Thiazole–Chalcone Hybrids as Prospective Antitubercular and Antiproliferative Agents: Design,Synthesis, Biological,Molecular Docking Studies and In Silico ADME Evaluation

Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a novel series of thiazole–chalcone hybrids (1–20) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones 12 and 7, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone 20 containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC₅₀ = 11 ± 1 µM) with an IC₅₀ value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.     

Synthesis of Trinorditerpenoid Derivatives and Evaluation of Antimicrobial and Cytotoxic Activity

The synthesis of optically active trinorditerpenes was carried out, and their antimicrobial and antitumor activity was tested. The synthetic derivative 12-hydroxypodocarpa-8,11,13-triene (7) showed GI₅₀ at 6.6 µM against breast cancer MDA-MB-435 (LC₅₀ = 50.9 µM and log10 GI₅₀ = −5.18). The 12-acetyloxypodocarpa-8,11,13-triene (8) showed GI₅₀ at 12.1 µM against leukemia RPMI-8226 (LC₅₀ = 76.1 µM and log₁₀GI₅₀ = −4.92).__________Published in Khimiya Prirodnykh Soedinenii, No. 3, pp. 255–259, May–June, 2005.     

Synthesis and Activity Evaluation of Novel Prenylated Flavonoids as Antiproliferative Agents

Twenty prenylated flavonoids 1-20 were synthesized by glycoside hydrolysis, dehydrogenation, selective O-methylation, O-prenylation and Claisen rearrangement reaction, from abundant and inexpensive natural flavonoids naringin, hespiredin, quercetin and myricetin. Among them, 1-7, 10-15 and 17-20 are novel compounds, the natural product 3,3',4',7-tetramethoxy-8-prenyl-5-hydroxy flavonoid(16) was synthesized in a high yield. Their antiprolirative activities were evaluated in vitro on a panel of three human cancer cell lines(HeLa, HCC1954 and SK-OV-3). The results show that most of the target compounds displayed moderate to potent antiprolirative activities against the three cancer cells with half maximal inhibitory concentration(IC₅₀) values from 0.49 μmol/L to 95.07 μmol/L. Among them, 3',4',7-trimethoxyl-5-hydroxyl-8-prenyl flavonoid(12) exhibited the strongest antiprolirative activity against the three cancer cells mentioned above with IC₅₀ values of 0.91-7.08 μmol/L. 3',7-Dimethoxy-5-O-prenyl flavone(6) and 3',4',7-trimethoxy-5-O-prenyl flavone(10) showed selective antiproliferative activity against HCC1954 cells with IC₅₀ value of 0.49 and 5.32 μmol/L, respectively.     

A Mild and Efficient CH2‐Extrusion Reaction for the Enantiospecific Synthesis of Highly Configurationally Stable Tröger Bases

A novel CH₂‐extrusion reaction leading to the transformation of ethano‐Tröger bases into disubstituted methano derivatives is reported (yields up to 93 %). Under mild and metal‐free oxidative conditions, a loss of CH₂ and a ring contraction are provoked. Despite two bond cleavages at stereogenic nitrogen and carbon centers and a temporary rupture of the bicyclic structure, a very high enantiospecificity (es≥98 %) is observed for this unusual reaction.     

Antiproliferative activities of 2-hydroxyethyl substituted benzimidazolium salts and their palladium complexes against human cancerous cell lines

Abstract

Benzimidazolium salts (1a and 1b) and respective palladium complexes (2a and 2b) were prepared and characterized with ¹H and ¹³C NMR, IR, elemental analysis as well as HRMS (for 2a). All target compounds were screened as potential anticancer agents against human cell lines for assessing their cytotoxicity. Heterocyclic organic compounds (1a and 1b) showed more cytotoxic activity than their complexes (2a and 2b) in the tested two cell lines. Particularly, a benzimidazolium salt including a 4-methylbenzyl group had a high cytotoxic potency towards MDA-MB-231 and DLD-1 cell lines with IC₅₀ values comparable to a well-known anticancer drug cisplatin, which is generally used in clinical studies. Furthermore, a compound namely 1-(2-hydroxyethyl)-3-(2,3,4,5,6-pentamethylbenzyl)-1H-benzo[d]imidazol-3-ium bromide was found to be more cytotoxic activity in MDA-MB-231 cell line compared to cisplatin with following IC₅₀ value of 7.59?±?0.68?μM.     

新型含吡啶基的不对称膦酸酯衍生物的合成与生物活性

通过2-氯-5-氯甲基吡啶与亚磷酸酯的Michaelis-Becker反应合成得到10个新型含吡啶基的不对称膦酸酯衍生物, 并对环状亚磷酸酯与2-氯-5-氯甲基吡啶反应的立体化学进行了研究, 结果表明: 不对称环状亚磷酸酯的电子效应和立体效应对反应的立体化学有着重要影响. 初步的生物活性结果表明, 该类化合物不具有杀虫活性, 但显现出较好的杀菌活性.     

Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioisomers for Antimalarial,Antiproliferative and Antimicrobial Activities

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC₅₀ = 24 nM) than Puromycin (IC₅₀ = 270 nM) and Doxorubicin (IC₅₀ = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).     

Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation-Inhibitory Activity

A synthetic methodology to access all possible stereoisomers of spectomycin A1 (SMA1) and A2 (SMA2) has been established through late-stage diversification. The key reaction for the construction of all four diastereomers is an intramolecular cyclization based on the umpolung of π-allyl palladium species with bis(pinacolato)diborane (B₂(pin)₂). Silyl group assisted direct benzylic oxidation of each isomer enabled construction of the fragile β-hydroxytetralone skeleton to provide the SMAs. The relative and absolute stereochemistry of SMA2 was also determined, and the absolute stereochemistry of SMA1 was extrapolated based on the optical rotation of SMA2. The axial chirality of SMAs is discussed based on circular dichroism spectra and DFT calculations, and it is concluded that the M isomer is predominant in solution. Biochemical assessment of all isomers in vitro revealed that the C9 hydroxyl group and dimeric structure were both important for protein SUMOylation-inhibitory activity.     

新型吲唑-查尔酮杂合物的合成及抗肿瘤活性

设计并合成了一系列新型含查尔酮-吲唑杂合衍生物,并对其体外肿瘤活性进行初步研究。 先以2,6-二氟苯腈和吗啉为起始原料,经过取代和环合两步反应合成4-吗啉-3-氨基-1H-吲唑。 4-吗啉-3-氨基-1H-吲唑与含羧基的查尔酮中间体与经过酰胺化反应制备了9个新型含查尔酮-吲唑杂合衍生物,其结构经傅里叶变换红外光谱仪(FTIR)、核磁共振波谱仪(NMR)、质谱(MS)和元素分析确证。 采用MTT法,以索拉菲尼为阳性对照药,以人胃癌细胞株(MKN45)和人肺癌细胞株(A549)为测试细胞株对目标化合物进行抗肿瘤活性评价。 结果表明,大部分目标化合物显示了较好的抗肿瘤活性,其中化合物4a和4d活性较好,其抑制人胃癌细胞株MKN45的IC₅₀分别为2.65和3.55 μmol/L,均优于阳性对照药索拉菲尼(IC₅₀=4.69 μmol/L)。     

Design,Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C₁ and C₄ on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, ¹H-NMR, ¹³C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents.     

Synthesis of Ultraviolet Absorber Benzotriazole by Nanoparticles Ag/SiO2 Catalytic Hydrogenation

The Ag/SiO2 nanoparticles had been successfully synthesized. The Ag/SiO2 nanoparticles can be an excellent catalyst for the synthesis of ultraviolet absorber benzotriazole by catalytic hydrogenation. The synthesis route is very efficient with less pollution and excellent yields. It is also easy to industrialized production.     

Synthesis and Antiproliferative Effect of Halogenated Coumarin Derivatives

A series of 6- and 6,8-halocoumarin derivatives have been investigated as potential antiproliferative compounds against a panel of tumor and normal cell lines. Cytotoxic effects were determined by the MTT method. To investigate the potential molecular mechanism involved in the cytotoxic effect, apoptosis assay, cell cycle analysis, reactive oxygen species (ROS), and reduced glutathione analysis were performed. Among the screened compounds, coumarins 6,8-dibromo-2-oxo-2H-chromene-3-carbonitrile 2h and 6,8-diiodo-2-oxo-2H-chromene-3-carbonitrile 2k exhibited the most antiproliferative effect in thyroid cancer-derived cells TPC-1. The apoptosis assay showed that both 2h and 2k induced apoptosis in TPC-1 thyroid cancer cells. According to these experiments, both coumarins induced a slight increase in TPC-1 cells in the G2/M phase and a decrease in the S phase. A significant increase in ROS levels was observed in TPC-1 treated with diiodocoumarin 2k, while the dibromocoumarin 2h induced a decrease in ROS in a dose and time-dependent manner.     

Synthesis and pharmacological evaluation of 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles

A fast access to novel 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles 4 was developed using the readily available preclinical candidate BYK 405879 (1) as starting material. The 5-amino function was installed by the Curtius rearrangement of carboxylic acid 2 or by the Hofmann rearrangement of carboxamide 8 furnishing benzimidazole 3 as key intermediate. In the Ghosh Schild rat, some of the target compounds 10-14 showed noteworthy activity as potassium-competitive acid blockers.     

8-O-烯丙基-4,4'-二甲基花椒毒酚的合成及其抗增殖活性

以焦性没食子酸和乙酰乙酸乙酯为原料,经Pechmann反应、Williamson成醚、环化、还原和脱水等反应合成了新化合物8-O-烯丙基-4,4'-二甲基花椒毒酚(5),总收率32.0%,其结构经1H NMR,13C NMR和ESI-MS表征。抗增殖活性测试结果表明:5对人类肝癌细胞Hep G2、结肠癌细胞HCT和子宫癌细胞SA具有一定的抗增殖活性,其中对Hep G2的抑制活性最高,IC50为(27.57±1.00)μmol·L-1。     

Antiproliferative and bactericidal activity of diiron and monoiron cyclopentadienyl carbonyl complexes comprising a vinyl-aminoalkylidene unit

A series of diiron complexes with two cyclopentadienyls, two carbonyls, and one bridging vinyl-aminoalkylidene as ligands, [ 3a – h ]CF₃SO₃ and [ 4a – d ]CF₃SO₃, was synthesized in 66–94% yields from diiron μ-aminocarbyne precursors. The subsequent reactions with pyrrolidine led to selective fragmentation to aminoalkylidene-ferracyclopentenone derivatives ( 5a – h and 6a – c ) in 30–84% yields. The compounds were characterized by elemental analysis, Fourier transform infrared and NMR spectroscopy, and by single crystal X-ray diffraction in three cases. The stability in aqueous media relevant to biological trials, the carbon monoxide release, and the catalytic activity in NADH oxidation were evaluated for selected compounds by NMR spectroscopy and gas chromatography. The in vitro antiproliferative activity of the compounds was determined towards cancer (A2780, A2780cisR) and noncancer (HEK-293) cell lines. Moreover, the antibacterial activity was tested on Gram-positive (vancomycin-resistant E. faecium and methicillin-resistant S. aureus) and Gram-negative strains (A. baumannii and P. aeruginosa).     

Synthesis,Characterization and Evaluation of the Antibacterial and Antitumor Activity of HalogenatedSalen Copper (II) Complexes derived from Camphoric Acid

Platinum metal complexes are the most common chemotherapeutics currently used in cancer treatment. However, the frequent adverse effects, as well as acquired resistance by tumor cells, urge the development of effective alternatives. In the recent past, copper complexes with Schiff base ligands have emerged as good alternatives, showing interesting results. Accordingly, and in continuation of previous studies in this area, three new camphoric acid-derived halogenated salen ligands and their corresponding Cu (II) complexes were synthesized and their antitumor activity was evaluated in order to determine the influence of the type and number of halogens present (Br, Cl). The in vitro cytotoxic activity was screened against colorectal WiDr and LS1034 and against breast MCF-7 and HCC1806 cancer cell lines. The results proved the halogenated complexes to be very efficient, the tetrachlorinated Cu (II) complex being the most promising, presenting IC₅₀ of 0.63–1.09 μM for the cell lines studied. The complex also shows selectivity to colorectal cancer cells compared to non-tumor colon cells. It is worth highlighting that the tetrachlorinated Cu (II) complex, our most efficient complex, shows a significantly more powerful antitumor effect than the reference drugs currently used in conventional chemotherapy. The halogenated salen and corresponding complexes were also screened for their antimicrobial activity against four bacterial species-Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa-and four fungal species-Candida albicans, Candida glabrata, Aspergillus fumigatus and Alternaria alternata. The compounds were found to exhibit moderate to strong antibacterial activity against the bacterial strains studied. NMR studies and theoretical calculations provided some insight into the structure of the ligands and copper complexes. Considering the results presented herein, our work validates the potential use of copper-based chemotherapeutics as alternatives for cancer treatment.     

Synthesis,Characterization, and Antiproliferative Activity of 2-(2-Bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2b][1,2,4]triazoles

Eight new 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles were synthesized by treating 5-(2-bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol with phenacyl bromides. The new products were characterized by spectroscopic and analytical methods. Five of the new compounds were evaluated for their antiproliferative activity. 2-(2-Bromo-5-methoxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3-thiazolo[3,2-b] [1,2,4]triazole exhibited promising activity.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

1,3-取代吲哚-2-酮衍生物的合成与肿瘤细胞毒活性研究

以苯胺为原料,通过肟化、环合生成二氢吲哚-2,3-二酮,再对其进行N-烷基化、亲核加成和磺酰化反应得到目标化合物5a～5g和7a～7e。通过¹H NMR、¹³C NMR确认其结构。采用噻唑蓝（MTT）法测试了目标化合物对乳腺癌细胞MDA-MB-231、鼠黑色素瘤细胞B16、鼠结肠癌细胞CT26三种肿瘤细胞的体外抑制活性。结果表明,化合物7d、7e具有明显的肿瘤细胞毒活性,其中化合物7d对MDA-MB-231的细胞毒活性比阳性药五氟尿嘧啶更强,IC₅₀为4.63±0.14μmol/L。本文结果可为进一步研究具有肿瘤细胞毒活性的吲哚酮类衍生物提供参考。     

22-降-豆甾-22-含氮化合物的合成及抗肿瘤活性

通过结构改造,合成了不同支链的甾体化合物并测定了它们的抗肿瘤细胞增殖活性,探讨了不同支链对抗肿瘤活性的影响。