Synthesis of novel antimitotic agents based on 2-amino-3-aroyl-5-(hetero)arylethynyl thiophene derivatives

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3′,4′,5′-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G₂/M and sub-G₁ phases of the cell cycle.     

Synthesis and in vitro anti-proliferative effects of 3-(hetero)aryl substituted 3-[(prop-2-ynyloxy)(thiophen-2-yl)methyl]pyridine derivatives on various cancer cell lines

A series of 3-(hetero)aryl substituted 3-[(prop-2-ynyloxy)(thiophen-2-yl)methyl]pyridine derivatives were designed as potential anticancer agents. These compounds were conveniently prepared by using Pd/C–Cu mediated Sonogashira type coupling as a key step. Many of these compounds were found to be promising when tested for their in vitro anti-proliferative properties against six cancer cell lines. All these compounds were found to be selective towards the growth inhibition of cancer cells with IC₅₀ values in the range of 0.9–1.7 μM (against MDA-MB 231 and MCF7 cells), comparable to the known anticancer drug doxorubicin.     

Synthesis of some new [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and [1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles starting from 5-nitro-2-furoic acid and evaluation of their antimicrobial activity

New series of fused 1,2,4-triazoles such as, 6-(aryl)-3-(5-nitrofuran-2-yl)-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 4-8, 6-(alkyl/aryl amino)-3-(5-nitrofuran-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 9-13 and 6-(4-substituted phenyl)-3-(5-nitrofuran-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 14-18 have been synthesized via the reaction of 4-amino-5-(5-nitrofuran-2-yl)-4H-1,2,4-triazole-3-thiol 3 with various reagents such as hetero aromatic aldehydes, alkyl/aryl isothiocyanates and 4-substituted phenacyl bromides, respectively. The structures of the newly synthesized compounds have been confirmed on the basis of elemental analysis and spectral studies. The newly synthesized triazolo derivatives have been investigated for their in vitro antibacterial activity. Most of the tested compounds showed interesting antibacterial activity against Staphylococcus aureus. Furthermore, the most potent antibacterial compounds 11-13 were evaluated for their in vitro cytotoxic activity against human cancer cell lines. It was found that compounds 11 and 13 showed higher cytotoxicity against Hep-G2 cell line as compared to standard.     

Identification of vibsanin A analog as a novel HSP90 inhibitor

Vibsanin A is the first natural product isolated from Viburnum awabuki and has several biological activities. We have reported that a vibsanin A analog, obtained from process of total synthesis of vibsanin A, has anti-proliferative activity against human cancer cell lines. In this study, we evaluated anti-proliferative effect of the vibsanin A analogs against various human cancer cell lines and examined molecular target of the analog in human cells. Among the vibsanin A analogs, vibsanin A analog C (VAC) showed anti-proliferative effect against various cancer cell lines, and the anti-proliferative activity was strongest among the vibsanin A analogs. Additionally, VAC fluctuated amounts of HSP90-related proteins in cells and inhibited HSP90-mediated protein refolding of luciferase in vitro. These results suggest that the anti-proliferative activity of VAC is due to HSP90 inhibition, and VAC has a potential as novel anti-cancer drug as HSP90 inhibitor.     

Synthesis and biological evaluation of 3-amino-, 3-alkoxy- and 3-aryloxy-6-(hetero)arylpyridazines as potent antitumor agents

Various 3-amino-, 3-aryloxy- and alkoxy-6-arylpyridazines have been synthesized by an electrochemical reductive cross-coupling between 3-amino-, 3-aryloxy- or 3-alkoxy-6-chloropyridazines and aryl or heteroaryl halides. In vitro antiproliferative activity of these products was evaluated against a representative panel of cancer cell lines (HuH7, CaCo-2, MDA-MB-231, HCT116, PC3, NCI-H727, HaCaT) and oncogenicity prevention of the more efficient derivatives was highlighted on human breast cancer cell line MDA-MB 468-Luc prior establishing their interaction with p44/42 and Akt-dependent signaling pathways.     

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold.     

Synthesis and antituberculosis activity of novel 5-styryl-4-(hetero)aryl-pyrimidines via combination of the Pd-catalyzed Suzuki cross-coupling and SNH reactions

Combination of the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (S_N^H) reactions proved to be a convenient method for the synthesis of 5-styryl-4-(hetero)aryl substituted pyrimidines from commercially available 5-bromopyrimidine. All intermediate 5-bromo-4-(hetero)aryl substituted pyrimidines and also the targeted 5-styryl-4-(hetero)arylpyrimidines were found to be active in micromolar concentrations in vitro against Mycobacterium tuberculosis H₃₇Rv, avium, terrae, and multi-drug-resistant strain isolated from tuberculosis patients in Ural region (Russia). It has been found that some of these compounds possess a low toxicity and have a bacteriostatic effect, comparable and even higher with that of first-line antituberculosis drugs.     

Design, synthesis, and biological evaluation of N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine and its analogs as a novel class of anticancer agents

N-Acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC) was identified as a metabolite of sulofenur. Sulofenur was demonstrated to have broad activity against solid tumors in preclinical studies but exhibited disappointing clinical responses due to its high protein binding related adverse effects. NACC exhibited low protein binding and excellent activity against a sulofenur sensitive human colon cancer cell line. In this study, analogs of NACC were synthesized and evaluated with four human cancer cell lines. Two of the NACC analogs showed excellent activity against two human melanoma cell lines, while NACC remains the most potent of the series. All three compounds were more potent than dacarbazine, which is used extensively in treating melanoma. NACC was shown to induce apoptosis without affecting the cell cycle. Further, NACC exhibited low toxicity against monkey kidney cells. The selective anticancer activity, low toxicity, an unknown yet but unique anticancer mechanism and ready obtainability through synthesis make NACC and its analogs promising anticancer agents.     

CIP2A Influences Survival in Colon Cancer and Is Critical for Maintaining Myc Expression

The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor that stabilises the c-Myc protein. CIP2A is overexpressed in several tumours, and expression levels are an independent marker for long-term outcome. To determine whether CIP2A expression is elevated in colon cancer and whether it might serve as a prognostic marker for survival, we analysed CIP2A mRNA expression by real-time PCR in 104 colon cancer samples. CIP2A mRNA was overexpressed in colon cancer samples and CIP2A expression levels correlated significantly with tumour stage. We found that CIP2A serves as an independent prognostic marker for disease-free and overall survival. Further, we investigated CIP2A-dependent effects on levels of c-Myc, Akt and on cell proliferation in three colon cancer cell lines by silencing CIP2A using small interfering (si) and short hairpin (sh) RNAs. Depletion of CIP2A substantially inhibited growth of colon cell lines and reduced c-Myc levels without affecting expression or function of the upstream regulatory kinase, Akt. Expression of CIP2A was found to be dependent on MAPK activity, linking elevated c-Myc expression to deregulated signal transduction in colon cancer.     

4β-[4′-(1-(Aryl)ureido)benzamide]podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents

A series of 4β-[4′-(1-(aryl)ureido)benzamide]podophyllotoxin congeners (11a–l) were synthesized and evaluated for their cytotoxic activity against six human cancer cell lines. Some of the compounds like 11a, 11h, 11k and 11l showed significant anti-proliferative activity in Colo-205 cells and were superior to etoposide. The flow-cytometric analysis studies indicated that these compounds show strong G1 cell cycle arrest, as well exhibited improved inhibitory activities on DNA topoisomerase I and IIα enzymes. These compounds induce apoptosis by up regulating caspase-3 protein as observed by ELISA and Western blotting analysis. In addition, a brief structure–activity relationship studies within the series along with docking results of representative compounds 11a, 11h, 11k, 11l were presented.     

Synthesis and biological evaluation of new 1,5-diazaanthraquinones with cytotoxic activity

A series of 1,5-diazaanthraquinone derivatives was synthesized and their in vitro cytotoxic activities were evaluated against several human cancer cell lines. The 1,5-diazaanthraquinone chromophore has been synthesized either on the basis of hetero Diels–Alder reactions involving different quinoline-5,8-diones and ,β-unsaturated aldehyde N,N-dimethylhydrazones or by thermolysis of different arylaminomethylene Meldrum’s acid derivatives. Some of these compounds showed cytotoxic activity comparable to that of mitoxantrone against most of the cell lines tested. Compounds 20, 30, 31 and 37 were 4–54 times more potent that mitoxantrone against A549, H116, PSN1 and T98G cancer cell lines but, interestingly, they were 3–16 times less potent against the human breast carcinoma SKBR3. Some structure–activity relationships are described, the most significant one being the increase in cytotoxicity resulting from the introduction of a halogen atom at the C-4 position.     

Antiproliferative and antioxidant properties of nematocysts crude venom from jellyfish Acromitus flagellatus against human cancer cell lines

This study aimed to investigate the antiproliferative and antioxidant properties of crude venom from the nematocyst of Jellyfish Acromitus flagellates on human lung cancer (A549) and liver cancer (HepG2) cell lines. The prepared crude venom was subjected to analyses of the biochemical constituents, protein profiles, antioxidant and anticancer activities by standard methods. The extracted venom was pale-yellow in color and viscous/sticky. The biochemical composition such as, protein (1.547 mg/ml), lipid (0.039 mg/ml) and carbohydrate (0.028 mg/ml) was estimated. Protein profiles were determined by SDS PAGE, the result revealed that the molecular weight range from 205 ? 3.5 kDa. The free radical scavenging activity was analyzed by the reducing potential (56.36%), DPPH (72.47%), hydroxyl (68.50%), superoxide anion (65.75%), and nitric oxide (33.04%). The cell viability was observed by using different concentrations (20 to 100 µg/ml) of crude venom on A549 and HepG2 cancer cell lines and the IC₅₀ values were recorded in (60 μg/ml and 40 μg/ml) respectively, while it had none cytotoxic effects on Vero cell line up to the concentration of 90 μg/ml. These results suggest that crude venom from nematocyst of A. flagellatus possesses anti-cancer activity and able to develop novel drugs on marine-derived compounds.     

Design,synthesis and evaluation of novel (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit as anticancer agents

A series of (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit were designed, synthesized and evaluated for their potential application as anticancer agents. The structures of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against HepG2, HeLa, CNE1 and A549 human cancer cell lines. Some of the synthesized compounds showed moderate to good anticancer activities against four selected cancer cell lines, among of which 6ag was found to be the most active analogue possessing IC₅₀ values 16.5–18.7?μM. Further mechanism studies revealed that compound 6ag could significantly induce HepG2 cell cycle arrest at G1 phase, promote cell apoptosis, and inhibit the colony formation as well.     

Synthesis and biological evaluation of novel biaryl type α-noscapine congeners

Natural α-noscapine, a known antitussive drug, is also now known to possess weak anticancer efficacy with relatively safe toxicity profile. In this study, we report synthesis and evaluation of novel biaryl type α-noscapine congeners designed by adding aryl unit to the tetrahydroisoquinoline part of natural α-noscapine core. Palladium catalyzed Suzuki cross coupling of 9-bromo α-noscapine with aryl boronic acids was employed using mild and inexpensive reagents to attain desired noscapinoids 5a–g in excellent yields. Screening anti-proliferative activity for new noscapinoids 5b–g, on human cancer cell lines resulted three compounds 5b, 5d and 5f as potent analogues, active against human breast epithelial (MCF-7), human cervix cancer (HeLa) and human lung adenocarcinoma epithelial (A549) cell lines.     

Synthesis and cytotoxic evaluation of novel paraconic acid analogs

A novel class of 2,3-tri- and tetrasubstituted γ-butyrolactones analogous to paraconic acids has been synthesized in one step using a straightforward three-component reaction among aryl bromides, dimethyl itaconate and carbonyl compounds. The in vitro cytotoxic activity of representative compounds has been evaluated against a panel of human cancer cell lines (KB, HCT116, MCF7, HL60). While most molecules exhibit a low to moderate background activity on both KB and HL60 cancer cell lines, one compound shows increased antiproliferative activities against both cell lines with IC(50) values in the 10(-7)-10(-6)mol/L range. An extended evaluation indicated that this compound also inhibits PC3, SK-OV3, MCF7R and HL60R cell growth in the same fashion.     

Synthesis of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives and their cytotoxic activity

A series of novel 1,2,3-triazole tagged pyrazolo[3,4-b]pyridine derivatives 3 and 4 were prepared respectively starting from 6-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 1 via selective N-propargylation, followed by reaction with diverse substituted alkyl/perfluoroalkyl/aryl/aryl amide azides under Sharpless conditions. All the synthesized compounds 3 and 4 were screened for cytotoxic activity against four human cancer cell lines such as U937, THP-1, HL60 and B16-F10. Compounds 3e, 4g, 4i and 4j which showed promising activity have been identified.     

A novel series of histone deacetylase inhibitors incorporating hetero aromatic ring systems as connection units

A series of structurally novel HDAC inhibitors, in which a hetero aromatic ring connects the spacer with the hydrophobic group, has been designed and synthesized. These new inhibitors are very potent in in vitro enzymatic assays and display antiproliferation activity against two human cancer cell lines.     

One-pot synthesis and anticancer studies of 2-arylamino-5-aryl-1,3,4-thiadiazoles

A series of 2-arylamino-5-aryl-1,3,4-thiadiazoles 1a-j were synthesized and screened for their anticancer activity against various human cancer cell lines. The novel one-pot synthesis of 1,3,4-thiadiazoles was achieved by refluxing aryl aldehydes, hydrazine hydrate, and aryl isothiocyanates in methanol followed by oxidative cyclization with ferric ammonium sulfate. The compounds 1g-j with trimethoxyphenyl at the C-5 position displayed extremely potent anticancer activity with at least twofold selectivity (IC₅₀: 4.3-9.2 μM). The nature of substituent on the C-2 arylamino ring may be critical in opting for the selectivity towards a particular cancer cell.     

Synthesis of new conjugated coumarin–benzimidazole hybrids and their anticancer activity

A series of novel coumarin–benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A significant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition) compared with other compounds and active known drug 5-fluorouracil (in some cell lines) as positive control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and breast cancer cell lines.     

Design,synthesis and biological evaluation of novel perimidine o-quinone derivatives as non-intercalative topoisomerase II catalytic inhibitors

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC₅₀ ≤ 1 μM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 μM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC₅₀ = 7.54 μM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.