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Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease’s aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent.

Background: Hexahydroquinoline as a small molecule was reported for good cytotoxicity and affinity towards Mcl-1. Hence, new compounds were explored as Mcl-1 inhibitors to be potent anticancer agents. Objective: Compounds were synthesized and screened for cytotoxicity. The active compound was evaluated for cell cycle analysis, Mcl-1 inhibition, caspase-3, and caspase-9 activation. Further compounds were docked with Mcl-1 to confirm the mechanism of cytotoxicity. Methods: Compounds were confirmed by spectral techniques and screened for cytotoxicity at National Cancer Institute (USA). The active derivatives were screened by SRB and MTT. In addition, the potent compound was studied for apoptosis and cell cycle analysis by PI staining, Mcl-1 inhibition by TR-FRET assay, and activation assay of caspase-3 and caspase-9 with the Elisa technique. Results: Compounds 6a and 6b exhibited the highest growth inhibition of 86.28% and 93.20% against SR and HOP- 62, respectively. Compound 6a showed higher cytotoxicity (IC50 = 0.4 μM) against THP-1 and HL-60. It showed 15- fold higher apoptosis compared to control by arresting cells at the Sub-G1 in the cell cycle. It also showed a potent inhibition with IC50 of 1.5 μM against the anti-apoptotic protein Mcl-1, which may induce apoptosis. Furthermore, apoptosis was evidenced by an increase in cleaved caspase-3 and caspase-9 to 4.20 and 3 folds, respectively higher than control. The docking score of compound 6a was in good agreement with the Mcl-1 inhibition assay. Conclusion: Compound 6a inhibited anti-apoptotic protein Mcl-1 and induced activation of pro-apoptotic proteins caspase-3 and caspase-9. These dual results suggested the mechanism of apoptosis and cytotoxicity.

Background Cancer is an ongoing worldwide health problem. Although chemotherapy remains the mainstay therapy for cancer, it is not always effective and has detrimental side effects. Here, we present piperidone compounds P3, P4, and P5 that selectively target cancer cells via protein- and stress-mediated mechanisms. Methods We assessed typical apoptotic markers including phosphatidylserine externalization, caspase-3 activation, and DNA fragmentation through flow cytometry. Then, specific markers of the intrinsic pathway of apoptosis including the depolarization of the mitochondria and the generation of reactive oxygen species (ROS) were investigated. Finally, we utilized western blot techniques, RT-qPCR, and observed the cell cycle profile after compound treatment to evaluate the possible behavior of these compounds as proteasome inhibitors. For statistical analyses, we employed the one-way ANOVA followed by Bonferroni post hoc test. Results P3, P4, and P5 induce cytotoxic effects towards tumorigenic cells, as opposed to non-cancerous cells, at the low micromolar range. Compound treatment leads to the activation of the intrinsic pathway of apoptosis. The accumulation of poly-ubiquitinated proteins and the pro-apoptotic protein Noxa, both typically observed after proteasome inhibition, occurs after P3, P4, and P5 treatment. The stress-related genes PMAIP1, ATF3, CHAC1, MYC, and HMOX-1 were differentially regulated to contribute to the cytotoxic activity of P3–P5. Finally, compound P5 causes cell cycle arrest at the G2/M phase. Conclusion Taken together, compounds P3, P4, and P5 exhibit strong potential as anticancer drug candidates as shown by strong cytotoxic potential, activation of the intrinsic pathway of apoptosis, and show typical proteasome inhibitor characteristics.

Murugesan K, Koroth J, Srinivasan PP, et al. Int J Nanomedicine. 2019;14:5257–5270. The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of H&E images in Figure 8. Specifically, Figure 8, ST06, Tumor image appears to be partly duplicated with the Figure 8, ST06-AgNPs, Tumor image. The authors responded to our queries but were unable to provide a satisfactory explanation for the alleged duplication, nor were they able to provide original data that could adequately verify the findings. The Editor requested to retract the article and the authors agreed with this decision. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

A series of 2-(naphthalen-1-yl)-methyl-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives was prepared and studied for cytotoxicity against murine leukemia L1210, human cervix carcinoma HeLa, and human T-lymphocyte CEM cell lines. The preliminary study showed that compounds 5g, 6g, 7a-c, 7e, and 8e were more potent among the tested compounds. The pharmacokinetic properties of all compounds were then investigated with FAF-Drugs, a tool for prediction of ADME and toxicity. Finally, in order to support in vitro studies, molecular docking studies were performed by using AutoDock Vina with a Lamarckian genetic algorithm to determine whether or not the synthesized compounds could be used as inhibitors for the protein structure 1m17 (EGFR). The docking scores of many compounds were found to be higher than [6,7-bis(2-methoxy-ethoxy)quinazoline-4-yl]-(3-ethynyl phenyl)amine, an inhibitor of the 1m17 EGFR receptor. Among the selected compounds 7b, 7c, 7e, 7f, 7g, and 8g showed better stability in the molecular dynamics simulation study.

In the present study, we have reported crystal structure of 6-(4-methoxyphenyl)-2-(naphthalen-1-ylmethyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (C23H17N3O2S) via single crystal X-ray diffraction. The compound crystallizes in the Triclinic, P 1 ¯ space group. The crystal structure shows intermolecular C – H…O, N – H…N, and π…π interactions. Quantum Theory of Atoms in Molecules (QTAIM) analysis confirmed presence of these interactions with acceptable topological parameters. The PIXEL Coulomb London Pauli (CLP) module was employed to characterize energetics associated with all interactions. Hirshfeld 2D fingerprint plots helped in evaluating intermoleular interactions quantitatively. The molecular electrostatic potential (MEP) was plotted to identify the reaction sites of the molecule. Interestingly, the centrosymmetric molecule exhibits nonlinear optical (NLO) properties calculated using Density Functional Theory (DFT). The mean and hyperpolarizability values are found to be 42.6314 × 10−24 and 11.4248 × 10−30 esu respectively indicating that the compound would be a potential candidate for the NLO applications.

Background Sulfonamides (sulfa drugs) and the metals like mercury, copper, and silver bear antimicrobial properties. The discovery of broad-spectrum antibiotics such as penicillins, cephalosporins, and fluoroquinolones has reduced their use. However, in some instances these drugs are the first-line treatment. The metal-based sulfonamide (e.g., silver sulfadiazine) is considered as first choice treatment in post-burn therapy while the use of silver nanoparticle-cephalexin conjugate to cure Escherichia coli infection explains the synergistic effect of sulfa drugs and their metal conjugates. With growing interest in metal-based sulfonamides and the Schiff base chemistry, it was decided to synthesize sulfonamide Schiff base metal complexes as antioxidant and antimicrobial agent. Results The Fe (III), Ru (III), Co (II), Ni (II), Cu (II), Pd (II), Zn (II), Cd (II), and Hg (II) metal complexes of 4-((thiophen-2-ylmethylene)-amino)-benzenesulfonamide (TMABS) were prepared and studied for thermal stability, geometry, and other electronic properties. The ligand TMABS (Schiff base) and its metal complexes were screened in-vitro for 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and antimicrobial properties against Gram-positive (+ve) Bacillus subtilis (MTCC-441), Staphylococcus aureus (MTCC 7443), Gram-negative (-ve) Escherichia coli (MTCC 40), Salmonella typhi (MTCC 3231), and fungal strains Aspergillus niger (MTCC-1344) and Penicillium rubrum by agar well diffusion method. Results summarized in Tables 3, 4, and 5 represent the inhibitory concentration (IC50) in micromole (μM). The zone of inhibition (ZI) in millimeter (mm) represents antimicrobial properties of TMABS and its metal complexes. Conclusions The synthesized sulfanilamide Schiff base (TMABS) behaved as a neutral and bidentate ligand coordinating with metal ions through its azomethine nitrogen and thiophene sulfur to give complexes with coordination number of 4 and 6 (Fig. 3). The nucleophilic addition of sulfanilamide amino group (–NH2) group to carbonyl carbon (>C=O) of benzaldehyde gave sulfanilamide Schiff base (imine) (Fig. 2). All the metal complexes were colored and stable at room temperature. With IC50 of 9.5 ± 0.1 and 10.0 ± 0.7 μM, the Co, Cu, and Pd complexes appeared better antioxidant than the ligand TMABS (155.3±0.1 μM). The zone of inhibition (ZI) of Hg (28 mm) and Ru complexes (20 mm) were similar to the ligand TMABS (20 mm) against Aspergillus niger (MTCC-1344) as in Figs. 4, 5, and 6. None of the synthesized derivatives had shown better antimicrobial properties than the standard streptomycin sulfate and fluconazole.

Purpose: Curcumin is known for its anticancer and migrastatic activity in various cancers, including breast cancer. Newer curcumin derivatives are being explored to overcome limitations of curcumin like low bioavailability, stability, and side effects due to its higher dose. In this study, the synthesis of ST09, a novel curcumin derivative, and its antiproliferative, cytotoxic, and migrastatic properties have been explored both in vitro and in vivo. Methods: After ST09 synthesis, anticancer activity was studied by performing standard cytotoxicity assays namely, lactate dehydrogenase (LDH) release assay, 3-(4, 5-dimethylthiazol-2-yl)-2&ndash, 5-diphenyletrazolium bromide (MTT), and trypan blue exclusion assay. Annexin-FITC, cell cycle analysis using flow cytometry, and Western blotting were performed to elucidate cell death mechanisms. The effect on the inhibition of cell migration was studied by transwell migration assay. An EAC (Ehrlich Ascites carcinoma) induced mouse tumor model was used to study the effect of ST09 on tumor regression. Drug toxicity was measured using aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and flow-cytometry based lymphocyte count. Histological analysis was performed for assessment of any tissue injury post ST09 treatment. Results: ST09 shows an approximate 100-fold higher potency than curcumin, its parent compound, on breast tumor cell lines MCF-7 and MDA-MB231. ST09 arrests the cell cycle in a cell type-specific manner and induces an intrinsic apoptotic pathway both in vitro and in vivo. ST09 inhibits migration by downregulating matrix metalloprotease 1,2 (MMP1,2) and Vimentin. In vivo, ST09 administration led to decreased tumor volume in a mouse allograft model by boosting immunity with no significant drug toxicity. Conclusion: ST09 exhibits antiproliferative and cytotoxic activity at nanomolar concentrations. It induces cell death by activation of the intrinsic pathway of apoptosis both in vitro and in vivo. It also inhibits migration and invasion. This study provides evidence that ST09 can potentially be developed as a novel antitumor drug candidate for highly metastatic and aggressive breast cancer.

Curcumin is known for its anticancer properties, but its clinical application is limited due to its poor bioavailability and chemical stability. In this study we report the curcumin derivative, ST03 (1,2-bis[(3E,5E)-3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidyl]ethane-1,2-dione) exhibits ∼ 14 fold better bioavailability compared to curcumin and is detectable in plasma up to 12 h. ST03 induces ROS, activates the intrinsic apoptotic pathway as evident by disruption of mitochondrial membrane potential, and induction of proapoptotic proteins in ovarian cancer lines PA1 and A2780. ST03 also blocked the migration of ovarian cancer cells. ST03 exerted its antitumor effect in-vivo in the EAC mouse model by activating the intrinsic apoptotic pathway. Our findings demonstrate ST03, a curcumin derivative, with better bioavailability and stability with no discernable toxicity in vivo to be a promising drug candidate for anticancer therapies., Highlights • Curcumin derivative ST03 induces apoptosis in ovarian cancer cell lines via intrinsic mitochondrial pathway along with induction of ROS. • ST03 inhibits the migration of ovarian cancer cells by altering MMP1. • ST03 treatment reduced tumor growth in EAC induced tumor bearing mouse without any adverse systemic toxicity. • Importantly, ST03 showed better bioavailability compared to its parent compound curcumin., Graphical abstract Image, graphical abstract

This study aims at investigating the cytotoxicity and some of the modes of action of 3,5-bis(3-dimethylamino-4-hydroxybenzylidene)-4-piperidone trihydrochloride 3 and two related compounds 2 (which lacks the dimethylaminomethyl groups) and 4 (which has an additional dimethylaminoethyl substituent in both aryl rings) in order to ascertain the contribution of dimethylaminoethyl substituent to bioactivity. The bioactivities of 2-4 were compared with curcumin 5. Both 2 and 3 displayed submicromolar GI50 values towards HCT-116 cells and were significantly more potent than 4, 5 and 5-fluorouracil (5-FU). All of the compounds displayed greater toxicity towards HCT-116 cells than human CRL-1790 non-malignant colon cells. In HCT-116 cells, the compounds 2, 3 and 5 increased the ratio of oxidised to reduced glutathione and destabilized the mitochondrial membrane potential. Both 2 and 5 produced an increase in mitochondrial superoxide and a burst in intracellular reactive oxygen species in HCT 116 cells. In addition, 2 and 4 stimulated respiration in rat liver mitochondria while 2 and 5 induced mitochondrial swelling. The results suggest that 2 and 5 cause oxidation or cross-linking of the thiols which control the mitochondrial permeability transition.

Background Curcumin is known for its multitude of medicinal properties, including anti-cancer and migrastatic activity. Efforts to overcome poor bioavailability, stability, and side effects associated with the higher dose of curcumin has led to the development of newer derivatives of curcumin. Thus, the focus of this study is to screen novel curcumin derivatives, namely ST03 and ST08, which have not been reported before, for their cytotoxicity and migrastatic property on cancer cells. Methods Anti-cancer activity of ST03 and ST08 was carried out using standard cytotoxicity assays viz., LDH, MTT, and Trypan blue on both solid and liquid cancer types. Flow cytometric assays and western blotting was used to investigate the cell death mechanisms. Transwell migration assay was carried out to check for migrastatic properties of the compounds. Results Both the compounds, ST03 and ST08, showed ~ 100 fold higher potency on liquid and solid tumour cell lines compared to its parent compound curcumin. They induced cytotoxicity by activating the intrinsic pathway of apoptosis in the breast (MDA-MB-231) and ovarian cancer cell lines (PA-1) bearing metastatic and stem cell properties, respectively. Moreover, ST08 also showed inhibition on breast cancer cell migration by inhibiting MMP1 (matrix metalloproteinase 1). Conclusion Both ST03 and ST08 exhibit anti-cancer activity at nanomolar concentration. They induce cell death by activating the intrinsic pathway of apoptosis. Also, they inhibit migration of the cancer cells by inhibiting MMP1 in breast cancer cells.

Kalaimathi Murugesan,*,1Jinsha Koroth,*,1,2 Padma Priya Srinivasan,1 Amrita Singh,3 Sanjana Mukundan,1 Subhas S Karki,4 Bibha Choudhary,1 Chhitar M Gupta11Institute of Bioinformatics and Applied Biotechnology (IBAB), Bangalore, India; 2Department of Pharmaceutical Chemistry, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; 3Water Analysis Laboratory, Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research, Lucknow, India; 4KLE Academy of Higher Education & Research, KLE College of Pharmacy, Bangalore, KN, India*These authors contributed equally to this workBackground: In recent years, green synthesized silver nanoparticles have been increasingly investigated for their anti-cancer potential. In the present study, we aimed at the biosynthesis of silver nanoparticles (AgNPs) using a curcumin derivative, ST06. Although, the individual efficacies of silver nanoparticles or curcumin derivatives have been studied previously, the synergistic cytotoxic effects of curcumin derivative and silver nanoparticles in a single nanoparticulate formulation have not been studied earlier specifically on animal models. This makes this study novel compared to the earlier synthesized curcumin derivative or silver nanoparticles studies. The aim of the study was to synthesize ST06 coated silver nanoparticles (ST06-AgNPs) using ST06 as both reducing and coating agent.Methods: The synthesized nanoparticles AgNPs and ST06-AgNPs were characterised for the particle size distribution, morphology, optical properties and surface charge by using UV-visible spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Elemental composition and structural properties were studied by energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction spectroscopy (XRD). The presence of ST06 as capping agent was demonstrated by Fourier transform infrared spectroscopy (FTIR).Results: The synthesized nanoparticles (ST06-AgNPs) were spherical and had a size distribution in the range of 50–100nm. UV-Vis spectroscopy displayed a specific silver plasmon peak at 410nm. The in vitro cytotoxicity effects of ST06 and ST06-AgNPs, as assessed by MTT assay, showed significant growth inhibition of human cervical cancer cell line (HeLa). In addition, studies carried out in EAC tumor-induced mouse model (Ehrlich Ascites carcinoma) using ST06-AgNPs, revealed that treatment of the animals with these nanoparticles resulted in a significant reduction in the tumor growth, compared to the control group animals.Conclusion: In conclusion, green synthesized ST06-AgNPs exhibited superior anti-tumor efficacy than the free ST06 or AgNPs with no acute toxicity under both in vitro and in vivo conditions. The tumor suppression is associated with the intrinsic apoptotic pathway. Together, the results of this study suggest that ST06-AgNPs could be considered as a potential option for the treatment of solid tumors.Keywords: silver nanoparticles, anticancer, Ehrlich Ascites carcinoma, apoptosis

The terminal step of ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of DNA ligases in all mammals. DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of DNA Ligase I, a therapeutic strategy to impede proliferation of cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesised putative DNA Ligase I inhibitors. Based on various biochemical and biophysical screening approaches, we identify two prospective DNA Ligase I inhibitors, SCR17 and SCR21. Both the inhibitors blocked ligation of nicks on DNA in a concentration-dependent manner, when catalysed by cell-free extracts or purified Ligase I. Docking studies in conjunction with biolayer interferometry and gel shift assays revealed that both SCR17 and SCR21 can bind to Ligase I, particularly to the DNA Binding Domain of Ligase I with KD values in nanomolar range. The inhibitors did not show significant affinity towards DNA Ligase III and DNA Ligase IV. Further, addition of Ligase I could restore the joining, when the inhibitors were treated with testicular cell-free extracts. Ex vivo studies using multiple assays showed that even though cell death was limited in the presence of inhibitors in cancer cells, their proliferation was compromised. Hence, we identify two promising DNA Ligase I inhibitors, which can be used in biochemical and cellular assays, and could be further modified and optimised to target cancer cells. © 2016 Wiley Periodicals, Inc.

Novel 4-piperidone derivatives 2a–f are disclosed as potent cytotoxins. Many of these compounds are more potent than the reference drug melphalan. The compounds in series 2, 4–7 display selective toxicities toward various neoplasms compared to some normal cells. 2a is one of the promising lead molecules that display >11-fold higher growth inhibiting potency than 5-fluorouracil against human colon cancer cells. 2a induces apoptosis, DNA fragmentation, and cleavage of poly ADP-ribose polymerase.

The Current study presents a detailed analysis of nature and strength of various intermolecular interactions in the crystal structure of 5‑bromo-2-(4-methylbenzyl)-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4] thiadiazole molecule. The conformation study of molecule shows the 4-methylbenzyl and nitro-phenyl rings are making dihedral angles of 71.71(8) and 4.39(1)° respectively with imidazo thiadiazole mean plane. The crystal structure generated by the interactions of type Br…N, S…O and Br…Br contacts with other additional surrogate interactions in the solid state. The nature and energy coupled with these interactions were obtained by using PIXEL and ab-initio methods. In addition, quantitative evaluation of intermolecular interactions presented using Hirshfeld fingerprint plots. Using Quantum Theory of Atoms in Molecules (QTAIM) analysis with topological parameters, the presence of these weak interactions are analyzed. Further, a complete analysis of weak interactions were performed by means of topological descriptors of theoretical electron density.

In this paper, a series of imidazo[2,l-b][1,3,4]thiadiazoles have been prepared by reacting 2-amino-1,3,4-thiadiazole with various phenacyl bromides in alcohol. The structures of all the derivatives were con- firmed by IR, NMR and mass spectroscopy. All the derivatives have been tested for cytostatic activity against human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), murine leukemia cell line (L1210), and antiviral activity. Among the tested compounds, derivatives 5b, 5c, and 7a were cytostatic between 49-63 mM against Hela and 7g was cytotoxic at 23 mM against L1210 and CEM cell lines. Compounds 5h and 7h emerged as antiviral agents with slight activity against influenza A and B.

A series of 2-(4-methylbenzyl)-5,6-substituted-imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized, characterized and evaluated for antiproliferative activity and cancer chemopreventive activity. Results showed that molecules with formyl and thiocyanate substiments at the 5 position exhibited an increase in activity against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. Derivative 22 displayed significant in vino anticancer activity against colon cancer (MID GI₅₀ = 0.75 μM). The cancer chemopreventive effect of 19 (IC₅₀ = 489 nM) was almost equipotent to standard oleanolic acid (IC₅₀ = 449 nM).

A series of 2-oxindole derivatives were synthesized and evaluated for cytotoxic activity against different human and murine cancer cell lines and cancer chemopreventive activity. Among the tested compounds VS-06, 08, 12 and 17 displayed cytotoxic activity in the range of 5.0 to 8.5 pM against human T-lymphocyte cells (CEM). Results showed that molecules with electron withdrawing substituent at 4 position of N-phenylacetamide group exhibited an increase in activity against the human tumor cell line CEM. The cancer chemo- preventive effect of VS-01 (IC₅₀ = 451 nM) displayed equipotent activity in comparison to standard oleanolic acid (IC₅₀ = 449 nM).

International audience; Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C18H14N4OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C18H12N4OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 inhibited DNA end joining catalyzed by Ligase IV, whereas their impact was minimal on Ligase III, Ligase I, and T4 DNA Ligase-mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV-null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell.

5,6-Bis(benzylideneamino)-2-mercaptopyrimidin-4-ol (SCR7) is a new anti cancer molecule having capability to selectively inhibit non-homologous end joining (NHEJ), one of the DNA double strand break (DSB) repair pathways inside the cells. In spite of the promising potential as an anticancer agent, hydrophobicity of SCR7 decreases its bioavailability. Herein the entrapment of SCR7 in Pluronic copolymer is reported. The size of the aggregates was determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS) which yields an average diameter of 23 nm. SCR7 encapsulated micelles (ES) were also characterized by small-angle neutron scattering (SANS). Evaluation of its biological properties by using a variety of techniques, including Trypan blue, MTT and Live-dead cell assays, reveal that encapsulated SCR7 can induce cytotoxicity in cancer cell lines, being more effective in breast cancer cell line. Encapsulated SCR7 treatment resulted in accumulation of DNA breaks within the cells, resulting in cell cycle arrest at G1 phase and activation of apoptosis. More importantly, we found ≈ 5 fold increase in cell death, when encapsulated SCR7 was used in comparison with SCR7 alone.

In the title imidazo[2,1-b][1,3,4]thiadiazole derivative, C19H14ClN3OS, the 4-methylbenzyl and chlorophenyl rings are inclined to the planar imidazo[2,1-b][1,3,4]thiadiazole moiety (r.m.s. deviation = 0.012 Å) by 64.5 (1) and 3.7 (1)°, respectively. The molecular structure is primarily stabilized by a strong intramolecular C—H...O hydrogen bond, leading to the formation of a pseudo-seven-memberedS(7) ring motif, and a short intramolecular C—H...N contact forming anS(5) ring motif. In the crystal, molecules are linked by pairs of C—H...S hydrogen bonds, forming inversion dimers. The dimers are linked by C—H...O and C—H...π interactions, forming chains propagating along [110].

Apoptosis is a highly regulated pathway of programmed cell death relying on the fine balance between pro and antiapoptotic binding partners. Overexpression of the antiapoptotic protein BCL2 in several cancers makes it an ideal target for chemotherapy, with minimum side effects. In one of our previous studies, we designed, synthesized and characterized Disarib, a BCL2-specific small molecule inhibitor. Interestingly, Disarib showed a novel mode of BCL2 inhibition, by predominantly binding to its BH1 domain, as compared to the BH3-specific action of other known BCL2 inhibitors. Here, we investigate the mechanism by which Disarib induces cell death, upon binding to BCL2. We find that Disarib specifically disrupted the BCL2-BAK interaction, but not that of BCL2-BAX or other members of the proapoptotic family such as PUMA and BIM, in vitro. Biochemical and biophysical studies demonstrate Disarib-induced inhibition of BCL2-BAK interaction with a Ki of 12.76 nM. Genetic knockout cells of BAK/BAX and double knockout (DKO) cells confirmed a BAK-specific action of Disarib, thereby facilitating apoptosis. Importantly, intracellular FRET in BAK/BAX single and double knockout cells demonstrated BCL2-BAK disruption, and activation of intrinsic pathway of apoptosis upon Disarib treatment. Thus, we report a unique mechanism of action of a BCL2 inhibitor, Disarib, by specifically targeting the interaction of BCL2-BAK, while sparing that of other proapoptotic binding partners. (C) 2017 Elsevier Inc. All rights reserved.

Eleven ruthenium complexes of the type Ru(L)2(Lı)]2+ have been prepared by reacting Ru(L)2C12 (where L=2,2’-bipyridine (bpy)/ 1.10-phcnanthrolinc (phenyl)/ dimethylsulfoxide (DMSO)) with ligands L,= HBT, FCl-HBT, IINH, NCb-MPC, OCH3-MPC, N(CH3’)2-MPC, Cl-MPC (where HBT=2-hydrazinyl-1,3-benzothiazole, FCl-HBT =5-chloro-6-fhıoro-2-hydrazinyl-l,3-benzothiazole, IINH=N-2-oxo-l,2-dihydro-3H-indol-3-ylidene]pyridine-4-carbo-hydrazide, N02-MPC=N(4-nitrophenyl)-methylidene-pyridine-4-carbohydrazide,OCH3-MPC=N(4-methoxyphenyl)methylidene-pyridine-4-carbohydrazide, N(CH3)2-MPC=N(4-dimethylaminophenyl)methylidene-pyridine-4-carbo-hydrazide, C1-MPC=N(4-clılorophenyl)methylidene-pyridine-4-carbohydrazide. The title complexes were subjected to in vitro cytostatic activity testing against the huınan cervix carcinoma HeLa and T-lymphocyte CEM celi lines, and the murine leukemia tumor celi line L1210. The most active ruthenium complex TKA-9 [Ru(phen)2(N(CH3)2-MPC)] revealed a cytostatic activity of 16 pM against CEM, 20 pM against L1210 and 5.5 pM against HeLa tumor cells. Ali complexes were also tested for antiviral activity against a wide variety of DNA and RNA vimses, but found not to display selective activity at subtoxic concentrations

Background In recent years, green synthesized silver nanoparticles have been increasingly investigated for their anti-cancer potential. In the present study, we aimed at the biosynthesis of silver nanoparticles (AgNPs) using a curcumin derivative, ST06. Although, the individual efficacies of silver nanoparticles or curcumin derivatives have been studied previously, the synergistic cytotoxic effects of curcumin derivative and silver nanoparticles in a single nanoparticulate formulation have not been studied earlier specifically on animal models. This makes this study novel compared to the earlier synthesized curcumin derivative or silver nanoparticles studies. The aim of the study was to synthesize ST06 coated silver nanoparticles (ST06-AgNPs) using ST06 as both reducing and coating agent. Methods The synthesized nanoparticles AgNPs and ST06-AgNPs were characterised for the particle size distribution, morphology, optical properties and surface charge by using UV-visible spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Elemental composition and structural properties were studied by energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction spectroscopy (XRD). The presence of ST06 as capping agent was demonstrated by Fourier transform infrared spectroscopy (FTIR). Results The synthesized nanoparticles (ST06-AgNPs) were spherical and had a size distribution in the range of 50–100 nm. UV-Vis spectroscopy displayed a specific silver plasmon peak at 410 nm. The in vitro cytotoxicity effects of ST06 and ST06-AgNPs, as assessed by MTT assay, showed significant growth inhibition of human cervical cancer cell line (HeLa). In addition, studies carried out in EAC tumor-induced mouse model (Ehrlich Ascites carcinoma) using ST06-AgNPs, revealed that treatment of the animals with these nanoparticles resulted in a significant reduction in the tumor growth, compared to the control group animals. Conclusion In conclusion, green synthesized ST06-AgNPs exhibited superior anti-tumor efficacy than the free ST06 or AgNPs with no acute toxicity under both in vitro and in vivo conditions. The tumor suppression is associated with the intrinsic apoptotic pathway. Together, the results of this study suggest that ST06-AgNPs could be considered as a potential option for the treatment of solid tumors.

Aim: Mammalian DNA Ligases play pivotal role in processes such as DNA replication, recombination, and repair, which qualifies them as potent therapeutic targets to eradicate cancer cells. Recently, we have identified a small molecule inhibitor, SCR7 and its oxidized form SCR7-pyrazine (2-mercapto-6,7-diphenylpteridin-4-ol) (SCR7-P), which can inhibit nonhomologous end-joining (NHEJ) in a Ligase IV-dependent manner. In the present study, we describe a water-soluble version of ligase inhibitor, sodium salt of SCR7-P (Na-SCR7-P) and its anti-tumor effects. Materials and Methods: Water soluble version of SCR7-P was synthesised. To study the inhibitory effect of Na-SCR7-P on ligases, we did in vitro DNA end joining assays using double strand DNA substrates. For this, different concentrations of Na-SCR7-P was used along with purified ligases or cell-free extracts. Further, cytotoxicity induced by Na-SCR7-P was evaluated through trypan blue exclusion assay, JC-1 assay and cell cycle analysis. Anti-tumor activity of Na-SCR7-P was investigated in Swiss albino mice and its off-target effects were studied by conducting kidney and liver test and histological evaluation. Further, the anti-angiogenic effect of the compound was studied using in ovo chorioallantoic membrane assay. Results: Na-SCR7-P inhibited NHEJ in a Ligase IV-dependent manner. However, unlike SCR7 and SCR7-P, it blocked joining catalyzed by all three ligases in vitro, making it an ideal cancer therapeutic agent, as it may target multiple DNA transaction processes within the cancer cells. Na-SCR7-P decreased mitochondrial membrane potential (MMP) leading to cell death in cancer cells. Importantly, the administration of Na-SCR7-P led to a significant reduction in tumor growth from 12th day of treatment, and its impact was significantly higher than previously described SCR7, which targets Ligase IV within cells. Antitumor activity of Na-SCR7-P in mice resulted in enhanced lifespan, with minimal side effects. In addition, the in ovo chorioallantoic membrane assay revealed potent antiangiogenic property of Na-SCR7-P. Conclusion: Our results suggest that Na-SCR7-P can target NHEJ and other DNA repair pathways by disrupting Ligase mediated joining and can potentially be used as a strategy for cancer treatment, owing to its water solubility.

A series of new β-isatin aldehyde-N,N′-thiocarbohydrazone, bis-β-isatin thiocarbohydrazones, bis-β-isatin carbohydrazones was synthesized by condensation of 5-substituted isatin with thiocarbohydrazide or carbohydrazide. The chemical structures of the newly synthesized compounds were confirmed by FT-IR, 1H NMR, and mass spectral analysis. The synthesized compounds were evaluated for in vitro antiviral activity against various strains of DNA and RNA viruses, but exhibited moderate antiviral activity compared with the reference compounds. Among all the compounds 6c exhibited the highest chemoprevention activity in a two-stage mouse-skin carcinogenesis test. Graphical abstract

New mononuclear Ru(II) complexes [Ru(A)2(B)]2+, where A = 2,2′-bipyridine/1,10-phenanthroline and B = 3,4,5-tri-OCH3-DPC, 4-CH3-DPC, 4-N(CH3)2-DPC, 4-NO2-DPC, N-BITSZ, PTSZ and PINH, were prepared and characterized by spectroscopic methods. The in vitro cytotoxic activities of the complexes and their corresponding ligands were investigated against the human cancer T-lymphocyte cell lines molt 4/c8 and CEM and the murine tumor leukemia cell line L1210, human promyelocytic leukemia cells (HL-60) and Bel-7402 liver cancer cells by MTT assay. The complexes [Ru(A)2(B)]2+ (A = 1,10-phenanthroline, B = 3,4,5-tri-OCH3-DPC) exerts rather more potent activities against all of these cell lines, especially for CEM and L1210. Ru complexes and structure–activity relationships and anticancer mechanisms are also discussed.

SummaryDNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.

A series of various substituted 3-(3-chloro-4-fluorophenylimino)indolin-2-on and 5-chloro-3-(3- chloro-4-fluorophenylimino)indolin-2-on Mannich base derivatives (IIIa-f) were synthesized. All the synthesized compounds were characterized on the basis of UV, IR, and 1H NMR spectral data. These synthesized compounds were tested for their antibacterial activities against Gram +ve and Gram –ve bacteria and beta lactamase inhibitory activity which found as moderate to good for all synthesized compounds. The compound IIId was most active against all strains of bacteria as compared to synthetic compounds

Resveratrol is one of the most widely studied bioactive plant polyphenols which possesses anticancer properties. Previously we have reported synthesis, characterization and identification of a novel resveratrol analog, SS28. In the present study, we show that SS28 induced cytotoxicity in several cancer cell lines ex vivo with an IC50 value of 3–5 μM. Mechanistic evaluation of effect of SS28 in non-small cell lung cancer cell line (A549) and T-cell leukemic cell line (CEM) showed that it inhibited Tubulin polymerization during cell division to cause cell cycle arrest at G2/M phase of the cell cycle at 12–18 h time period. Immunofluorescence studies confirmed the mitotic arrest upon treatment with SS28. Besides, we show that SS28 binds to Tubulin with a dissociation constant of 0.414 ± 0.11 μM. Further, SS28 treatment resulted in loss of mitochondrial membrane potential, activation of Caspase 9 and Caspase 3, leading to PARP-1 cleavage and finally cell death via intrinsic pathway of apoptosis. Importantly, treatment with SS28 resulted in regression of tumor in mice. Hence, our study reveals the antiproliferative activity of SS28 by disrupting microtubule dynamics by binding to its cellular target Tubulin and its potential to be developed as an anticancer molecule.

The title imidazo[2,1-b][1,3,4]thia­diazole derivative is non-planar, with the 4-methyl­benzyl and chloro­phenyl rings being inclined to the imidazo[2,1-b][1,3,4]thia­diazole ring system by 64.5 (1) and 3.7 (1)°, respectively., In the title imidazo[2,1-b][1,3,4]thia­diazole derivative, C19H14ClN3OS, the 4-methyl­benzyl and chloro­phenyl rings are inclined to the planar imidazo[2,1-b][1,3,4]thia­diazole moiety (r.m.s. deviation = 0.012 Å) by 64.5 (1) and 3.7 (1)°, respectively. The mol­ecular structure is primarily stabilized by a strong intra­molecular C—H⋯O hydrogen bond, leading to the formation of a pseudo-seven-membered S(7) ring motif, and a short intra­molecular C—H⋯N contact forming an S(5) ring motif. In the crystal, mol­ecules are linked by pairs of C—H⋯S hydrogen bonds, forming inversion dimers. The dimers are linked by C—H⋯O and C—H⋯π inter­actions, forming chains propagating along [110].

A series of 2,5,6-substituted imidazo2,1-b]1,3,4]thiadiazole derivatives have been prepared and were tested for antiproliferative activity on cancer cells at the National Cancer Institute. Results showed that molecules with a benzyl group at position 2, exhibited an increase in activity for the introduction of a formyl group at the 5 position. The compound 2-benzyl-5-formyl-6-(4-bromophenyl)imidazo 2,1-b]1,3,4]thiadiazole 22 has been chosen for understanding the mechanism of action by various molecular and cellular biology studies. Results obtained from cell cycle evaluation analysis, analysis of mitochondrial membrane potential and Annexin V-FITC by flow cytometric analysis, ROS production and expression of apoptotic and DNA-repair proteins suggested that compound 22 induced cytotoxicity by activating extrinsic pathway of apoptosis, however, without affecting cell cycle progression. (C) 2014 Elsevier Ltd. All rights reserved.

Antiapoptotic protein BCL2, serves as an excellent target for anticancer therapy owing to its increased level in cancers. Previously, we have described characterization of a novel BCL2 inhibitor, Disarib, which showed selective cytotoxicity in BCL2 `high' cancer cells and CLL patient cells. Here, we have investigated the mechanism of Disarib-induced cytotoxicity, and compared its efficacy with a well-established BCL2 inhibitor, ABT199. We show that Disarib administration caused tumor regression in mouse allograft and xenograft models, exhibited platelet sparing property and did not exhibit significant side effects. Importantly, comparison between Disarib and ABT199, revealed higher efficacy for Disarib in mouse tumor model and cancer cell lines. Disarib induced cell death by activating intrinsic apoptotic pathway. Interestingly, Disarib showed synergism with paclitaxel, suggesting its potential for combination therapy. Thus, we provide mechanistic insights into the cell death pathways induced by Disarib, report that Disarib exhibited better effect than currently used ABT199 and demonstrate its combinatorial potential with paclitaxel. (C) 2016 Elsevier Inc. All rights reserved.

The antiapoptotic protein BCL 2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL 2 inhibitor. Disarib showed selective cytotoxicity in BCL 2 high cancer cell lines, and CLL patient primary cells, as compared to BCL 2 low cell lines. BCL 2 knockdown in cells rendered remarkable resistance to Disarib, while sensitivity was regained upon its ectopic expression, establishing target specificity. In silico , biochemical and biophysical studies demonstrated strong affinity of Disarib to BCL 2, but not to other antiapoptotic BCL 2 family members viz., BCL ‐xL , BCL 2A1 etc. Interestingly, biophysical studies showed that BH 1 domain deletion mutant demonstrated ~ 67‐fold reduction in BCL 2‐Disarib interaction, while it was only ~ 20‐fold in the case of BH 3 deletion mutant, suggesting predominant involvement of the BH 1 domain for Disarib binding. Thus, we report identification of a novel BCL 2 inhibitor with a unique mechanism of BCL 2 inhibition, as opposed to the well‐studied BH 3 domain targeting.

Various 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (4a, b) and 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-(phenyl-4-substituted)hydrazinecarbothioamide (5a–h) derivatives were synthesized. The compounds were screened for cytotoxicity against human HeLa and CEM T-lymphocytes as well as murine L1210 cells. The compounds were also screened for β-lactamase inhibitory activity, antiviral, antibacterial, and antifungal activity against various strains of microorganisms. Several of these compounds were endowed with low micromolar 50 %-cytostatic concentration (IC50) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells (L1210) were also the most inhibitory against human T-lymphocyte (CEM) tumor cells. Derivative 2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazinecarbothioamide 5c emerged as the most potent cytostatic compound among the tested compounds. Derivatives 4b, 5a, 5b, and 5d showed antiviral activity against HEL cell cultures (IC50 11–20 μM). Moderate antimicrobial activity was observed for all derivatives. The encouraging cytostatic and antiviral activity data provide an adequate rationale for further modification of these molecular scaffolds. Graphical abstract Derivative 5c (1.9–4.4 μM) emerged as the most potent cytostatic compound among the tested compounds. Derivatives 4b, 5a, 5b, and 5d showed antiviral activity against HEL cell cultures (IC50 11–20 μM).

The synthesis and spectroscopic characterization of ruthenium complexes ( R-1 to R-8 ) of the type [Ru(A) 2 (B)], (where A = 1,10-phenanthroline/2,2′-bipyridine and B = 3,4,5-tri-OCH 3 -DPC, 4-CH 3 -DPC, 4-N-(CH 3 ) 2 -DPC, 4-NO 2 -DPC are described. These ligands form bidentate octahedral ruthenium complexes. The title complexes were subjected to in vitro cytotoxic activity measurements against the human cancer T-lymphocyte cell lines MTT assay. In vitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.24 to 1.4 μg/mL against CEM, 0.44 to 1.9 μg/mL against Molt4/C8, 0.28 to 1.5 μg/mL against L1210, 0.24 to 0.98 μg/mL against HL60, and 0.25 to 1.2 μg/mL against BEL7402, depending the nature of the compound.

The synthesis, antineoplastic, cytotoxic, and antibacterial activities of Ru(II) complexes derived from quinazoline and thiosemicarbazone ligands are reported. These complexes have been prepared and characterized by UV-Vis, IR, 1H-NMR, FAB-mass spectroscopy, and elemental analysis. The ligands and resulting complexes were subjected to in vivo antineoplastic activity against a transplantable murine tumor cell line Ehrlich ascites carcinoma (EAC) and in vitro cytotoxic activity against human cancer cell line Molt 4/C8, CEM, and murine tumor cell line L 1210. The ruthenium complexes show promising biological activity especially in decreasing tumor volume and viable ascitic cell counts. These complexes prolonged the life span of mice bearing EAC tumors by 10–52%. In vitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.29 to 2.9 µmol L−1 against Molt 4/C8, 0.22 to 2.1 µmol L−1 against CEM and 0.42 to 4.7 µmol L−1 against L1210 cell proliferation, depending on the nature of the compo...

A number of imidazo[2,1-b][1,3,4]thiadiazole derivatives having alkyl and aryl moieties attached to positions 2 and 6 of imidazo[2,1-b][1,3,4]thiadiazole nucleus, respectively, were prepared and characterized by IR, NMR and mass spectroscopy. Antiinflammatory activity was evaluated by carrageenan-induced rat paw edema assay. By 5th hours, all compounds demonstrated anti-inflammatory activity similar or higher than that of standard NSAID, ibuprofen.

The synthesis and characterization of ruthenium complexes (Rul-Ru8) of the type [Ru(S)2(K)], (where S = 1,10-phenanthroline/ 2,2’-bipyridine and K = iinh, inhba, na, mitsz) are described. These ligands form bidentate octahedral ruthenium complexes. The title compounds were subjected to in vitro cytostatic activity measurements against the human cancer T-lymphocyte cell lines Molt 4/C8 and CEM, and the murine tumor leukemia cell line LI210. In vitro evaluation of these ruthenium compounds revealed cytotoxic activity from 0.84 to 119 ug/mL against CEM, 3.7 to 158 ug/mL against Molt and 15 to >200 ug/mL against LI 210 cell proliferation, depending the nature of the compound

A series of 1,3,5-trisubstituted-2-oxindole derivatives have been synthesized by reaction of 2,3-dihydro-2,3-dioxindol , l-benzyl-2,3-dihydro-2,3-dioxindole and an appropriate benzoyl hydrazide. Structures of these compounds were established by IR, !H NMR, I3C NMR, Mass spectroscopy. All the compounds were evaluated for their preliminary in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain using broth dilution assay method. The results show that compounds 3a, 3c, 4a, 4b and 4h exhibited anti-tubercular activity at 25 ug/mL. Some of the selected compounds were evaluated for their preliminary in vitro antibacterial activity against Bacillus subtilis and Staphylococcus aureus and displayed mild antibacterial activity on comparison to standard streptomycin

A simple and efficient method was developed for the synthesis of 2,6-disubstituted-imidazo[2,1-b][1,3,4]thiadiazoles under microwave (MW) activation using 2-amino-5-substituted-1,3,4-thiadiazoles and appropriate bromo ketones as materials. All reactions demonstrated the benefits of MW reactions: convenient operation, short reaction time, and good yields. All derivatives were characterized by IR, NMR, and Mass spectroscopy. Antibacterial and antifungal activity was performed using cup plate method against Staphylococcus aureus, Klebsiella, and Candida albicans microorganisms. 2-(4-nitro benzyl)-6-(4-bromo phenyl)imidazo[2,1-b][1,3,4]thiadiazole (4Ce) was the only derivative which showed activity against Klebsiella at low micromolar concentration (5 μg/ml) with moderate zone of inhibition. And 2-(4-nitro benzyl)-6-(4-fluoro phenyl)imidazo[2,1-b][1,3,4]thiadiazole (4Cf) as the most potent antifungal active derivative at 50 μg/ml against C. albicans on comparison to standard fluconazole.

Mononuclear Ru complexes were evaluated for its cytotoxicity against two human leukemic cell lines such as acute myeloblastic leukemia (HL-60) and chronic myelogenic leukemia (K-562). Cytotoxicity was assayed by MTT assay. Fluorescent microscopic analysis, DNA fragmentation study by agarose gel electrophoresis, flow cytometric analysis, and caspase activity by spectrofluorimetry were carried out to evaluate the apoptosis-inducing property of Ru complexes. Ru complexes exhibited cytotoxicity against both the tested cell lines in a dose-dependent manner. Microscopic examination of ruthenium complex-treated cells showed characteristic morphological features of apoptosis, like cell shrinkage and formation of apoptotic bodies. Fluorescent staining with Hoechst 33342 revealed distinct chromatin condensation and nuclear fragmentation. DNA fragmentation pattern and flow cytometric analysis indicated that the cells treated with ruthenium complexes underwent apoptotic cell death. Thus from this investigation it may be concluded that Ru complexes act by the induction of apoptosis in tested human leukemic cell lines.