Synthesis and anticancer activity of para-xylyl linked bis-benzimidazolium salts and respective Ag(I) N-heterocyclic carbene complexes

The article describes synthesis, characterization (NMR, FT-IR, microanalysis, X-ray crystallography), and in vitro anticancer activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag–NHC complexes. All the compounds were tested for their cytotoxicity against human colorectal cancer (HCT 116) and promyelocytic leukemia (HL-60) cell lines. According to cell viability measurements using MTT assay, all tested compounds showed dose-dependent cytotoxic activity against both cell lines. The tested compounds demonstrated significant activity with IC₅₀ values range 0.01–18.7 μM for HCT 116 and 0.7–55.7 μM for HL-60 cells. 5-Fluorouracil was used as standard drug (IC₅₀ 19.2 μM for HCT 116 and 5.4 μM for HL-60). We found that as the size of N-alkyl substitution on benzimidazolium salt increases its cytotoxicity decreases whereas a reverse occurred in case of respective complexes.     

Two new compounds from the broth of the marine fungus Penicillium griseofulvum Y19-07

Two new compounds, 4-hydroxyphenethyl methyl succinate (1) and 4-hydroxyphenethyl 2-(4-hydroxyphenyl)acetate (2), were isolated from the EtOAc extract of the broth of the marine fungus Penicillium griseofulvum Y19-07. Five known compounds were also obtained in this study. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopy and mass spectrometry. All of the isolates were evaluated for their scavenging properties toward the 2,2-diphenyl-1-picrylhydrazyl free radical by spectroscopic assays. Also, in the cytotoxicity assay of the two new compounds against HL-60 and PC-3 prostate cancer cell lines, compound 2 showed potential activity with an IC₅₀ value of 64.5 μM against human HL-60 cancer cells.     

Design, synthesis, and biologic evaluation of some novel N-arylpyrazole derivatives as cytotoxic agents

A novel series of N-arylpyrazole derivatives (5a–5d, 7a–7c) has been designed and synthesized via aromatic substitution reaction of N-nonsubstituted pyrazoles with 4-fluoronitrobenzene in the presence of base. The structures of these compounds were established on the basis of elemental (C, H, and N) and spectral analysis (¹H NMR, ¹³C NMR, HRMS, and FT-IR). All the compounds were tested for their cytotoxic activity in vitro against four human tumor cell lines: carcinoma (Bel-7402), nasopharyngeal carcinoma (KB), immature granulocyte leukemia (HL-60), and gastrocarcinoma (BGC-823) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The results showed that most of the obtained compounds exhibited promising cytotoxicity against tested carcinoma cell lines with low IC₅₀ values. The bis-pyrazole derivative 7c, bearing alkoxy group on the 5-position of phenyl ring, was the most effective one. It is inhibition of cell growth of Bel-7402 cells was 1.5-fold higher than that found for cisplatin. And, also mono-pyrazole derivatives 5a and 5b, decorated with trifluoromethyl group on the phenyl ring, displayed better cytotoxicity than that of cisplatin against Bel-7402 cell line.     

Cytotoxicity and Structure-activity Relationships of Naphthyridine Derivatives in Human Cervical Cancer,Leukemia, and Prostate Cancer

Naphthyridine compounds are important, because they exhibit various biological activities including anticancer, antimicrobial, and anti-inflammatory activity. Some naphthyridines have antimitotic effects or demonstrate anticancer activity by inhibiting topoisomerase II. These compounds have been investigated as potential anticancer agents, and several compounds are now part of clinical trials. A series of naphthyridine derivatives were evaluated for their in vitro cytotoxic activities against human cervical cancer (HeLa), leukemia (HL-60), and prostate cancer (PC-3) cell lines using an MTT assay. Some compounds (14, 15, and 16) were more potent than colchicine against all three human cancer cell lines and compound (16) demonstrated potency with IC₅₀ values of 0.7, 0.1, and 5.1 µM, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used for quantitative structure-activity relationship (QSAR) molecular modeling of these compounds. We obtained accurate and predictive three-dimensional QSAR (3D-QSAR) models as indicated by the high PLS parameters of the HeLa (q², 0.857; r², 0.984; r²_pred, 0.966), HL-60 (q², 0.777; r², 0.937; r²_pred, 0.913), and PC-3 (q², 0.702; r², 0.983; r²_pred, 0.974) cell lines. The 3D-QSAR contour maps suggested that the C-1 NH and C-4 carbonyl group of the naphthyridine ring and the C-2 naphthyl ring were important for cytotoxicity in all three human cancer cell lines.     

Comparative cytotoxicity of 2,3,9-trimethoxypterocarpan in leukemia cell lines (HL-60, Jurkat,Molt-4, and K562) and human peripheral blood mononuclear cells

The purpose of this study was to investigate the antiproliferative activity of 2,3,9-trimethoxypterocarpan, a known pterocarpan with cytotoxic activity against many tumor cell lines, in a panel of four leukemia cell lines (HL-60, Molt-4, Jurkat, and K562) and on human peripheral blood mononuclear cells (PBMC). The pterocarpan showed IC₅₀ ranging from 0.1 to 0.5 μg/ml at leukemic cells after 72 h of incubation, with K562 being the most resistant cell line. This compound seemed to be selective to tumor cell lines, since at a concentration of 10 μg/ml after 72 h, it only reduced 19% of viable peripheral mononuclear cells.     

Steroid constituents from the soft coral Sinularia microspiculata

A methanol extract of the soft coral Sinularia microspiculata revealed five sterols, including two new compounds. Using combined chromatographic and spectroscopic experiments, the new compounds were found to be 7-oxogorgosterol (1) and 16α-hydroxysarcosterol (2). Their structures were determined on the basis of spectroscopic data (¹H and ¹³C NMR, HSQC, HMBC, ¹H-¹H COSY, NOESY, and FT-ICR-MS) and by comparing obtained results to the values indicated in previous studies. Among the isolated compounds, 3 showed weak cytotoxic effects against HL-60 (IC_50? = 89.02 ± 9.93?μM) cell line, whereas 5 was weakly active against HL-60 (IC_50? = 82.80 ± 13.65?μM) and SK-Mel2 (IC_50? = 72.32 ± 1.30?μM) cell lines.     

Two new triterpenoid acids from <Emphasis Type="Italic">Kadsura coccinea</Emphasis>

An investigation of EtOAc extracts of Kadsura coccinea (Lem.) A. C. Smith, has led to the isolation of two new compounds characterized as 3-hydroxy-12-hydroxyl coccinic acid (1) and 3-hydroxy-neokadsuranic acid A (2). Their structures were established by 1D and 2D NMR techniques and mass spectroscopy. Antiproliferative effects of the isolated compounds were evaluated against four human tumor cell lines (A549, HCT116, HL-60 and HepG2), and it was found that compound 1 exhibited antiproliferative effects with IC₅₀ values ranging from 3.01 to 18.08 μg/mL.     

Cytotoxic Compounds from Brucea mollis

Ten compounds, including soulameanone (1), isobruceine B (2), 9-methoxy-canthin-6-one (3), bruceolline F (4), niloticine (5), octatriacontan-1-ol (6), bombiprenone (7), α-tocopherol (8), inosine (9), and apigenin 7-O-β-D-glucopyranoside (10), were isolated from the leaves, stems, and roots of Brucea mollis Wall. ex Kurz. Their structures were determined using one-and two-dimensional NMR spectroscopy and mass spectrometry. All compounds were evaluated for their cytotoxic activity against KB (human carcinoma of the mouth), LU-1 (human lung adenocarcinoma), LNCaP (human prostate adeno-carcinoma), and HL-60 (human promyelocytic leukemia) cancer cell lines. Compound 2 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC₅₀ values of 0.39, 0.40, 0.34, and 0.23 μg/mL, respectively. In addition, compounds 3 and 5 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC₅₀ values around 1–4 μg/mL. Compounds 9-methoxycanthin-6-one (3) and niloticine (5) have been discovered for the first time from the Brucea genus.     

Synthesis and cytotoxic evaluation of novel N-substituted amidino-1-hydroxybenzimidazole derivatives

A new class of N-substituted amidino-1-hydroxybenzimidazole derivatives (15–24) were synthesized and evaluated for their in vitro cytotoxic activities against human leukemia cell lines, HL-60 and K562. The preliminary results showed that compounds 16, 20, 21 and 23 had moderate antitumor activity against HL-60 cell line. Further investigation on the mechanism of the observed cytotoxic effects demonstrated that compound 21 increased the expression of autophagic and apoptotic genes and induced apoptosis of HL-60 cells.     

有机锡化合物抗肿瘤生物活性研究

有机锡(IV)化合物能明显地抑制大鼠脑组织中PKC活性和肿瘤细胞增殖，且两者之间存在着相关性。抗肿瘤活性的构效关系是：(1)有机基团R决定整个化合物的生物活性，Ph>Et>n-Bu；(2)卤素的电负性影响化合物活性的大小。抗肿瘤活性可能通过[snR₂]²⁺实现。并能部分地阻断HL-60细胞周期中的G_I期向S期的移行。[SnPh₂F₂]，[SnPh₂(CysOS)]H₂O和[SnPh₂Cl2·phen(CH₃)₂]对PKC的IC₅₀值分别为25，15和20 umol·L^-1，对HL-60细胞的IC₅₀值分别为0．5，4．0和0．3umol·L^-1。但它们无诱导分化HL-60和K562细胞的作用。     

那可丁衍生物合成及其作为微管干扰药物的生物学评估(英文)

以2-羟基-3-甲氧基苯甲醛为原料,经13步反应合成了26个那可丁衍生物。以HL-60细胞为靶细胞,采用MTT法进行了初步的体外抗肿瘤活性研究。结果表明,大多数化合物对HL-60细胞株显示出较好的抑制活性和对微管聚合的抑制作用。优选出的化合物31对HL-60细胞株以及微管聚合的抑制活性是那可丁的3倍并诱导HL-60细胞在G2/M期累积,这为那可丁及其衍生物的抗肿瘤活性构效关系的研究打下了基础,值得进一步研究。     

Cytotoxic activity assessment and c-Src tyrosine kinase docking simulation of thieno[2,3-b] pyridine-based derivatives

Thienopyridine derivatives possess various promising biological properties and particularly cytotoxic effect. In vitro cytotoxic activities of some thienopyridine analogous were evaluated by MTT reduction assay in three human cancer cell lines (HL-60, MCF-7, and LS-180). The compounds showed a wide range of cytotoxic activities and their IC₅₀ values ranged from 0.2 to 100 μM and above. Compound 4e was the most potent derivative and 4i showed good cytotoxic activity against all three cell lines (IC₅₀ <20 μM). Docking simulation of thienopyridine derivatives was implemented on c-Src tyrosine kinase involved in tumor progression and metastases. Results showed that these compounds might potentially bind to the key amino acid Thr339 in the c-Src tyrosine kinase active site. Ligand efficiency (LE) values calculated by using free binding energies obtained from experimental data were predicted by the docking study. Also, experimental and predicted LEs were in good agreement. Based on the LE indices and other findings, some of the thienopyridine derivatives might be efficient candidates for further development as anticancer agents.     

Synthesis and cytotoxicity of triterpenoids derived from betulin and betulinic acid via click chemistry

In this study, a series of triazole substituted betulin and betulinic acid derivatives was designed and synthesized via click chemistry at C-30 position. Eighteen target compounds were evaluated in vitro for their antitumor activities against leukemia cell-line HL-60. Seventeen compounds have not reported before. The cytotoxic experiment showed that most of betulinic acid derived triazoles have higher cytotoxic profile than betulinic acid. Among them, compound 30-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl] betulinic acid (7b) showed the best IC₅₀ value (1.3 μM) against leukemia cell-line HL-60 (eight- to ninefold higher potency than betulinic acid).     

Synthesis and biological evaluation of novel AM80 derivatives as antileukemic agents

A series of novel AM80 derivatives as antileukemic agents were synthesized and their structures were confirmed by IR, ¹H-NMR, and HR-MS spectra. All the target compounds were evaluated for in vitro antiproliferative activities against human leukemic HL-60, NB4, and K562 cell lines. Among these derivatives, compound 4g showed much stronger antiproliferative activities against all the three human leukemic cell lines than the positive control AM80, and compound 4b exhibited more active antiproliferative effects against HL-60 and K562 cells than AM80. Furthermore, the preliminary SAR analysis suggested that AM80 conjugating with HDAC inhibitors with small steric hindrance could give more effective antileukemic agents. These results would be helpful to design more potent antileukemic drugs for the treatment of human leukemia.     

Antiproliferative effect of alkaloids via cell cycle arrest from Pseuduvaria rugosa

Context: Pseuduvaria rugosa (Blume) Merr. (Annonacaea) grows widely in the south and southeast regions of Thailand. Preliminary screening for biological activities revealed that crude hexane, ethyl acetate, and acetone extracts from mixtures of leaves and twigs of P. rugosa showed cytotoxicity.

Objective: Chemical constituents and their antiproliferative activity in K562, U937, and HL-60 human leukemic cell lines from P. rugosa were performed for the first time.

Materials and methods: The isolated compounds were obtained from chromatographic separation. The structures were established by spectroscopic techniques including IR, UV, NMR together with 2D NMR (HMBC, COSY, and NOE) and MS. The K562, U937, and HL-60 cell lines were treated with isolated aporphine alkaloids (0–100 µg/mL) and cell viability was measured with the MTT assay. Cell cycle analysis was performed using propidium iodide (PI) based staining methods.

Results: Two known aporphine alkaloids, 1,2,3-trimethoxy-5-oxonoraporphine (1) and ouregidione (2) were isolated. Treatment of the cells with compounds 1 and 2 at a concentration of 100 µg/mL for 72?h reduced the viability of K562, U937, and HL-60 cell lines to 63 and 64, 38 and 66, and 49 and 64%, respectively. In addition, compounds 1 and 2, at a concentration of 100 µg/mL, exposed to U937 and HL-60 cell lines showed cell cycle arrest. The U937 cell line treated with compounds 1 and 2 increased significantly the proportion of the cell in S phase, whereas the HL-60 cell line-induced G2/M and G1 phase, respectively.

Discussion and conclusion: The results showed that 1,2,3-trimethoxy-5-oxonoraporphine and ouregidione-induced cytotoxicity with HL-60, U937, and K562 cells where 1,2,3-trimethoxy-5-oxonoraporphine was more active than ouregidione.     

Synthesis and cytostatic properties of structure-simplified analogs of dolastatin 15*

Abstract: The linear peptide dolastatin 15 ( 1 ), a potent antineoplastic constituent from the shell-less mollusk Dolabella auricularia, has been selected as the lead compound for developing novel antitumor drugs. Recently LU103793 ( 2 ), a synthetic and structure-simplified analog of dolastatin 15, has been demonstrated to be highly cytotoxic [IC₅₀ = 0.1 nm ; M. De Arruda, C.A. Cocchiaro, C.M. Nelson, C. M. Grinnel, B. Janssen, A. Haupt & T. Barlozzari (1995) Cancer Res. 55 , 3085–3092]. Both compounds have been undergoing human cancer clinical trials in Europe and North America. Based on the novel structure of LU103793, a series of analogs modified at the N-terminal dolavalyl moiety and -Pro-Pro-benzylamide unit was developed. These synthesized analogs were tested using a sulforhodamine B (SRB) assay for the drug-screening program at NCI on a variety of human cancer cell lines. As expected, most analogs exhibited potent and selective growth inhibition against leukemia. Analog 18 was specifically active against HL-60 and K-562 cell lines (GI₅₀s: 0.05 µm and 0.07 µm , respectively) while analogs 14 and 17 were selectively potent against prostate and breast cancer cell lines (GI₅₀s at micromolar levels). However, all analogs were less potent than 2 as growth inhibitors of some breast and colon cancer cell lines (e.g. MDA-MB-435 and HT-29). We believe that modification of novel marine natural products as synthetic analogs might show particular promise for developing novel anticancer candidates with moderate specificity.     

Synthesis, evaluation and docking studies on steroidal pyrazolones as anticancer and antimicrobial agents

A series of new steroidal pyrazolones have been synthesized, characterised and evaluated for their in vitro anticancer activity. They were tested against five cancer (SW480, HepG2, A549, HeLa and HL-60) cell lines. The synthesized compounds showed high selectivity and compound 4 showed the strongest inhibitory activity against human SW480 (IC₅₀ = 11.67 μmol L^?1). In addition, the synthesized compounds were tested for their antimicrobial activity by disc diffusion assay and MIC by broth micro dilution method against Gram-positive, Gram-negative strains of bacteria as well as fungus strains and we found a correlation between the observed and predicted antimicrobial activities. Docking studies were performed to investigate the hypothetical binding mode of the target compounds. This study provided a new molecular scaffold for the further development of anticancer as well as antimicrobial agents.     

Synthesis,cytotoxicity, and DNA-binding property of berberine derivatives

9-Substituted berberine derivatives (4a–4f) with polyethylene glycol side chain and terminal group were synthesized and characterized by elemental (C, H, and N) and spectral analysis (NMR, HRMS and FTIR). These compounds were tested for their in vitro cytotoxic activity against four human tumor cell lines: granulocyte leukemia (HL-60), gastrocarcinoma (BGC-823), carcinoma (Bel-7402), and nasopharyngeal carcinoma (KB) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The DNA-binding properties were investigated by UV–Vis absorption, fluorescence, CD spectroscopies, and thermal denaturation measurements. The results indicated that 4a–4f exerted cytotoxic effects with selectivity against tested cell lines. 4a exhibited higher cytotoxicity than cisplatin, berberine, and berberrubine against HL-60 and BGC-823 cell lines. The length of side chains and nature of terminal groups played an important role in the cytotoxicity. Berberine derivatives binded to CT-DNA in an intercalating mode. The binding affinities decreased with the increasing length of side chains. Compounds 4a–4c and 4e could change the DNA conformation from B to A-like form.     

Design and synthesis of new tetrandrine derivatives and their antitumor activities

A series of tetrandrine derivatives were designed and synthesized using Suzuki coupling reaction. Eleven targeted compounds with over 50% inhibition against HL60 and A549 human cancer cell lines at 10 μM were further evaluated for the in vitro antitumor activities by MTT or SRB assay. The biological results revealed that some compounds exhibited potent antitumor activities. Thiophene derivative 6 and acetylphenyl derivative 5 were the most active ones against HL60 and A549 cell lines, with IC₅₀ values less than 5 μM, which thus could be considered as useful candidate for further development of new antitumor agents.