Indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents

A new series of indolylhydrazones (6) and indole-based 4-thiazolidinones (7, 8) have been designed, synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. 4-Thiazolidinone derivatives 7g–7j, 8g, 8h and 8j displayed notable antituberculosis (anti-TB) activity showing 99% inhibition at MIC values ranging from 6.25 to 25.0?µg/ml. Compounds 7g, 7h, 7i, 8h and 8j demonstrated anti-TB activity at concentrations 10-fold lower than those cytotoxic for the mammalian cell lines. The indolylhydrazone derivative 6b has also been evaluated for antiproliferative activity against human cancer cell lines at the National Cancer Institute (USA). Compound 6b showed an interesting anticancer profile against different human tumor-derived cell lines at sub-micromolar concentrations with obvious selectivity toward colon cancer cell line COLO 205.     

2-Benzoylbenzofuran derivatives possessing piperazine linker as anticancer agents

A series of novel 2-benzoylbenzofuran derivatives possessing piperazine linker have been prepared, and their in vitro anticancer activity against a panel of human tumor cell lines by MTT assay were evaluated. The results demonstrated that tertiary amine derivatives exhibited better cytotoxic activity, and SAR study revealed that electron-donating substituents on the phenyl ring of the derivatization functionality contributed to potent anticancer activities. Among them, compounds 6, 9, 11, 18, 23 and 25 displayed both better anti-tumor activity and lower cytotoxic effect on human normal liver cell L02. Further apoptosis analysis showed that compound 18 significantly induced apoptosis in A549 cell, which was considered as the most potent anticancer agent.     

Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells

Fourteen new naphthalene-based thiosemicarbazone derivatives were designed as anticancer agents against LNCaP human prostate cancer cells and synthesized. MTT assay indicated that compounds 6, 8 and 11 exhibited inhibitory effect on LNCaP cells. Among these compounds, 4-(naphthalen-1-yl)-1-[1-(4-hydroxyphenyl)ethylidene)thiosemicarbazide (6), which caused more than 50% death on LNCaP cells, was chosen for flow cytometric analysis of apoptosis. Flow cytometric analysis pointed out that compound 6 also showed apoptotic effect on LNCaP cells. Compound 6 can be considered as a promising anticancer agent against LNCaP cells owing to its potent cytotoxic activity and apoptotic effect.     

Synthesis and biological evaluation of thiobenzanilides as anticancer agents

A series of novel thiobenzanilides is described. These compounds have been previously found to show strong biological activity such as antimycotic and antifungal actions. This is the first demonstration on the mechanism of the anticancer effect of thiobenzanilide agents (4a–c) on human melanoma A375 cells. The cytotoxic studies of compounds 4a–c on human melanoma A375 cells indicate thiobenzanilides induced higher cytotoxicity than nitrobenzanilides (3a–c). In addition, DNA flow cytometric analysis shows that 4a–c displays a significant G2/M phase arrest, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Because cellular apoptosis is often preceded by the disruption of mitochondrial function, the assessment of mitochondrial function in 4a–c-treated cells is worthy of investigation. Our data revealed that treatment of A375 cells with 4a–c resulted in the loss of mitochondrial membrane potential (ΔΨ_mt), a reduction of ATP synthesis, increased reactive oxygen species (ROS) generation, and activation of caspase-3. Thus, we suggest that 4a–c agents are potent inducers of cell apoptosis in A375 cells.     

Synthesis of 13-amino costunolide derivatives as anticancer agents

A number of costunolide derivatives (4a-p) have been synthesized and evaluated for their in vitro cytotoxicity against eight tumor and a non-tumor cell lines. Compound 4d showed around 2-fold better cytotoxicity against SW-620 (colon) cell line with improved safety index than costunolide (1). While compounds 4e, 4g, and 4p have shown around 2- to 3-fold better cytotoxicity against MIAPaCa2 (pancreas), K-562 (leukemia) and PA-1 (ovary) cell lines as well as better safety index in comparison to costunolide (1). Compound 4p also exhibited cytotoxicity against HBL100 (breast) cell line with 2-fold better safety index. Structure-activity relationship has been described.     

Benzothiazole derivatives as anticancer agents

Abstract

Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The BTA scaffolds showed a crucial role in the inhibition of the metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over the last decade discloses the role of BTA derivatives mainly as anticancer agents. Such compounds are effective against various types of cancer cell lines through a multitude of mechanisms, some of which are poorly studied or understood. The inhibition of tumour associated CAs by BTA derivatives is on the other hand better investigated and such compounds may serve as anticancer leads for the development of agents effective against hypoxic tumours.     

Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies

A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC₅₀ values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC₅₀ values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket.     

Synthesis and characterisation of celastrol derivatives as potential anticancer agents

In the present study, three series of novel celastrol derivatives were designed and synthesised by modifying the carboxylic acid at the 20th position with amino acid, amine, and triazole derivatives. All the synthesised compounds were screened for their anticancer activities using MTT assay against AGS, MGC-803, SGC-7901, HCT-116, A549, HeLa, BEL-7402, and HepG-2 cell lines. Most of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound 3-Hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic amide, N-(R)-methyl-3-(1H-indol-2-yl)propanoate (11) showed considerable high anticancer activity against AGS cell lines, with an IC₅₀ value of 0.44?μM, and considerably higher activities against HCT-116, BEL-7402, and HepG-2 cell lines, with IC₅₀ values of 0.78, 0.63, and 0.76?μM, respectively. The results of apoptosis tests and molecular docking study of compound 11 binding to Caspase-3 revealed that its mechanism of action with antiproliferative was possibly involved in inducing apoptosis by inducing the activation of caspase-3.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Tubulin-interactive stilbene derivatives as anticancer agents

Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.     

Synthesis and biological evaluation of novel 4,7-dihydroxycoumarin derivatives as anticancer agents

A series of novel 4,7-dihydroxycoumarin based acryloylcyanohydrazone derivatives were synthesized and evaluated for antiproliferative activity against four different cancer cell lines (A549, HeLa, SKNSH, and MCF7). Most of the compounds displayed potent cytotoxicity with IC₅₀ values ranging from 3.42 to 31.28 µM against all the tested cancer cell lines. The most active compound, 8h was evaluated for pharmacological mechanistic studies on cell cycle progression and tubulin polymerization inhibition assay. The results revealed that the compound 8h induced the cell cycle arrest at G2/M phase and inhibited tubulin polymerization with IC₅₀ = 6.19 µM. Experimental data of the tubulin polymerization inhibition assay was validated by molecular docking technique and the results exhibited strong hydrogen bonding interactions with amino acids (ASN-101, TYR-224, ASN-228, LYS-254) of tubulin.     

Synthesis and evaluation as potential anticancer agents of novel tetracyclic indenoquinoline derivatives

We report the synthesis and evaluation as potential anticancer agents of a series of tetracyclic indenoquinolines. The compounds, which are obtained through the photoisomerization of Diels–Alder adducts formed between purpurogallin derivatives and nitrosobenzene, have in vitro antiproliferative activities in the μM to nM range against breast (MCF-7), lung epithelial (A-549), and cervical (HeLa) adenocarcinoma cells. The cytotoxicities of several of the novel tetracycles are comparable to or better than that of camptothecin. A strong correlation between the activity of the compounds and their aromaticity and planarity was observed, suggesting a mode of action similar to that of topoisomerase poisons.     

Synthesis of macrocyclic bisbibenzyl derivatives and their anticancer effects as anti-tubulin agents

Based on the core skeleton of the total synthesized bisbibenzyl marchantin C, riccardin D and plagiochin E, a series of brominated and aminomethylated derivatives of above three bisbibenzyls have been synthesized and their cytotoxic activity against KB, MCF-7 and PC3 cell lines has been preliminary evaluated. The bio-test results revealed that the brominated derivatives 21, 22, 24, 25 and 28 exhibited excellent antiproliferative activity, with IC(50) value lower than their parent compounds. As a most potent microtubule depolymerization agent, compound 28 was found to arrest cells at the G(2)/M phase of the cell cycle as determined by the flow cytometry assay in PC3 cell line. The remarkable biological profile and novel structure of these bisbibenzyl derivatives make them possible as promising candidates for clinical development as chemotherapeutic agents.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Gallic acid-based indanone derivatives as anticancer agents

Gallic acid-based indanone derivatives have been synthesised. Some of the indanones showed very good anticancer activity in MTT assay. Compounds 10, 11, 12 and 14 possessed potent anticancer activity against various human cancer cell lines. The most potent indanone (10, IC₅₀ = 2.2 μM), against MCF-7, that is, hormone-dependent breast cancer cell line, showed no toxicity to human erythrocytes even at higher concentrations (100 μg/ml, 258 μM). While, indanones 11, 12 and 14 showed toxicities to erythrocytes at higher concentrations.     

Synthesis and biological evaluation of baicalein derivatives as potent antitumor agents

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one), a major flavonoid extracted from the root of Scutellaria baicalensis Georgi (Chinese name: Huangqin), showed potent anti-proliferative activity against a broad panel of human cancer cell lines both in vitro and in vivo. A novel series of baicalein derivatives were synthesized by introducing a group to C6-OH and a nitrogen-containing hydrophilic heterocyclic ring to C7-OH via a length of 3 or 4-carbon chain in this study. The in vitro antiproliferative activities of the 30 derivatives against HepG2, A549, BCG-823 cancer cell lines were evaluated. Among them, 10 compounds exhibit more potent cytotoxicity than baicalein against the three cancer cell lines. The most potent compound 9b possesses highest anti-proliferative potency against HepG2, A549, and BCG-823 with an IC₅₀ value of 2.0 μM, 0.8 μM and 3.2 μM, respectively. Preliminary mechanism studies with compound 9b using Annexin V/PI double-staining assay and DAPI staining assay indicated that 9b inhibits tumor cell proliferation potentially through inducing apoptosis.     

Design and synthesis of aminocoumarin derivatives as DPP-IV inhibitors and anticancer agents

DPP-IV “a moonlighting protein” has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100 µM concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC₅₀ value 24 ± 0.1 nM against A549 cell line.     

Thiazolidin-4-one and hydrazone derivatives of capric acid as possible anti-inflammatory,analgesic and hydrogen peroxide-scavenging agents

Starting from capric acid, hydrazone and thiazolidin-4-one derivatives have been synthesized in the present investigation. Decanoic acid hydrazide was reacted appropriately to yield hydrazones, which were then cyclized to yield the corresponding thiazolidin-4-ones. The structures of the newly synthesized compounds were confirmed by analytical and spectral methods. Anti-inflammatory, analgesic, and hydrogen peroxide-scavenging activity of the title compounds were evaluated. Among synthesized compounds, 2-hydroxyphenyl thiazolidinone with 44.90% inhibition of inflammation was the most potent anti-inflammatory agent. Similarly, 4-methoxybenzylidine hydrazide with 64.90% inhibition of writhing was observed to be the most potent analgesic agent of the synthesized compounds. All the synthesized compounds exhibited potent hydrogen peroxide-scavenging activity.     

Synthesis and bioactivity evaluation of 2,3-diaryl acrylonitrile derivatives as potential anticancer agents

Thirty novel derivatives of 2,3-diaryl acrylonitrile were synthesized and evaluated for biological activity. Preliminary investigations of antitumor activity in vitro showed that most of the synthesized compounds have significant antiproliferative effects on human cancer cell lines, such as BEL-7402, HeLa, and HCT116 with IC₅₀ values in the range of 0.13–60.23 μM without significant toxic effects on the non-cancerous human liver cell line L-02. In particular, compounds 4d and 4p were found to be the most potent against HeLa (4.20 μM) and HCT116 cells (0.13 μM), respectively, with superior or similar in vitro efficacy to that of the broad-spectrum anticancer drug taxol.     

Design,synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC₅₀?=?2.1?μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.