Cytotoxic Activity and Quantitative Structure Activity Relationships of Arylpropyl Sulfonamides

B13 is a ceramide analogue and apoptosis inducer with potent cytotoxic activity. A series of arylpropyl sulfonamide analogues of B13 were evaluated for their cytotoxicity using MTT assays in prostate cancer PC-3 and leukemia HL-60 cell lines. Some compounds (4, 9, 13, 14, 15, and 20) showed stronger activities than B13 in both tumor cell lines, and compound (15) gave the most potent activity with IC₅₀ values of 29.2 and 20.7 µM, for PC-3and HL-60 cells, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed to build highly reliable and predictive CoMSIA models with cross-validated q² values of 0.816 and 0.702, respectively. Our results suggest that long alkyl chains and a 1R, 2R configuration of the propyl group are important for the cytotoxic activities of arylpropyl sulfonamides. Moreover, the introduction of small hydrophobic groups in the phenyl ring and sulfonamide group could increase biological activity.     

Cytotoxic Activity and Structure Activity Relationship of Ceramide Analogues in Caki-2 and HL-60 Cells

B13, a ceramide analogue, is a ceramidase inhibitor and induces apoptosis to give potent anticancer activity. A series of thiourea B13 analogues was evaluated for their in vitro cytotoxic activities against human renal cancer Caki-2 and leukemic cancer HL-60 in the MTT assay. Some compounds (12, 15, and 16) showed stronger cytotoxicity than B13 and C6-ceramide against both tumor cell lines, and compound (12) gave the most potent activity with IC₅₀ values of 36 and 9 µM, respectively. Molecular modeling of thiourea B13 analogues was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). We obtained highly reliable and predictive CoMSIA models with cross-validated q² values of 0.707 and 0.753 and CoMSIA contour maps to show the structural requirements for potent activity. These data suggest that the amide group of B13 could be replaced by thiourea, that the stereochemistry of 1,3-propandiol may not be essential for activity and that long alkyl chains increase cytotoxicity.     

Cytotoxic Activity and Three-Dimensional Quantitative Structure Activity Relationship of 2-Aryl-1,8-naphthyridin-4-ones

A series of substituted 2-arylnaphthyridin-4-one analogues, which were previously synthesized in our laboratory, were evaluated for their in vitro cytotoxic activity against human lung cancer A549 and human renal cancer Caki-2 cells using MTT assay. Some compounds (11, 12, and 13) showed stronger cytotoxicity than colchicine against both tumor cell lines, and compound 13 exhibited the most potent activity with IC₅₀ values of 2.3 and 13.4 µM, respectively. Three-dimensional quantitative structure activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed. Predictive 3D-QSAR models were obtained with q² values of 0.869 and 0.872 and r²_ncv values of 0.983 and 0.993 for CoMFA and CoMSIA, respectively. These results demonstrate that CoMFA and CoMSIA models could be reliably used in the design of novel cytotoxic agents.     

Cytotoxic butanolides from the stem bark of Formosan Lindera communis.

Two new butanolides, lincomolide A (1), lincomolide B (2), along with seven known compounds, isolinderanolide E, sepesteonol, beta-sitosterol, beta-sitosterol-beta-glucoside, tetradecane, nonanoic acid and decanol, were isolated from the chloroform-soluble portion of the stem bark of Lindera communis. Compound 1 showed cytotoxicity against P-388, KB16 and A549, and 2 exhibited cytotoxicity against P-388 cancer cell lines. Moreover, 1 showed marginal activity against HT-29, and 2 against KB16, A549 and HT-29 cancer cell lines. The structures of these compounds were determined by spectral analyses.     

Synthesis and cytotoxicity of new aromatic ceramide analogs with alkylsulfonamido chains

A series of D-erythro ceramide analogues, N-(2S, 3R, 4E)-1, 3-dihydroxy-5-phenyl pent-4-en-2-yl alkyl sulfonamides, were synthesized and evaluated for their in vitro cytotoxic activities against five human tumor cell lines. The aromatic sulfon amido ceramide analogue (10f) showed more potent cytotoxic activity than that of the B13, indicating that a sulfonamide group appears to serve as a bioisostere of an amide in drug design. Variations in the alkyl sulfonyl chain length significantly influenced the cytotoxic activity of the sulfonamido ceramide analogues, but the introduction of a para halogen on the phenyl ring of aromatic ceramide analogues had no affect on the activity.     

Synthesis and anticancer activity of some new s-triazine derivatives

New s-triazine derivatives 13a–h were synthesized for the structure–activity relationship studies as potent anticancer agents. The prepared analogues were evaluated for their in vitro inhibitory activity against the growth of PA-1 (Ovarian cancer), A549 (Lung cancer), MCF-7 (Breast cancer), and HT-29 (Colon cancer). Tri-substituted s-triazine derivatives (13e–h) with morpholino group on s-triazine scaffold exhibited potent anticancer activities compared to di-substituted s-triazine derivatives. Compounds 13e–h also showed relatively selective PA-1 and HT-29 cancer cell inhibition over other cancer cell lines. Structure–activity relationships provided useful insights in these classes of compounds and paved the way to design novel analogues with more potency.     

Cytotoxic butanolides and secobutanolides from the stem wood of Formosan Lindera communis

Bioassay-guided fractionation of the chloroform-soluble fraction from the stem wood of Formosan Lindera communis led to the isolation of two new cytotoxic butanolides, lincomolide C (1), lincomolide D (2), as well as two new secobutanolides, secolincomolide A (3), secolincomolide B (4), together with four known compounds, including one butanolide, isoobtusilactone A (5), and one secobutanolide, secoisolancifolide (6), one sesquiterpene, epi-cubenol (7), one steroid: beta-sitosterol (8). Compound 4 existed in enol [(2E)-2-[(1R)-1-hydroxy-2-oxo-propyl]-6,9-dimethyl-8-hydroxy-hexadec-2,7-dienoic acid methyl ester] (4a) and keto [(2E)-2-[(1R)-1-hydroxy-2-oxo-propyl]-6,9-dimethyl-8-oxo-hexadec-2-enoic acid methyl ester] (4b) tautomers. Compound 2 showed significant cytotoxicity against P-388 and HT-29 cancer cell lines. Also, 2 exhibited marginal activity against A549, 5 against P-388, and 1 against P-388, A549 and HT-29 cancer cell lines. Their structures were determined by spectroscopic analyses.     

通过碳碳双键连接的吲哚-2-酮与喹唑啉-4（3H）-酮杂合物的合成与抗肿瘤活性评价

通过2-甲基4-氧代喹唑啉-6-甲醛与不同的吲哚-2-酮的缩合反应,制备了一系列吲哚-2-酮与喹唑啉-4（3H）-酮的杂合物5a-j。MTT法测试结果表明,只有化合物5e对人肿瘤细胞A549、MCF-7、HeLa、HT-29和HCT-116表现出一定的细胞毒活性,50μM浓度下的抑制率为32．0％-62．3％。     

Cytotoxic cyclopenta[b]benzofuran derivatives from the stem bark of Aglaia formosana

A new cytotoxic cyclopenta[b]benzofuran derivative, aglaiformosanin (1) and three known cyclopenta[b]benzofuran derivatives (2 - 4) were isolated from the stem bark of Aglaia formosana. Compounds 1 - 4 exhibited potent cytotoxicity against the P-388, KB, HT-29, HL-60, and A549 cell lines. The structure of compound 1 was determined by spectroscopic analysis.     

Design,synthesis, and biological evaluation of tetrahydroisoquinoline stilbene derivatives as potential antitumor candidates

Herein, a novel class of tetrahydroisoquinoline stilbene derivatives were synthesized, and their potential in vitro anticancer activities were evaluated. Most of the compounds displayed inhibitory activity against one or more representative human cancer cell lines (lung cancer A549 cells, breast cancer MCF-7 cells, and human colorectal carcinoma HT-29 cells), especially compound 16 e, which exhibited outstanding cytotoxicity to A549 cells. The tubulin polymerization assay demonstrated that compound 16 e displayed better inhibition than colchicine when tested at the same concentration. It was found that 16 e arrested A549 cells in G2/M phase by downregulating the expression of cell division cycle 2 (Cdc2) and upregulating the expression of proliferating cell nuclear antigen (PCNA) and cyclin B1. Flow cytometry and Western blot analysis indicated that 16 e caused apoptosis via the mitochondrial-dependent apoptotic pathway by reducing mitochondrial membrane potential, inducing ROS accumulation, promoting the release of cytochrome C from the mitochondria into the cytoplasm, and further increasing the protein level of cleaved caspase-3. This work may inspire new ideas for the further improvement of tubulin-related anticancer drugs and treatments.     

Synthesis and structure-activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogues of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB-231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data, the SAR study concluded that more than 75% of the open-chain Lam-D analogues tested showed cytotoxicity in a low micromolar GI50 range.     

The cytotoxic activity of the total alkaloids isolated from different parts of Solanum pseudocapsicum

The total alkaloid fractions of the methanolic extracts of the leaves, ripe fruits, roots, seeds and stem of Solanum pseudocapsicum were subjected to in-vitro cytotoxicity, short-term toxicity and long-term survival studies. All the five fractions exhibited potent activity. The total alkaloid fraction of leaves was found to be the most potent. The HT-29 cell line was the most sensitive to the fractions. The cytotoxic concentration (CTC(50)) values for all these fractions ranged between 0.39-0.91, 0.68-2.8, 0.92-3.56, 4.05-8.2, 3.28-5.65 and 0.95-5.55 microg/ml, respectively for HT-29, RD-228, A-549, HEp-2, B(16)F(10) and Vero cell lines. In short-term toxicity studies, the fractions showed 50% viability at 93-128 microg/ml for DLA cells and 141-189 microg/ml for human lymphocytes. In the long-term survival studies on the cell lines RD-228, HEp-2 and Vero, cells retained their regenerative capacities at concentrations below 8 microg/ml. The total alkaloids of the plant, especially from the leaves merit further investigations to identify the active constituents in animal models.     

Synthesis and cytotoxicity of bis-1,3,4-oxadiazoles and bis-pyrazoles derived from 1,4-bis[5-thio-4-substituted-1,2,4-triazol-3-yl]-butane and their DNA binding studies

A new series of 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio-4-substituted-1,2,4-triazol-3-yl]-butane 7-12 and 1,4-bis[5-(1-oxo-1-(3,5 dimethyl pyrazol-1-yl)-methyl)-thio-4-substitued-1,2,4-triazol-3-yl]-butane 13-18 were prepared from 1,4-bis(5[hydrazinocarbonylmethylthio]-4-substituted-1,2,4-triazol-3-yl) butane based derivativess were synthesized 1-6. All the synthesized compounds were characterized by IR, NMR and Mass spectral studies. The synthesized compounds 7-18 were screened for in-vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, colon carcinoma HT-29 and breast cancer MDA MB-231. DNA binding studies were conducted for three potent molecules by absorption titration method.     

Design,synthesis and antitumor activity evaluation of novel 2,6-dichloro-3,5-dinitrotoluene derivatives

A series of novel 2,6-dichloro-3,5-dinitrotoluene derivatives were designed, synthesized in the present study, and their antitumor activities against five cell lines (A431, HepG2, A549, HT-29 and HEK-293) were tested. Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines in comparison with cisplatin. Studies on their preliminary structure-activity relationships (SARs) indicated that compounds containing phenyl (piperazin-1-yl) methanone groups, especially chlorine atom at 4-position of the phenyl ring, were more effective. Compound 4g was found to be the most potent derivative with IC₅₀ values of 1.04, 3.20, 6.93, 4.10 and 20.15 μmol/L against A431, Hep G2, A549, HT-29 and HEK-293 cell lines, respectively, which was better than positive control cisplatin, one of the most clinically used chemotherapeutic drugs.     

Synthesis of cytotoxic 6E-hydroximino-4-ene steroids: structure/activity studies

In an effort to determine the pharmaceutical utility and the structural requirements for activity against various tumor cell lines, several 6E-hydroximino-4-ene steroids with different side chains and degrees of unsaturation on ring A were synthesized in our laboratory. Evaluation of the synthesized compounds for cytotoxicity against P-388, A-549, HT-29, and MEL-28 tumor cells revealed that some important structural features are required for activity. The presence of a cholesterol-type side chain, which appears to play a major role in determining the biological activity, the existence of a ketone functionality at C-3, and an elevated degree of oxidation on ring A all result in higher bioactivity than other structural motifs.     

Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents

Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.     

4,6-双苯基-2-氨基-3-氰基吡啶类化合物的合成及其 抗肿瘤活性研究

目的 设计合成一系列4,6-双苯基-2-氨基-3-氰基吡啶类化合物,并对其体外抗肿瘤活性进行初步评价。方法 以取代苯甲醛、取代苯乙酮、丙二腈和醋酸铵为原料,经一步反应制得目标化合物。采用MTT法,以 MX-58151 为阳性对照药,以 A549、HT-29 和 SMMC-7721为测试细胞株对目标化合物进行体外抗肿瘤活性评价。 结果与结论 合成了13 个未见报道的4,6-双苯基-2-氨基-3-氰基吡啶类化合物, 其结构经¹H-NMR、MS 和 IR 谱确证。体外活性测试结果显示,多数化合物能够在较低的浓度下抑制肿瘤细胞增殖。其中,2-氨基-6-（4-氟苯基）-4-（2,3,4-三甲氧基苯基）-3-氰基吡啶 具有显著的抗肿瘤细胞增殖活性,IC₅₀值达纳摩尔级水平,明显优于阳性对照药MX-58151。     

Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization

An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitors of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (5a). This substance was almost as potent as combretastatin A-4 (1a), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a greater than 8a greater than 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (1a), dihydrocombretastatin A-4 (1c), and trans-combretastatin A-4 (1b). The relative potencies 5a greater than 8a greater than 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.     

Antiproliferative ent-Kauranoids from Isodon parvifolius

Nine new 7alpha,20-epoxy- ENT-kaurane diterpenoids, parvifolines O - W (1 - 9), together with five known analogues, lasiocarpanin (10), rosthorin A (11), longikaurin E (12), adenolin D (13) and longikaurin B (14), were isolated from the leaves of Isodon parvifolius. Their structures were determined by means of spectroscopic analysis. Selected diterpenoids (1 - 10) were tested for their antiproliferative activity against A549, HT-29 and K562 cells. Compounds 3, 7, 8 and 10 showed moderate inhibitory activity against all three cell lines.