) is applied to activate stable microbubble oscillations, thereby triggering the release of PLGA-PTX. The generated mechanical force and microstreaming facilitate the penetration of released PLGA-PTX into the thickened vascular tissue and enhance their internalization by smooth muscle cells (SMCs), thereby reducing the clearance by blood flow. In an ex vivo experiment, magnetic targeting improved the accumulation amount of MMB-PLGA-PTX by 10 folds, while the LIFU facilitated the penetration of released PLGA-PTX into the tunica media region of the porcine coronary artery, resulting in prolonged retention time at the stented vascular tissue. With the combination effects, this strategy holds great promise in the precision delivery of antiproliferative drugs to the stented vascular tissue for ISR treatment.     

Ring-closing metathesis as key step in the synthesis of Luffarin I, 16-<Emphasis Type="Italic">epi</Emphasis>-Luffarin I and Luffarin A

Natural sesterterpenolides, luffarin I and luffarin A, from Luffariella geometrica have been synthesized, and this is the first reported synthesis of luffarin A. The Yamaguchi esterification of the nor-diterpenic fragment, obtained from 2.8–15 \(\upmu \)M, with the appropriate furane alcohols yielded the necessary diene intermediates for the synthesis of the target molecules. The key strategic step in this synthesis was the ring-closing metathesis (RCM) reaction of the diene intermediates. This strategy allowed for the synthesis of 16-epi-luffarin I and analogues for structure–activity relationship (SAR) studies. The most active compound exhibited antiproliferative activity against a panel of six human solid tumour cell lines with \(\hbox {GI}_{50}\) values in the range 2.8–15 M.     

类呋喃香豆素的合成与DNA的结合及细胞毒性研究

呋喃香豆素类化合物无紫外光辅助照射时抗肿瘤活性低,为提高其正常情况下的抗肿瘤活性,依据“最小嵌入”假说对其进行结构改造。把呋喃香豆素结构中的呋喃环拆分出来,使其与香豆素由原来稠环相并的结合方式转变为通过化学键相连,得到合成简化的类呋喃香豆素。利用DNA熔解曲线、吸收光谱、荧光发射光谱和粘度测试考察了这些类呋喃香豆素与DNA的相互作用。综合DNA溶解曲线、光谱法和粘度测试的结果,推测除目标产物5b是一DNA嵌入剂外,其他化合物嵌入DNA能力下降,5a以部分嵌入方式与DNA结合,5c和5d是通过极为少见、鲜有报道的“桥型结构”与DNA相结合。利用“罗丹明B蛋白染色法”考察了目标化合物的体外细胞毒性,测试结果显示,与对照品补骨脂素相比这些化合物对肿瘤细胞体外生长抑制作用明显增强,并且非经典嵌入结合的化合物活性增强更明显。该研究拓展了“最小嵌入”假说的应用范围,同时为呋喃香豆素类化合物结构改造提供了依据。     

Solid-phase synthesis of model libraries of 3 α17β-dihydroxy-16α-(aminoethyl-N-substituted)-5α-androstanes for the development of steroidal therapeutic agents

The solid-phase synthesis of 16-derivatives of 5-androstane-3,17-diol with one, two or three levels of molecular diversity was accomplished using the diethylsilyloxy linker. Libraries with one level of diversity (10 members) and two levels of diversity (40 members) were synthesized in a parallel fashion in good yields and acceptable HPLC purities for the majority of library members. Compounds with three levels of diversity (15 pools) were realized in a split and pool fashion to allow further deconvolution by the positional scanning method. The screening of the generated model libraries revealed interesting preliminary structure–activity relationships related to their antiproliferative activities on androgen-sensitive Shionogi cells. In the case of the two-level library, the presence of a hydrophobic amino acid at R₁ (isoleucine (Ile) or phenylalanine (Phe)) and a six-membered ring (aromatic or not) at R₂ seems an important requirement for activity. In the three-level library, the amino acid residues isoleucine and phenylalanine clearly provided a better antiproliferative activity than glycine (Gly) and proline (Pro). These model libraries will serve as basis for the generation of larger libraries of peptidosteroids toward the development of therapeutic agents.     

Crystal Structures, Interactions with Biomacromolecules and Anticancer Activities of Mn(II), Ni(II), Cu(II) Complexes of Demethylcantharate and 2-Aminopyridine

Three novel transition metal complexes (Hapy)(2)[M(DCA)(2)]·6H(2)O (M?=?Mn(II) (1), Ni(II) (2), Cu(II) (3); DCA?=?demethylcantharate, 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylate, C(8)H(8)O(5); Hapy?=?2-aminopyridine acid, C(5)H(7)N(2)) were synthesized and characterized by elemental analysis, infrared spectra, thermogravimetric analysis and X-ray diffraction. DNA binding properties of the complexes were investigated by electronic absorption spectra, fluorescence spectra and viscosity measurements. Results indicated the complexes could bind to DNA through partial intercalation mode with binding constants K ( b )/(L·mol(-1)) of 1.91?×?10(4) (1), 5.13?×?10(4) (2) and 1.12?×?10(5) (3) at 298?K. Meanwhile, the interactions of the complexes with BSA were also studied by fluorescence spectra. The results suggested that the complexes could quench the fluorescence of BSA through static quenching with the binding constants K ( A )/(L·mol(-1)) of 1.44?×?10(6) (1), 1.14?×?10(7) (2) and 2.98?×?10(4) (3). And the main contribution was tryptophan residues of BSA. The antiproliferative activity test revealed that complexes showed more intense inhibition ratios against human hepatoma cells lines and human gastric cancer cells lines in vitro. Copper(II) complex (3) possesses the strongest inhibition ratio against human hepatoma cells.     

Energy-dispersive X-ray fluorescence – A tool for interdisciplinary research

Trace elements have been at the focus of attention for decades with considerable emphasis on their role in biology and biomedical sciences, environmental sciences, geology, archaeology and material sciences. They comprise a large number of elements, some having essential physiological functions, whereas others are toxic, mutagenic or carcinogenic. A few even have antiproliferative and anticarciniogenic properties. The advent of various instrumental techniques and sophisticated instrumentations has made their detection to very low limits possible, making this a very important multidisciplinary study. Among these techniques the energy-dispersive X-ray fluorescence (EDXRF) technique is being widely used for trace element detection in various fields of science. Keeping the importance of trace elements in mind, the Kolkata centre of UGC-DAE Consortium for Scientific Research initiated several research schemes in different fields of trace element research using various techniques, EDXRF being one of the main techniques. A Xenemetrix (erstwhile Jordan Valley) EX 3600 EDXRF spectrometer is being used to carry out the research. This presentation aims to highlight some of the very recent applications of EDXRF in the study of the role of trace elements in pre-cancerous tissues, medicinal plants and also in some environmental studies.     

Antiproliferative and antiinflammatory coxib–combretastatin hybrids suppress cell cycle progression and induce apoptosis of MCF7 breast cancer cells

In our study, some newly synthesized aryl-substituted pyrazole derivatives mimicking cis-diphenylethylene scaffold of two apoptotic inducing agents celecoxib and combretastatin A-4 were found to have strong antiproliferative as well as antiinflammatory activities. Among these coxib–combretastatin hybrids, two lead compounds 8 and 6c simultaneously inhibited prostaglandin E2 (PGE2) production in LPS-activated murine macrophage RAW 264.7 cells and suppressed cell cycle progression of MCF7 cells at G2/M or G0/G1 phases, but only compound 8 induced apoptosis via caspase-3 activation. Both the lead compounds showed good docking energies with both protein targets COX-2 and tubulin in the molecule interaction modeling. The cis-diphenylethylene scaffold of celecoxib or combretastatin A-4 as well as functional groups such as the ethyl ester group and the sulfonamide could be considered as potential key features for the dual activity of studied compounds meanwhile the trimethoxybenzene remained the crucial characterization of the newly derived compounds of combretastatins.

     

Synthesis and evaluation of functionalized indoles as antimycobacterial and anticancer agents

A new series of 5-fluoro-N(2)-(cyclohexylidene)-3-phenyl-1H-indole-2-carbohydrazides (6a-6e) and their cyclization products 5-fluoro-N-(3-oxo-1-thia-4-azaspiro [4.5]dec-4-yl)-3-phenyl-1H-indole-2-carboxamides (7a-7e, 8a-8e) have been synthesized and evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using the Microplate Alamar Blue Assay (MABA). Compounds showed moderate to good inhibitory activity at 6.25 μg/mL. Among them, 7b, 7d, 8b, and 8d were the most potent analogs with an inhibition range of 91-95?%. Additionally, compounds 6a, 7a, 7e, 8a, and 8e were subjected to the National Cancer Institute's (NCI) in vitro disease-oriented antitumor screening to be evaluated for antitumor activity. 8e, the most potent compound examined, displayed broad spectrum antiproliferative activity with particular selectivity against four leukemia cell lines (CCRF-CEM, HL-60 (TB), K-562, and RPMI-8226) with log (10) GI (50) values between -5.68 and -6.09.     

Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition,and an evaluation of their antiproliferative activities in vitro

Efficient synthesis of novel 16-spiroisoxazolines in the androst-5-ene series was carried out by 1,3-dipolar cycloadditions of different aryl nitrile oxides to 3 \(\upbeta \) -acetoxy-16-methylene-androst-5-en-17-one. During the intermolecular ring closures, the attack of the O terminus of the nitrile oxide dipole from the \(\upalpha \) side on C-16 predominated for steric reasons permitting the reactions to occur in a regio- and stereoselective manner. The minor isomers in which the angular methyl group on C-13 and the O atom of the isoxazoline heteroring were in the \(\upbeta \) , \(\upbeta \) -cis orientation were obtained in a yield of only \(\sim \) 10 %. Moreover, the conversions were influenced to a certain extent by the substituents on the aromatic moiety of the 1,3-dipoles. The stereostructures of the related diastereomers were confirmed by 2D NMR methods. Deacetylation of the primarily formed main products resulted in the corresponding 3 \(\upbeta \) -OH analogs, which were further reduced to furnish 3 \(\upbeta \) , 17 \(\upbeta \) -diols. All of the synthetized compounds were subjected to in vitro pharmacological studies in order to investigate their antiproliferative effects on three malignant human adherent cell lines (HeLa, MCF7, and A431).     

Libraries of 2β-(N-substituted piperazino)-5α-androstane-3α, 17β-diols: chemical synthesis and cytotoxic effects on human leukemia HL-60 cells and on normal lymphocytes

Libraries of steroid derivatives with two levels of molecular diversity were prepared to optimize the antiproliferative activity on leukemia HL-60 cells by first varying the amino acid (AA) at R¹ (libraries A, B, C, and D: with 45, 45, 20, and 20 members, respectively) and, subsequently, the capping group at R² (library E: 168 members). The screening of these aminosteroids revealed interesting structure–activity relationships. In library A, the compounds bearing a tetrahydroisoquinolone residue as the first element of diversity showed potent cytotoxicity, principally when isovaleric or cyclohexyl acetic acid was used as a capping group (>40% of cell growth inhibition at 1 μM). In library B, the phenylalanine (Phe) derivatives bearing a cyano group induced a higher growth inhibition than the other Phe derivatives. The screening of library C indicated the increase of hydrophobicity of proline (Pro) seems to preserve the cytotoxic effect achieved by the lead compound. However, the synthesis of structural Pro variants (library D) clearly shows weaker activities when compared to L-Pro building blocks. Finally, by incorporating some of the most active AA of libraries A–D in library E, we observed that the amide coupling functionality gave stronger cytotoxic activity compared to the corresponding sulfonamides or benzylamines. Six of the most active amide derivatives (E-37P, E-41P, E-42P, E-46P, E-48F, and E-12T) were selected and IC₅₀ determined on HL-60 cells as well as on normal human lymphocytes. Among this series of new anticancer agents, good to high selectivity indices (SI = IC₅₀ (lymphocytes)/IC₅₀ (HL-60 cells) = 5 - 55) were obtained.     

Synthesis, Characterization, DNA-Binding and Antiproliferative Activity of Nd(III) Complexes With N-(Nitrogen Heterocyclic) Norcantharidin Acylamide Acid

Three novel complexes [Nd(L)(NO₃)(H₂O)₂]·NO₃·2H₂O (HL¹ = N-pyrimidine norcantharidin acylamide acid, C₁₂H₁₃N₃O₄; HL² = N-pyridine norcantharidin acylamide acid, C₁₃H₁₄N₂O₄; HL³ = N-phenyl norcantharidin acylamide acid, C₁₄H₁₅NO₄) were synthesized. HL¹, HL² and HL³ are the ligand of complex(1), complex(2) and complex(3), respectively. Their structures were characterized by elemental analysis, conductivity measurement, infrared spectra and thermogravimetric analysis. The DNA-binding properties of the complexes have been investigated by fluorescence spectroscopy and viscosity measurements. The results suggest that the complexes can bind to DNA by partial intercalation. The liner Stern-Volmer quenching constant K_sq values are 3.3(±0.21)(1), 1.7(±0.19)(2) and 0.9(±0.04)(3), respectively. Complex (1) and (2) have been found to cleave pBR322 plasmid DNA at physiological pH and temperature. The test of antiproliferation activity indicates that complex(1) has strong antiproliferative ability against the SMMC7721 (IC₅₀ = 131.7 ± 23.4 μmol·L⁻¹) and A549 (IC₅₀ = 128.4 ± 19.9 μmol·L⁻¹) cell lines. The inhibition rates of complex(2) (IC₅₀ = 86.3 ± 11.3 μmol·L⁻¹) are much higher than that of NCTD (IC₅₀ = 115.5 ± 9.5 μmol·L⁻¹) and HL² (111.0 ± 5.7 μmol·L⁻¹) against SMMC7721 cell lines.     

Substituted <Emphasis Type="Italic">N</Emphasis>-aminothioglycolurils containing thiosemicarbazone moiety and their cytotoxic activity in vitro

A library of hybrid molecules bearing thioglycoluril and (hetero)aromatic aldehyde thiosemicarbazone moieties was synthesized via a tandem hydrazone formation—ring contraction reaction of 5,7-dialkyl-3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (hetero)aromatic aldehydes. All synthesized compounds were tested for their cytotoxic activity against rhabdomyosarcoma, A549, and MS human cancer cell lines by MTT-assay. Among the derivatives, (E)-4-benzylideneamino-1,3-dimethyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one 1f was found to have the most marked antiproliferative activity toward the tested cell lines (1f: IC\(_{50}= 20.6,\) 23.7, and 6.4 \(\upmu \)M, respectively). The IC\(_{50}\) value of thioglycoluril 1f against normal human embryonic kidney cells HEK293 was 72.5 \(\upmu \)M, which appeared to be 3–11-fold higher than IC\(_{50}\) values of 1f against human cancer cells.     

Cytotoxic and radiosensitizing effects of nano-C<Subscript>60 </Subscript>on tumor cells in vitro

There is growing evidence in recent years that the pristine fullerene may be endowed with strong pro-oxidant capacity to biological samples. In this investigation we tested the hypothesis that water-soluble fullerene-C₆₀ (nano-C₆₀) may interact with ionizing radiation enhancing its antiproliferative effects. The two tumor cell lines with different radiosensitivity B16 and SMMU-7721 were treated by a combination of pristine fullerene and ⁶⁰Co γ irradiation. We measured cell survival rates, apoptotic characteristics, reactive oxygen species (ROS) production and alteration of cell diameter with or without γ-irradiation. There was reduced survival with B16 and SMMU-7721 cells exposed to nano-C₆₀, with the inhibitory concentrations reducing the viability by 50% to 65 part per billion (ppb) and 150 ppb respectively. For cells exposed to nano-C₆₀ prior to γ-irradiation, damage to cell membranes and increased numbers of apoptotic cells were detected by morphologic Hoechst-staining analysis and Annexin V/propidium iodide double-staining. In cells exposed to nano-C₆₀, there were increased levels of ROS, as measured by fluorescence detection under laser confocal microscopy. Preincubation with non-toxic pristine C₆₀ before γ-ray caused enlargement of cells with increased diameter. The results show that nano-C₆₀ inhibits the growth of tumor cells at certain concentrations and increases the effects of ⁶⁰Co γ-irradiation, possibly through the elevated production of cellular ROS and the membrane disruption. Data in this study indicates a possible consideration of using C₆₀ as a candidate of sensitization modifier in tumor radiation biology.     

Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity

A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a–4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a–2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a–3f. Treatment of 2a–2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a–4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC₅₀?=?9.5 μM (SI?=?6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of >?4.09 μM and could be a promising antiproliferative agent.