Tumour-specific cytotoxicity and structure–activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones

A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3–7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC₅₀ and CC₅₀ values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells.     

Cytotoxic 2-benzylidene-6-(nitrobenzylidene)cyclohexanones which display substantially greater toxicity for neoplasms than non-malignant cells

Various 2-benzylidene-6-(nitrobenzylidene)cyclohexanones were prepared as candidate cytotoxins in which the nitro group was located in the ortho, meta and para positions leading to series 1–3, respectively. The CC₅₀ values towards human HSC-2 and HSC-4 oral squamous cell carcinomas as well as human HL-60 promyelocytic leukemic cells are in the low micromolar range in general. On the other hand, most of the compounds afforded clear evidence of being far less toxic towards human HGF gingival fibroblasts, HPC pulp cells and HPLF periodontal ligament fibroblasts which are non-malignant cells. Selectivity index (SI) figures were generated which are the ratios of the average CC₅₀ values towards normal cells and the CC₅₀ figure towards a malignant cell line. Huge SI values were obtained for many of the compounds. In particular 1c, 2f, 3c and 3g which have average SI values of >76, >38, 124 and 341, respectively, are clearly lead molecules affording direction for amplification of this area of study. A lead compound 1c caused internucleosomal DNA fragmentation and activation of caspase-3 in HL-60 cells but not in HSC-2 carcinomas. In a short-term toxicity study, doses up to and including 300 mg/kg of the majority of the compounds prepared in this study did not cause any mortalities to mice. Some guidelines for development of these tumor-selective cytotoxins are presented.     

Synthesis of some acrylophenones with N-methylpiperazine and evaluation of their cytotoxicities

In this study, the compounds having acrylophenone structure, 1-aryl-2-(N-methylpiperazinomethyl)-2-propen-1-one dihydrochlorides, were synthesized and their chemical structures were identified with ¹H NMR, ¹³C NMR and HRMS spectra. The cytotoxicities of the compounds were tested towards Ca9-22 (human gingival carcinoma), HSC-2 (human oral squamous carcinoma), HSC-3 (human oral squamous carcinoma) and HSC-4 (human oral squamous carcinoma) cell lines as tumor cell lines and HGF (gingival fibroblasts), HPLF (periodontal ligament fibroblasts) and HPC (pulp cells) cell lines as non-tumor cell lines. PSE of the compound TA2, which has a methyl substituent on phenyl ring, pointed out the compound TA2 as a leader compound to be considered.     

2-(3-Aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides: A novel cluster of tumor-specific cytotoxins which reverse multidrug resistance

A series of 2-(3-aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides 3a–l were prepared by condensation of various aryl aldehydes with 2-acetyl-3-methylquinoxaline-1,4-dioxide 2. These compounds inhibit the growth of human Molt 4/C8 and CEM T-lymphocytes and the IC₅₀ values are mainly in the 5–30 μM range. The quinoxaline 1,4-dioxide 3j inhibited the growth of 58 human tumor cell lines, particularly leukemic and breast cancer neoplasms. All of the compounds 3a–l reversed the multidrug resistance (MDR) properties of murine L-5178Y leukemic cells which were transfected with the human MDR1 gene. The MDR-reversing effect may be due to the conjugated π-electron system forming a weak electron charge transfer complex with the P-glycoprotein-mediated efflux pump. The compounds in series 2 and 3 were assessed against HL-60, HSC-2, HSC-3 and HSC-4 malignant cells as well as HGF, HPC and HPLF normal cell lines which revealed that the majority of the compounds displayed a greater toxicity to neoplastic than normal cells. Various ways in which the project may be expanded are presented.     

1-(3-Aminomethyl-4-hydroxyphenyl)-3-pyridinyl-2-propen-1-ones: A novel group of tumour-selective cytotoxins

Two series of 1-(3-aminomethyl-4-hydroxyphenyl)-3-pyridinyl-2-propen-1-ones, designed as novel cytotoxins, were synthesized. The compounds had low CC₅₀ values in the micromolar range against HL-60 promyelocytic leukemic cells and HSC-2, HSC-3 and HSC-4 oral squamous cell carcinomas. The CC₅₀ values of these compounds were higher towards non-malignant HGF (gingival fibroblasts), HPC (pulp cells), and HPLF (periodontal ligament fibroblasts) cells, which reveals the tumour-selectivity of these enones. A representative compound 4c caused cleavage of PARP1 in HSC-2 cells but not in HGF cells, which may be a contributing factor to the tumour-selectivity.     

Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids

The concept of sequential cytotoxicity, which states that successive chemical attacks on cellular constituents can be more deleterious to neoplasms than normal cells, was evaluated using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines 1 and related phosphonic acids 2, which were screened against a panel of malignant and normal cell lines. The compounds proved to be not only potent cytotoxins (71% of the CC(50) figures are submicromolar) but to display greater cytotoxicity to the neoplastic cells. QSAR revealed that both cytotoxic potencies and selective toxicity were increased by a rise in the electron-withdrawing properties and a decrease in the hydrophobicity of the aryl substituents. Utilisation of the PL10 concept and evaluation of druglike properties revealed 1c as the lead tumour-specific cytotoxin. This molecule activated caspase-3 in HL-60 cells but not in the HSC-2 cell line. While 1c caused internucleosomal DNA fragmentation in HL-60 cells, it did not elicit this effect in either HSC-2 and HSC-4 cells. Clearly 1c exerts its cytotoxic potencies by different mechanisms and such pleiotropy is likely the principal reason for the remarkable display of preferential toxicity towards malignant cells of the compounds in series 1 and 2.     

Synthesis,Antiproliferative and Cytotoxic Activities,DNA Binding Features and Molecular Docking Study of Novel Enamine Derivatives

Novel enamine derivatives were synthesized from the reaction of lactone and chalcones and their antiproliferative and cytotoxic activities against six cancer cell lines (e. g., HeLa, HT29, A549, MCF7, PC3 and Hep3B) and one normal cell lines (e. g., FL) were investigated along with their mode of interactions with CT‐DNA. Most of the enamine derivatives with IC₅₀ values of 86–168 μM demonstrated much stronger antiproliferative activity than the starting molecules against the cancer cells. While, among the enamine derivatives, four compounds displayed higher cytotoxic potency than the control drugs (5‐fluorouracil and cisplatin) against the Hep3B cell lines, these compounds did not exhibit any significant toxicity against normal cells, FL. The UV/VIS spectral data suggest that eight compounds cause hypochromism with a slight bathochromic shift (～6 nm), indicating that they bind to the DNA by way of an intercalative or minor groove binding mode. The binding constants of the compounds are in the range of 0.1×103 M^?1–2.3×104 M^?1. The antiproliferative activity of studied enamine derivatives could possibly be due to their DNA binding as well as their cytotoxic properties. In addition to these assays, the chalcones and enamine derivatives were investigated by molecular docking to calculate the synergistic effect of antiproliferative activities against six human cancer cell lines.     

Microwave accelerated solvent-free synthesis and antifungal evaluations of flavanones

Microwave irradiation of 2-hydroxy chalcones under solvent-free conditions resulted in a “green-chemistry” procedure for the preparation of flavanones in good yields, using an unmodified household microwave oven and silica as solid support. By irradiation of 2-hydroxy chalcones with trifluoroacetic acid over silica gel, 11 known flavanones were prepared in high yields. The synthesised compounds were characterised using spectroscopic techniques, namely, ¹H NMR, ¹³C NMR and IR, and screened for their antifungal activity in vitro against Sclerotium rolfsii and Rhizoctonia solani by poisoned food technique. The compounds tested were found to be more active against R. solani, whereas against S. rolfsii, moderate activity was observed, as evident from LC₅₀ values. The most potent compound 2-(4-fluorophenyl)-2,3-dihydrochromen-4-one (4a) had LC₅₀ value of 12.0 mg L^?1 followed by 11, 11a, 3a, 9a, 8a, 10a and 10 having LC₅₀ values 18.21, 18.3, 32.9, 50.7, 88.8, 118.8 and 119.7 mg L^?1, respectively.     

Synthesis and biological evaluation of some new N4-substituted isatin-3-thiosemicarbazones

A new series of 12 N⁴-substituted isatin-3-thiosemicarbazones 2a-l has been synthesized, characterized and screened for in vitro cytotoxic, phytotoxic and urease inhibitory effects. All the compounds proved to be active in the brine shrimp bioassay; 2a, 2b, 2d, 2f and 2h-l exhibited a high degree of cytotoxic activity (LD₅₀ = 1.10 × 10^{? 5} M–3.10 × 10^{? 5} M). In urease-inhibition assay, compounds 2a, 2b, 2e, 2f, 2h-j and 2l proved to be potent inhibitors displaying relatively much greater inhibition of the enzyme with IC₅₀ values ranging from 20.6 μM to 50.6 μM. Amongst these, 2a and 2f were found to be the most potent ones exhibiting pronounced inhibition with IC₅₀ value 20.6 μM. All the synthetic compounds showed weak to moderate (10–40%) phytotoxicity at the highest tested concentration (500 μg/mL) indicating their usefulness as inhibitors of soil ureases.     

Synthesis,antitumor activity evaluation of some new N-aroyl-α,β-unsaturated piperidones with fluorescence

Novel N-aroyl-α,β-unsaturated piperidones, series 1, series 2 and series 3 (featuring 2-bromo-4,5-dimethoxybenzylidene, 4-dimethylaminobenzylidene and 4-trifluoromethylbenzylidene, respectively), were synthesized as candidate cytotoxins. Most of the compounds displayed potent cytotoxicity against the human neoplastic cell lines SK-BR-3, PG-BE1, NCI-H460, MIA PaCa-2 and SW1990 in vitro, and approximately 64% of the IC₅₀ values were lower than 5?μM. Among those tested, compound 1b of series 1, 3a, 3d and 3e of series 3 proved to be the most active. Importantly, 1b displayed marked inhibitory effects on tumor growth in vivo and had no apparent toxicity to mice; this was evaluated by a nude mouse PG-BE1 xenograft model. In addition, the fluorescent properties of compounds series 1–3 were investigated. The interesting fluorescence exhibited by these compounds could be useful for their visualization in tumor cells, permitting further studies on these α,β-unsaturated piperidones as candidates for novel fluorescent antitumor agents.     

Novel cytotoxic chalcones from Litsea rubescens and Litsea pedunculata

Two novel flavonoids with chalcone skeleton, together with seven known flavonoids, were isolated from the stem barks of Litsea rubescens and Litsea pedunculata. The structures of the new compounds were elucidated on the basis of spectral methods including IR, UV, 1D and 2D NMR. The new chalcones were found to contain the rare epoxy or ethylidenedioxy group. This is the first report on the presence of chalcone in the plant genus Litsea. The cytotoxic potential of two new chalcones was evaluated in vitro against three human tumor cell lines. Both new chalcones displayed potent cytotoxic activities against myeloid leukaemia (HL-60) and epidermoid carcinoma (A431) cell lines and more active than cisplatin (DDP). Interestingly, compound 1 exhibited cytotoxic activity against HL-60 with IC₅₀ value 2.1-fold more sensitive to DDP.     

Synthesis of new N,N′-bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides and evaluation of their cytotoxicity against human hepatoma and breast cancer cells

Abstract

N,N′-Bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides were synthesized by the reaction of 2 mols of 1-aryl-3-(piperidine-1-yl)-1-propanone hydrochlorides with 1?mol of hydrazine hydrate. Aryl part was C₆H₅ (P1), 4-CH₃C₆H₄ (P2), 4-CH₃OC₆H₄ (P3), 4-HOC₆H₄ (P4), 4-ClC₆H₄ (P5), 3-CH₃OC₆H₄ (P6), 4-FC₆H₄ (P7) and 4-BrC₆H₄ (P8). Except P1, all compounds were reported for the first time. The chemical structures were confirmed by UV, ¹H NMR, ¹³C NMR and HRMS spectra. P1, P2, P7 and P8 against human hepatoma (Huh7) cells and P1, P2, P4, P5, P6, P7 and P8 against breast cancer (T47D) cells have shown cytotoxicity. P1, P2 and P7 had more potent cytotoxicity against Huh7 cells than the reference compound 5-FU, whereas only P2 was more potent than the 5-FU against T47D cells. Representative compound P7 inhibited the mitochondrial respiration at 144, 264 and 424?µM concentrations dose-dependantly in liver homogenates. The results suggest that P1, P2, P7 and P8 may serve as model compounds for further synthetic studies.     

Synthesis of novel β-carboline based chalcones with high cytotoxic activity against breast cancer cells

A series of novel β-carboline based chalcones was synthesized and evaluated for their cytotoxic activity against a panel of human cancer cell lines. Among them we found that two of the compounds 7c and 7d, showed marked anti-proliferative activity in a panel of solid tumor cell lines with highest effect in breast cancer. The compounds 7c and 7d showed an IC₅₀ of 2.25 and 3.29 μM, respectively against human breast cancer MCF-7 cell line. Further, the compound 7c markedly induced DNA fragmentation and apoptosis in breast cancer cells.     

1-Arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones as leads for developing cytotoxins and anticonvulsants

Various substituted 1-arylmethyl-2,3-dioxo-2,3-dihydroindole thiosemicarbazones 3a-h, 1-benzyl-2,3-dioxo-2,3-dihydroindole N⁴-aryl thiosemicarbazones 4a-i and 1-benzyl-2,3-dioxy-2,3-dihydroindole N⁴-cyclohexylthiocarbazone 5 were synthesized. All of these compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Nearly 40% of these compounds possess low micromolar IC₅₀ values and some are either more potent than, or equipotent with, melphalan. Various correlations between the structures of these compounds and cytotoxic potencies were obtained which included the use of QSAR and molecular modeling techniques. Representative compounds displayed anticonvulsant properties in rats and were well tolerated by these animals. The encouraging biodata noted affords adequate rationale for outlining guidelines for further development of these molecular scaffolds.     

Synthesis and antiproliferative activity of some steroidal lactams

Using cholesterol as starting material, a series of 6-substituted-3-aza-A-homo-3-oxycholestanes and 6-substituted-4-aza-A-homo-3-oxycholestanes were synthesized by the oxidation, reduction, oximation, Beckman rearrangement and condensation reaction. These synthesized compounds displayed a distinct cytotoxicity against MGC 7901, HeLa and SMMC 7404 cancer cells. Our results revealed that the structures of functional groups at position-6 on the steroidal ring are crucial for the IC₅₀ value of antiproliferative activities of these compounds and the cytotoxic activity against MGC 7901 and SMMC 7404 cells was not significantly different between 4-N-lactams and 3-N-lactams when its 6-substituted group was a carbonyl or a hydroximino, but all 3-N-lactams showed a higher cytotoxicity against HeLa cells than 4-N-lactams. In particular, compounds 6, 8, 9 (IC₅₀6: 6.5 μmol/L; 8: 7.7 μmol/L; 9: 5.6 μmol/L) were even more cytotoxic than cisplatin to HeLa cells (positive contrast, 10.1 μmol/L). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.     

Synthesis and investigations into the anticancer and antibacterial activity studies of β-carboline chalcones and their bromide salts

A series of sixteen β-carbolines, bearing chalcone moiety at C-1 position, were prepared from easily accessible 1-acetyl-β-carboline and various aldehydes under basic conditions followed by N²-alkylation using different alkyl bromides. The prepared compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. N²-Alkylated-β-carboline chalcones 13a-i represented the interesting anticancer activities compared to N²-unsubstituted β-carboline chalcones 12a-g. Off the prepared β-carbolines, 13g exhibited broad spectrum of activity with IC₅₀ values lower than 22.5?µM against all the tested cancer cell lines. Further, the N²-alkylated-β-carboline chalcone 13g markedly induced cell death in MDA-MB-231 cells by AO/EB staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48. Additionally, the prepared β-carboline chalcones displayed moderate antibacterial activities against tested bacterial strains.     

Synthesis,Antitumor, and DNA Binding Behavior of Novel 4-(2-Hydroxyquinolin-3-yl)-6-Phenyl-5, 6 Dihydropyrimidin Derivatives in Aqueous Medium

This article deals with the synthesis of 4-(2-hydroxyquinolin-3-yl)-6-phenyl-5,6-dihydropyrimidin derivatives (2a–f), on condensation with various aromatic aldehydes and ketones in aqueous ethanolic NaOH solution yielding the corresponding chalcones (3). These chalcones were further reacted with thiourea/urea in the presence of a base, which led to the formation of the titled derivatives (2a–f). The newly synthesized heterocyles were characterized by elemental analysis, FTIR, ¹HNMR, and electronic and mass spectral data. The compounds (2a and 2b) were evulated for in vitro cyctotoxicity against human breast adenocarcinoma cell (MCF-7). In MTT cytotoxicity studies, both quinolinde derivatives were found most effective. The binding interaction behavior of the compound (2a) and (2d) with calf thymus-DNA (CT-DNA) was studied by electronic spectra, viscosity measurements, and thermal denaturation studies. On binding to CT-DNA, the absorption spectrum underwent bathochromic and hypochromic shifts. The binding constant (K_b) observed 4.3 × 10⁵ M^?1 for (2a), and 3.8 × 10⁵ M^?1 for (2d) suggested that compound (2a) binds more strongly with base pairs than (2d).     

Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents

A novel series of nitrogen-containing chalcones were synthesized by Mannich reaction and were screened for anti-inflammatory related activities such as inhibition of cyclooxygenase-2 (COX-2), trypsin and β-glucuronidase. The antioxidant potential was demonstrated using 1,1-diphenyl-2-picryl hydrazine (DPPH) radical scavenging activity. The results of the above studies shows that the compounds synthesized were found to be effective inhibitors of above pro-inflammatory enzymes, and were found to be possess moderate radical scavenging potential. Overall, the results of the studies reveal that the chalcones with N-methyl piperazine methyl and piperidine methyl substitution (4c, 3b, 4d, 6b) seems to be important for inhibition of β-glucuronidase. Whereas the chalcones with piperidine methyl substitution (8b, 7b, 7c, 6c, 4b, 3c, 3b) were observed as effective inhibitors of COX-2, while the same compounds were found to be less reactive against COX-1 as compared to COX-2.     

Synthesis,cyclooxygenase inhibition and anti-inflammatory evaluation of new 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives possessing methanesulphonyl pharmacophore

A new series of 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives 13a–p were synthesized via aldol condensation of 3/4-nitroacetophenones with appropriately substituted aldehydes followed by cyclization of the formed chalcones with 4-methanesulfonylphenylhydrazine hydrochloride. All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity and ulcerogenic liability. All compounds were more potent inhibitors for COX-2 than COX-1. While most compounds showed good anti-inflammatory activity, compounds 13d, 13f, 13k and 13o were the most potent derivatives (ED₅₀?=?66.5, 73.4, 79.8 and 70.5?μmol/kg, respectively) in comparison with celecoxib (ED₅₀?=?68.1?μmol/kg). Compounds 13d, 13f, 13k and 13o (ulcer index?=?3.89, 4.86, 4.96 and 3.92, respectively) were 4–6 folds less ulcerogenic than aspirin (ulcer index?=?22.75) and showed approximately ulceration effect similar to celecoxib (ulcer index?=?3.35). In addition, molecular docking studies were performed for compounds 13d, 13f, 13k and 13o inside COX-2 active site which showed acceptable binding interactions (affinity in kcal/mol ?2.1774, ?6.9498) in comparison with celecoxib (affinity in kcal/mol ?6.5330).     

Synthesis of 3-aroyl-4-aryl-1-isopropylamino-4-piperidinols and evaluation of the cytotoxicities of the compounds against human hepatoma and breast cancer cell lines

Abstract

Some 4-piperidinol derivatives were synthesized and their cytotoxicity was tested against human hepatoma (Huh7) and breast cancer (T47D) cells. Aryl part was changed as phenyl in 2a, 4-methylphenyl in 2b, 4-methoxyphenyl in 2c, 4-chlorophenyl in 2d, 4-fluorophenyl in 2e, 4-bromophenyl in 2f, 4-nitrophenyl in 2g and 2-thienyl in 3. Compounds were synthesized and reported for the first time by this study except 2a and 2d. Chemical structures were confirmed by ¹H NMR, ¹³C NMR, IR, MS and elemental analyses. Compounds 2a (3.1 times), 2c (3.8 times), 2f (4.6 times), 2g (1.3 times) and 3 (3.2 times) had 1.3–4.6 times higher cytotoxic potency than the reference compound 5-FU against Huh7 cell line while all the compounds synthesized had shown lower activities against T47D cell line than 5-FU. In the light of these results, compounds 2a, 2c, 2f, 2g and 3 may serve as model compounds for further studies.