pH-sensitive nanomedicine of novel tubulin polymerization inhibitor for lung metastatic melanoma.

Microtubule binding agents such as paclitaxel and vincristine have activity in metastatic melanoma. However, even responsive tumors develop resistance, highlighting the need to investigate new drug molecules. Here, we showed that a new compound, CH-2-102, developed by our group, has high anti-tumor efficacy in human and murine melanoma cells. We confirmed that CH-2-102 robustly suppresses the microtubule polymerization process by directly interacting with the colchicine binding site. Our results unveil that CH-2-102 suppresses microtubule polymerization and subsequently induces G2 phase cell arrest as one of the possible mechanisms. Notably, CH-2-102 maintains its efficacy even in the paclitaxel resistance melanoma cells due to different binding sites and a non-Pgp substrate. We developed a pH-responsive drug-polymer Schiff bases linker for high drug loading into nanoparticles (NPs). Our CH-2-102 conjugated NPs induced tumor regression more effectively than Abraxane® (Nab-paclitaxel, N-PTX), free drug, and non-sensitive NPs in B16-F10 cell-derived lung metastasis mouse model. Furthermore, our results suggest that the formulation has a high impact on the in vivo efficacy of the drug and warrants further investigation in other cancers, particularly taxane resistant. In conclusion, the microtubule polymerization inhibitor CH-2-102 conjugated pH-responsive NPs induce tumor regression in lung metastasis melanoma mice, suggesting it may be an effective strategy for treating metastatic melanoma.

Palladium(II) Schiff base complex arrests cell cycle at early stages, induces apoptosis, and reduces Ehrlich solid tumor burden: a new candidate for tumor therapy.

Although many cancer drugs are clinically approved, they still suffer from no adequate efficiency or drug resistance, or bad side effects. Therefore, developing safer alternatives of competitive efficiency is needed. This study aimed to investigate, for the first time, the antitumor and apoptotic activities of palladium(II) 2-hydroxyimino-3-(2-hydrazonopyridyl)-butane complex against Ehrlich carcinoma. In vitro, EAC cells were incubated with the complex, and the cells' viability, caspase 8 activity, and cell cycle changes were evaluated. In vivo, eighty adult female Swiss albino mice were distributed randomly in the following groups (n = 10): Normal, EAC, EAC + Cisplatin, and four groups EAC + Complex as well as Normal + Complex. Bodyweight changes were noted. On day 22 mice were sacrificed. Tumors' volume and weight were recorded. Blood picture was routinely investigated. The median survival time (MST) and percent increase in life span (%ILS) were monitored. In vitro, the complex reduced the %viable EAC cells, increased caspase 8 activity, arrested cell cycle at G0/G1, and reduced G2(M) population indicating antiproliferative and antitumor activities via inducing apoptosis. Treatment with the complex in a dose-dependent mode significantly decreased tumor volume and weight, extended the MST and the %ILS, increased mice body weight gain, and improved the blood indexes. Treatment of EAC-bearing mice with the complex highest dose showed more desirable outcomes than treatment with cisplatin. The Normal + Complex group showed no pathological changes indicating safety. In conclusion, our outcomes recommend the Pd(II) complex as a new optimistic candidate for tumor therapy after further studies for validation.

Novel amino acid Schiff base Zn(II) complexes as new therapeutic approaches in diabetes and Alzheimer's disease: Synthesis, characterization, biological evaluation, and molecular docking studies.

Schiff bases are compounds that have gained importance in the paint industry due to their colorful nature and in the field of chemistry and biochemistry due to their biological activities. Various biological applications of Schiff bases, such as antitumor, antifungal, antibacterial, antioxidant, antituberculosis, and anthelmintic, have been widely studied. Within the scope of the study, 5-bromo-2-hydroxybenzaldehyde and amino acid methyl esters (isoleucine, phenylalanine, and methionine) and amino acid Schiff bases were synthesized first. The synthesis of the new Zn(II) complexes of these Schiff bases was carried out by the reaction of synthesized Schiff bases and Zn(OAc)2 ·2H2 O. The structures of the synthesized complexes were elucidated using elemental analysis, Fourier transform infrared, nuclear magnetic resonance, UV-visible, and thermal analysis spectroscopy techniques. These synthesized salts were found to be effective inhibitor compounds for the α-glycosidase, and acetylcholinesterase enzyme with Ki values in the range of 30.50 ± 3.82-38.17 ± 6.26 µM for α-glycosidase, 3.68 ± 0.54-10.27 ± 1.68 µM for butyrylcholinesterase, and 6.26 ± 0.83-15.73 ± 4.73 µM for acetylcholinesterase, respectively.

Synthesis and Spectroscopic Investigations of Schiff Base Ligand and Its Bimetallic Ag(I) Complex as DNA and BSA Binders.

Generation of well-defined potential metallotherapeutics for cancer treatment, one of the most population-threatening diseases, is challenging and an active area of modern research in view of their unique properties and thus multiple possible pathways of action in cells. Specifically, Schiff base ligands were recognized as very promising building blocks for the construction of stable and active complexes of numerous geometries and topologies. Incorporation of Ag(I) ions allows for the formation of flat complexes with potential unoccupied coordination sites, thus giving rise to specific interactions between the metallotherapeutic and biomolecule of interest. Herein, we present the design, synthesis and characterization of new Schiff base ligand L and its Ag(I) bimetallic complex [Ag2L2]2+ with two planar moieties formed around the metal ions and connected through cyclohexane rings, confirmed by X-ray measurements. The compounds were described in context of their potential use as anticancer drugs through DNA and BSA binding pathways by several spectroscopic methods (CD, UV-Vis, fluorescence). We revealed that both, L and [Ag2L2]2+, interact with similar affinity with CT-DNA (Kb~106 M-1), while they differ in the type and strength of interactions with the model albumin-BSA. [Ag2L2]2+ binds BSA in both a dynamic and static manner with the Ksv = 8.8 × 104 M-1 in the Trp-134 and Trp-213 sites, whereas L interacts with BSA only dynamically (KSV = 2.4 × 104 M-1). This found further confirmation in the CD studies which revealed a reduction in α-helix content in the albumin of 16% in presence of [Ag2L2]2+.

Effects of co-administration of arsenic trioxide and Schiff base oxovanadium complex on the induction of apoptosis in acute promyelocytic leukemia cells.

Acute promyelocytic leukaemia (APL) is commonly treated with arsenic trioxide (As2O3) that has many side effects. Given the increasing trend of studies on beneficial therapeutic properties of synthetic compounds containing vanadium, the present study sought to use Schiff base oxovanadium complex to reduce the needed concentration of arsenic trioxide. The HL-60 cell line, which is a model of APL, was selected and the effects of arsenic trioxide and Schiff base oxovanadium complex were individually and simultaneously evaluated on the cell viability by the MTT assay. Flow cytometry and Real-time RT-PCR were also performed to investigate the rate of apoptosis and the expression of P53 and P21 genes, respectively. The IC50 of arsenic trioxide and Schiff base oxovanadium complex on Hl-60 cells was 8.37 ± 0.36 µM and 34.12 ± 1.52 µg/ml, respectively. At the simultaneous administration of both compounds, the maximum decrease in the cell viability was seen in co-administration of 40 µg/ml of Schiff base oxovanadium complex and 0.001 µM of arsenic trioxide. Real-time RT-PCR indicated that the co-administration of Schiff base oxovanadium complex 40 µg/ml and arsenic trioxide 0.001 µM could increase the expression of P53 and P21 genes by 3.76 ± 0.19 and 6.57 ± 1.29 fold change, respectively to the control sample. The flow cytometry studies also indicated that this co-administration could induce apoptosis up to 67% ± 0.9% significantly higher than the control sample. The use of Schiff base oxovanadium complex could significantly reduce the required dose of arsenic trioxide to induce apoptosis in HL-60 cells.

Design, synthesis and biological evaluation of pleuromutilin-Schiff base hybrids as potent anti-MRSA agents in vitro and in vivo.

A series of pleuromutilin derivatives with 1,2,4-triazole-3-substituted Schiff base structure were designed and synthesized under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against 4 strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus 144 and S.aureus AD3) and 1 strain of E. coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, compound 60 exhibited superior in vitro antibacterial effect against MRSA (MIC = 0.25 µg/mL) than tiamulin (MIC = 0.5 µg/mL), and compound 60 (-2.28 log10 CFU/mL) also displayed superior in vivo antibacterial efficacy than tiamulin (-1.40 log10 CFU/mL) in reducing MRSA load in the mouse thigh infection model. The time-kill study and the post-antibiotic effect study indicated that compound 60 showed a faster bactericidal kinetic and longer PAE time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 4.06 and 4.27 h) against MRSA compared with tiamulin (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.72 and 2.14 h). Meanwhile, most of these compounds had no significant inhibitory effect on RAW 264.7 cells and HepG2 cells at the concentration of 4 µg/mL. Additionally, the development of resistance study showed that MRSA did not easily develop resistance against compound 60 compared with tiamulin after induction for 8 passages.

SCR7, a potent cancer therapeutic agent and a biochemical inhibitor of nonhomologous DNA end-joining.

BACKGROUND: DNA double-strand breaks (DSBs) are harmful to the cell as it could lead to genomic instability and cell death when left unrepaired. Homologous recombination and nonhomologous end-joining (NHEJ) are two major DSB repair pathways, responsible for ensuring genome integrity in mammals. There have been multiple efforts using small molecule inhibitors to target these DNA repair pathways in cancers. SCR7 is a very well-studied anticancer molecule that blocks NHEJ by targeting one of the critical enzymes, Ligase IV. RECENT FINDINGS: In this review, we have highlighted the anticancer effects of SCR7 as a single agent and in combination with other chemotherapeutic agents and radiation. SCR7 blocked NHEJ effectively both in vitro and ex vivo. SCR7 has been used for biochemical studies like chromosomal territory resetting and in understanding the role of repair proteins in cell cycle phases. Various forms of SCR7 and its derivatives are discussed. SCR7 is also used as a potent biochemical inhibitor of NHEJ, which has found its application in improving genome editing using a CRISPR-Cas system. CONCLUSION: SCR7 is a potent NHEJ inhibitor with unique properties and wide applications as an anticancer agent. Most importantly, SCR7 has become a handy aid for improving genome editing across different model systems.

Schiff bases of 4-Phenyl-2-Aminothiazoles as hits to new antischistosomals: Synthesis, in vitro, in vivo and in silico studies.

The treatment of schistosomiasis is based on a single drug, the praziquantel (PZQ), an oral bioavailable and efficient agent which causes minimal side effects. The main concern about this approach, however, is that relying on only one drug to treat a helminthic disease is a dangerous strategy since history shows that pathogens easily evolve to resistant forms. Actually, reports about experimental strains exhibiting low sensibility to PZQ can be found in literature. The search for new antischistosomals, consequently, is urgent. Here we report the synthesis of seventeen Schiff bases of 4-(4-Substituted phenyl)-N-(4-substituted benzylidene)thiazole-2-amines which were tested in vitro and in vivo against Schistosoma mansoni adult worms. Moreover, in silico studies to propose potential macromolecular targets and to predict the oral bioavailability were also performed. The analog GPQF-108 exhibited the best in vitro performance (IC50: 29.4 µM, SI:6.1) associated with promising in vivo activity, with a significant decrease in the adult life forms and oviposition. Oral bioavailability could be impaired by the predicted low water solubility of GPQF-108, although it also exhibited good membrane permeability. The water solubility, however, could be improved by decreasing the particles size. Serine/Threonine- and Tyrosine Kinases, Carbonic Anhydrase, Tyrosine Phosphatase and Arginase were predicted as potential macromolecular targets through which the GPQF-108 could be acting against the helminth. This class of compounds exhibited an interesting initial therapeutic profile with the advantage of being chemically diverse from the PZQ and be easily synthesized from commercial reagents which could lead to low-cost drugs. These aspects make this class of compounds interesting hits to be explored against schistosomiasis.

In vivo acute toxicity and anti-gastric evaluation of a novel dichloro Schiff base: Bax and HSP70 alteration.

Chlorine is shown to possess anti-gastric ulcer activity, since it can inactivate Helicobacter pylori, which is regarded as one of the most common risk factors for causing gastric problems. In the current study, the gastroprotective property of a novel dichloro-substituted Schiff base complex, 2, 2'- [-1, 2-cyclohexanediylbis(nitriloethylidyne)] bis(4-chlorophenol) (CNCP), against alcohol-induced gastric lesion in SD rats was assessed. SD rats were divided into four groups, i.e. normal, ulcer control, testing, and reference groups. Ulcer area, gastric wall mucus, and also gastric acidity of the animal stomachs were measured. In addition, antioxidant activity of CNCP was evaluated and its safe dose was identified. Immunohistochemistry staining was also carried to evaluate two important proteins, i.e. Bcl2-associated X protein (Bax) and heat shock protein 70 (HSP70). Moreover, the activities of super oxide dismutase and catalase, as well as the levels of prostaglandin E2 (PGE2) and malondialdehyde (MDA) were also measured. Antioxidant activity of CNCP was approved via the aforementioned experiments. Histological evaluations showed that the compound possesses stomach epithelial defense activity. Additionally, periodic acid-Schiff staining exhibited over-expression of HSP70 and down-expression of Bax protein in the CNCP-treated rats. Moreover, CNCP caused deceased MDA level and elevated PGE2 level, and at the same time increased the activities of the two enzymes.

A Cobalt Schiff-Base Complex as a Putative Therapeutic for Azide Poisoning.

There is presently no antidote available to treat azide poisoning. Here, the Schiff-base compound Co(II)-2,12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)2,11,13,15-pentaenyl dibromide (Co(II)N4[11.3.1]) is investigated to determine if it has the capability to antagonize azide toxicity through a decorporation mechanism. The stopped-flow kinetics of azide binding to Co(II)N4[11.3.1] in the absence of oxygen exhibited three experimentally observable phases: I (fast); II (intermediate); and III (slow). The intermediate phase II accounted for ∼70% of the overall absorbance changes, representing the major process observed, with second-order rate constants of 29 (±4) M-1 s-1 at 25 °C and 70 (±10) M-1 s-1 at 37 °C. The data demonstrated pH independence of the reaction around neutrality, suggesting the unprotonated azide anion to be the attacking species. The binding of azide to Co(II)N4[11.3.1] appears to have a complicated mechanism leading to less than ideal antidotal capability; nonetheless, this cobalt complex does protect against azide intoxication. Administration of Co(II)N4[11.3.1] at 5 min post sodium azide injection (ip) to mice resulted in a substantial decrease of righting-recovery times, 12 (±4) min, compared to controls, 40 (±8) min. In addition, only two out of seven mice "knocked down" when the antidote was administered compared to the controls given toxicant only (100% knockdown).

Anticancer Potential of Palladium(II) Complexes With Schiff Bases Derived from 4-Aminoacetophenone Against Melanoma In Vitro.

BACKGROUND/AIM: Melanoma represents a big challenge for clinical treatment. Besides being the most aggressive and the deadliest form of skin cancer, it is often refractory to commonly used anticancer drugs. Hence, developing new anti-cancer agents is crucial to improve refractory melanoma treatment. Studies using palladium(II) complexes have reported antitumor effects on cancer cells. In this study, we aimed to determine the cytotoxic effect of three novel synthesized Pd(II) complexes with Schiff bases derived from 4-aminoacetophenone on the MDA-MB-435 melanoma cell line. MATERIALS AND METHODS: Cells were treated with ligand and Pd(II) complexes. Cell viability, morphology and death induction upon treatment were examined. RESULTS: Novel synthesized Pd(II) complexes led to decreased viability of cells. They also induced morphological alterations and cell death, mainly in the C3 complex. CONCLUSION: The novel synthesized complexes have a significant cytotoxic effect on cell line MDA-MB-435, especially C3 and can be considered as an antitumor agent for further studies.

Traceable in-cell synthesis and cytoplasm-to-nucleus translocation of a zinc Schiff base complex as a simple and economical anticancer strategy.

We have proposed a facile and cheap cancer therapeutic strategy by in-cell synthesizing theranostic Zn Schiff base complexes with nuclear targeting and DNA damaging capability. The in-cell synthesis can be traced via a green-to-blue fluorescence shift, and the subsequent cytoplasm-to-nucleus translocation realizes cancer-specific therapy both in vitro and in vivo.

Induction of the Endoplasmic Reticulum Stress Pathway by Highly Cytotoxic Organoruthenium Schiff-Base Complexes.

Current anticancer drug discovery efforts focus on the identification of first-in-class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its π-acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds.

Pyrazole Schiff Base Hybrids as Anti-Malarial Agents: Synthesis, In Vitro Screening and Computational Study.

BACKGROUND: Malaria is one of the most vital infectious diseases caused by protozoan parasites of the Plasmodium genus. As P. falciparum, the cause of most of the severe cases of malaria, is increasingly resistant to available drugs such as amodioquine, chloroquine, artemisinin, and antifolates, there is an urgent need to identify new targets for chemotherapy. OBJECTIVE: This study screened novel pyrazole derivatives carrying iminium & benzothiazole group for antimalarial potential against P. falciparum chloroquine sensitive (3D7) strain. MATERIALS & METHODS: Several pyrazole schiff base hybrids with a wide range of substitution have been synthesized via condensation of substituted aniline with substituted 4-formylpyrazole and evaluated for their in vitro antimalarial activity against asexual blood stages of human malaria parasite, Plasmodium falciparum. The interaction of these conjugate hybrids was also investigated by molecular docking studies in the binding site of P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction. RESULTS: Among all compounds, 6bf and 6bd were found to be potential molecules with EC50 1.95µg/ml and 1.98µg/ml respectively. Docking study results reveal that the pyrazole schiff base derivatives occupy the PfFP binding sites and they show good interactions with significant values of binding energies. CONCLUSION: We provide evidence which implicates pyrazole Schiff base hybrids as potential prototypes for the development of antimalarial agents.

Induction of apoptosis in human colorectal cancer cell line, HCT-116 by a vanadium- Schiff base complex.

Vanadium compounds are well known for their therapeutic interventions against several diseases. Various biochemical attributes of vanadium complexes inspired us to evaluate the cancer cell killing efficacy of the vanadium complex, viz., vanadyl N-(2-hydroxyacetophenone) glycinate [VO(NG)2]. Previously we showed that VO(NG)2 is an effective anticancer agent in in vitro and in vivo cancer models and imposed miniscule side effects. Herein we report that VO(NG)2 is significantly cytotoxic to various cancer cell lines. Furthermore, this redox active vanadyl complex altered the redox homeostatsis of many human cancer cell lines significantly. VO(NG)2 actuates programmed cell death in human colorectal carcinoma cells(HCT-116) through mitochondrial outer membrane permeabilization but in caspase independent manner, possibly by altering cellular redox status and by inflicting DNA damage. Thus, the present work is an attempt to provide many evidences regarding the potent and selective chemotherapeutic efficacy of the novel VO(NG)2.

Schiff base complexes of copper and zinc as potential anti-colitic compounds.

The design, synthesis and activity of polymodal compounds for the treatment of inflammatory bowel disease are reported. The compounds, being based on a metal-Schiff base motif, are designed to degrade during intestinal transit to release the bioactive components in the gut. The compounds have been developed sequential with the biomodal compounds combining copper or zinc with a salicylaldehyde adduct. These compounds were tested in a formalin induced colonic inflammation model in BK:A mice. From these studies a trimodal compound based on a zinc Schiff base analogue of sulfasalazine was designed. This was tested against a trinitrobenzenesulfonic acid (TNB) induced colitic model in Wistar rats. The use of two models allows us to test our compounds in both an acute and a chronic model. The trimodal compound reported is observed to provide anticolitic properties in the chronic TNB induced colitis model commensurate with that of SASP. However, the design of trimodal compound still has the capacity for further development. This the platform reported may offer a route into compounds which can markedly outperform the anti-colitic properties of SASP.

Recent Developments of Hydrazide/Hydrazone Derivatives and Their Analogs as Anticonvulsant Agents in Animal Models.

Preclinical Research Epilepsy is a chronic devastating neurological disorder characterized by synchronous interictal discharges. Treatment with antiepileptic drugs (AEDs) can alleviate spontaneous seizure activity without preventing the progression and development of epileptogenesis. Current design and development of new AEDs and strategies for the prevention of epilepsy is focused mainly on attenuating uncontrolled seizures, severe side effects and toxicity in chronic drug therapy. It has thus become necessary to discover new chemical pharmacophores with a broad spectrum of activity and less neurotoxicity. Hydrazide/hydrazone derivatives that possess a -CO-NHN=CH- group constitute an important class of compounds for drug development. This review highlights the specific characteristics of various hydrazide/hydrazone derivatives and structurally related semicarbazones, semicarbazides and Schiff base compounds and their anticonvulsant activities. It is focused on the influence of differently substituted pharmacophores developed through SAR studies and testing their activity against different pharmcological targets. Drug Dev Res 77 : 379-392, 2016. © 2016 Wiley Periodicals, Inc.

Schiff Bases of Benzothiazol-2-ylamine and Thiazolo[5,4-b] pyridin-2-ylamine as Anticonvulsants: Synthesis, Characterization and Toxicity Profiling.

BACKGROUND: Schiff bases have a broad spectrum of biological activities like antiinflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic and so forth. Thus, after a thorough perusal of literature, it was decided to conjugate benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine with aromatic and heteroaromatic aldehydes to get a series of Schiff bases. OBJECTIVE: Synthesis, characterization, in-silico toxicity profiling and anticonvulsant activity of the Schiff bases of Benzothiazol-2-ylamine and Thiazolo [5, 4-b] pyridin-2-ylamine. METHOD: Aniline/4-aminopyridine was converted to the corresponding thiourea derivatives, which were cyclized to obtain benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine. Finally, these were condensed with various aromatic and heteroaromatic aldehydes to obtain Schiff bases of benzothiazol-2-ylamine and thiazolo [5, 4-b] pyridin-2-ylamine. The synthesized compounds were characterized and screened for their anticonvulsant activity using maximal electroshock (MES) test and isoniazid (INH) induced convulsions test. In-silico toxicity profiling of all the synthesized compounds was done through "Lazar" and "Osiris" properties explorer. RESULTS: Majority of the compounds were more potent against MES induced convulsions than INH induced convulsions. Schiff bases of benzothiazol-2-ylamine were more effective than thiazolo [5, 4-b] pyridin-2-ylamine against MES induced convulsions. The compound benzothiazol-2-yl-(1H-indol-2-ylmethylene)-amine (VI) was the most potent member of the series against both types of convulsions. CONCLUSION: Compound VI exhibited the most significant activity profile in both the models. The compounds did not exhibit any carcinogenicity or acute toxicity in the in-silico studies. Thus, it may be concluded that the Schiff bases of benzothiazol-2-ylamine exhibit the potential to be promising and non-toxic anticonvulsant agents.

A Schiff base derivative for effective treatment of diethylnitrosamine-induced liver cancer in vivo.

Hepatocellular carcinoma is one of the most prevalent cancers, with a high morbidity rate, even in developed countries. In the present study, the curative effect of the Schiff base (SB) heterodinuclear copper(II)Mn(II) complex on diethylnitrosamine (DEN)-induced liver carcinoma was investigated. Hepatocarcinoma was initiated by an injection of DEN and promoted by phenobarbital (0.05%) in the diet. In addition, the potential nephrotoxicity of SB was evaluated in a cisplatin-induced nephrotoxicity model. Rats were administered the SB complex (1 and 2 mg/kg body weight/day) for 24 weeks, and cancer progression was investigated by macroscopic, histopathological, and western blot examinations. The administration of SB decreased the incidence and the number of hepatic nodules in a dose-dependent manner by regulating inflammation response and the apoptotic pathway. Western blot analyses from the livers of rats treated with SB after DEN induction showed significantly enhanced Bax and caspase-3 levels, with a marked decrease in the levels of Bcl-2, NF-κB p65 and cyclooxygenase (COX)-2. Results from the nephrotoxicity study showed that, whereas cisplatin increased serum urea nitrogen and creatinine levels, no increase in serum biochemical parameters was detected in SB-treated animals. Moreover, protein levels of NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 were lower, whereas nuclear factor-κB (NF-κB p65) and activator protein-1 levels were higher in the kidneys of cisplatin-treated animals compared with that of the SB groups. Therefore, the SB complex could be an alternative chemotherapeutic option for liver cancer treatment once its safety in clinical applications has been examined.

Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel Schiff's bases as fenamate isosteres.

A series of certain novel Schiff bases as fenamate isosteres (VI:a-k) were synthesized to locate analgesic, anti-inflammatory agent with minimal ulcerogenic potential. The structures of the newly synthesized compounds were elucidated on the basis of their elemental analysis as well as IR, and NMR and mass spectroscopic data. All the compounds were evaluated for their anti-inflammatory activity by carrageenan induced paw oedema method. The compounds possessing good anti-inflammatory activity were further tested for analgesic, ulcerogenic, lipid peroxidation potentials and liver toxicity. Compounds (VI-c), (VI-f), (VI-h) and (VI-i) showed the best anti-inflammatory and significant analgesic activities at doses comparable to that of the standard drug Indomethacin. However, compounds (VI-c) and (VI-f) could be considered the most potent anti-inflammatory and analgesic molecules with maximum reduction in gastro-intestinal ulceration with no hepatocyte necrosis or liver degeneration.