Facile synthesis of rapamycin-peptide conjugates as mTOR and Akt inhibitors.

A simple and straightforward process for the synthesis of rapamycin peptide conjugates in a regio and chemoselective manner was developed. The methodology comprises the tagging of chemoselective functionalities to rapamycin and peptides which enables the conjugation of free peptides, without protecting the functionality of the side chain amino acids, in high yield and purity. From this methodology, we successfully conjugate free peptides containing up to 15 amino acids. Rapamycin is also conjugated to the peptides known for inhibiting the kinase activity of Akt protein. These conjugates act as dual target inhibitors and inhibit the kinase activity of both mTOR and Akt.

Gedunin isolated from the mangrove plant Xylocarpus granatum exerts its anti-proliferative activity in ovarian cancer cells through G2/M-phase arrest and oxidative stress-mediated intrinsic apoptosis.

Gedunin is a natural tetranorterpenoid secondary metabolite found in plants of the Meliaceae family, which has been reported for its antiparasitic, antifungal and anticancer activities. Here, we describe the molecular mechanisms underlying the in vitro anti proliferative activity of gedunin (isolated from the mangrove plant Xylocarpus granatum) in human ovarian cancer cells. We observed that gedunin triggered severe ROS generation leading to DNA damage and cell cycle arrest in G2/M phase thus inhibiting cell proliferation. ROS upregulation also led to mitochondrial stress and membrane depolarization, which eventually resulted in mitochondria-mediated apoptosis following cytochrome C release, caspase 9, 3 activation, and PARP cleavage. Transmission electron microscopy of gedunin treated cells revealed sub-cellular features typical of apoptosis. Moreover, an upregulation in stress kinases like phospho-ERK 1/2, phospho-p38 and phospho-JNK was also observed in gedunin treated cells. Free radical scavenger N-Acetyl-L-Cysteine (NAC) reversed all these effects resulting in increased cell survival, abrogation of cell cycle arrest, rescue of mitochondrial membrane potential and suppression of apoptotic markers. Interestingly, gedunin is also an inhibitor of the evolutionarily conserved molecular chaperone Heat Shock Protein 90 (hsp90) responsible for maintaining cellular homeostasis. Targeting this chaperone could be an attractive strategy for developing cancer therapeutics since many oncogenic proteins are also client proteins of hsp90. Collectively, our findings provide insights into the molecular mechanism of action of gedunin, which may aid drug development efforts against ovarian cancer.

7-hydroxyfrullanolide, isolated from Sphaeranthus indicus, inhibits colorectal cancer cell growth by p53-dependent and -independent mechanism.

Sphaeranthus indicus Linn. is commonly used in Indian traditional medicine for management of multiple pathological conditions. However, there are limited studies on anticancer activity of this plant and its underlying molecular mechanisms. Here, we isolated an active constituent, 7-hydroxyfrullanolide (7-HF), from the flowers of this plant, which showed promising chemotherapeutic potential. The compound was more effective in inhibiting in vitro proliferation of colon cancers cells through G2/M phase arrest than other cancer cell lines that were used in this study. Consistent with in vitro data, 7-HF caused substantial regression of tumour volume in a syngeneic mouse model of colon cancer. The molecule triggered extrinsic apoptotic pathway, which was evident as upregulation of DR4 and DR5 expression as well as induction of their downstream effector molecules (FADD, Caspase-8). Concurrent activation of intrinsic pathway was demonstrated with loss of ΔΨm to release pro-apoptotic cytochrome c from mitochondria and activation of downstream caspase cascades (Caspase -9, -3). Loss of p53 resulted in decreased sensitivity of cells towards pro-apoptotic effect of 7-HF with increased number of viable cells indicating p53-dependent arrest of cancer cell growth. This notion was further supported with 7-HF-mediated elevation of endogenous p53 level, decreased expression of MDM2 and transcriptional upregulation of p53 target genes in apoptotic pathway. However, 7-HF was equally effective in preventing progression of HCT116 p53+/+ and p53-/- cell derived xenografts in nude mice, which suggests that differences in p53 status may not influence its in vivo efficacy. Taken together, our results support 7-HF as a potential chemotherapeutic agent and provided a new mechanistic insight into its anticancer activity.

Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition.

Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and ß-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to ß-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC50=5.2µM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000mg/kg oral dose.

Synthesis of 3,5-dihydroxy-7,8-dimethoxy-2-(4-methoxyphenyl)benzopyran-4-one derivatives as anticancer agents.

Different alkyl amide (15a-l) and alkyl amine (16a-e) derivatives of 7,8-dimethoxy-3-hydroxy-2-(4-methoxyphenyl)benzopyran-4-one were synthesized and evaluated for their anticancer activity against five different cancer cell lines using SRB assay. Compounds 15e, 15i, 15j and 16a-e showed significant anticancer activity within the range of IC50 2.58-34.86µM. The most promising molecule, 16c, was further analyzed for its effect on cell cycle and apoptosis of estrogen receptor positive cancer cells (MCF-7 cells) which showed that 16c triggered apoptosis in MCF-7 cells and arrested cells population at sub-G0 (apoptotic) and G2M phase. In tubulin polymerization assay, 16c interfered with kinetics of tubulin polymerization.

Synthesis of neolignans as microtubule stabilisers.

Tubulin is a well established target for anticancer drug development. Lignans and neolignans were synthesized as tubulin interacting agents. Neolignans 10 and 19 exhibited significant anticancer activity against MCF-7 and MDAMB-231 human breast cancer cell lines. Both the compounds effectively induced stabilization of microtubule at 4 and 20 µM concentrations respectively. Neolignan 10 induced G2/M phase arrest in MCF-7 cells. Docking experiments raveled that 10 and 19 occupied the same binding pocket of paclitaxel with some difference in active site amino acids and good bioavailability of both the compounds. In in vivo acute oral toxicity 10 was well tolerated up to 300 mg/kg dose in Swiss-albino mice.

Productivity, soil health, and carbon management index of soybean-wheat cropping system under double zero-tillage and natural-farming based organic nutrient management in north-Indian plains.

Conservation-agriculture and organic-farming are two sustainable-agriculture approaches to ensure food security and environmental-sustainability. Hence, a field study assessed the productivity, soil-health and carbon-dynamics of soybean-wheat cropping system (SWCS) under four tillage and residue-management practices (TRMPs) viz., Conventional-tillage without residues (CT-R), conventional-tillage with residue-retention in both crops at 3 t ha-1 each (CT + R), zero-tillage without residues (ZT-R), and zero-tillage with residue-retention in both crops at 3 t ha-1 each (ZT + R); and five organic-nutrient-management-practices (ONMPs) in both crops viz., 100 % RDF (N1), 100 % RDN through FYM (N2), 100 % RDN through VC (N3), 100 % RDN through FYM + Biofertilizers + Cow-urine + Panchgavya + Jeevamrut (N4), and 100 % RDN through VC + Biofertilizers + Cow-urine + Panchgavya + Jeevamrut (N5), in split-plot-design replicated-thrice. Among TRMPs, ZT + R enhanced system-productivity (SEY) by ∼17.2 % over CT-R, besides improved soil available-N, P, K by 6.4, 6.5 and 6.5 %, respectively. SMBC, SMBN and SMBP were higher under ZT + R by 16.2, 21.5 and 10.8 % over CT-R, respectively. ZT + R had higher soil enzyme activities of DHA, Acid-P, ALP, URA, and FDA over CT-R by 19.4, 20.7, 21.5, 20.7 and 15.2 %, respectively. ZT + R also had higher VLC, ACP, LI and CMI over CT-R. Among ONMPs, the natural-farming based ONMP, N5 considerably improved SMBC, SMBN, SMBP, FDA, DHA, Acid-P, URA, and ALP by 12.7-12.9 % over N1 (100 % RDF). ONMP-N5 improved the available-N, P, K content over N1 by 6.6, 5.8 and 6.7 %, respectively. ONMP-N5 had higher (p < 0.05) microbial-count, VLC, APC, LI and CMI; however, system-productivity was ∼4.1 % lower than N1 in this two-years' short-study which further need investigation in multi-location long-term experiments. Overall, the dual-crop basis ZT + R at 6 t ha-1 year-1 + NF-based ONMPs (N5) may harness higher and sustained productivity under SWCS besides advancing soil-health and soil carbon-pools in sandy-loam soils of north-Indian plains and similar soils across south-Asia.

The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype. SIGNIFICANCE: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.

Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy.

Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.

LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL.

LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1- and Cdkn2a-deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL coinhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1-mutant cancer. SIGNIFICANCE: EGFR and AXL are substrates of LZTR1-CUL3 ubiquitin ligase. The frequent somatic and germline mutations of LZTR1 in human cancer cause EGFR and AXL accumulation and deregulated signaling. LZTR1-mutant tumors show vulnerability to concurrent inhibition of EGFR and AXL, thus providing precision targeting to patients affected by LZTR1-mutant cancer. This article is highlighted in the In This Issue feature, p. 517.

Inhibition of p21 activates Akt kinase to trigger ROS-induced autophagy and impacts on tumor growth rate.

Owing to its ability to induce cellular senescence, inhibit PCNA, and arrest cell division cycle by negatively regulating CDKs as well as being a primary target of p53, p21 is traditionally considered a tumor suppressor. Nonetheless, several reports in recent years demonstrated its pro-oncogenic activities such as apoptosis inhibition by cytosolic p21, stimulation of cell motility, and promoting assembly of cyclin D-CDK4/6 complex. These opposing effects of p21 on cell proliferation, supported by the observations of its inconsistent expression in human cancers, led to the emergence of the concept of "antagonistic duality" of p21 in cancer progression. Here we demonstrate that p21 negatively regulates basal autophagy at physiological concentration. Akt activation, upon p21 attenuation, driven ROS accumulation appears to be the major underlying mechanism in p21-mediated modulation of autophagy. We also find p21, as a physiological inhibitor of autophagy, to have oncogenic activity during early events of tumor development while its inhibition favors survival and growth of cancer cells in the established tumor. Our data, thereby, reveal the potential role of autophagy in antagonistic functional duality of p21 in cancer.

Microtubule disrupting agent-mediated inhibition of cancer cell growth is associated with blockade of autophagic flux and simultaneous induction of apoptosis.

OBJECTIVES: Given that autophagy inhibition is a feasible way to enhance sensitivity of cancer cells towards chemotherapeutic agents, identifying potent autophagy inhibitor has obvious clinical relevance. Here, we investigated ability of TN-16, a microtubule disrupting agent, on modulation of autophagic flux and its significance in promoting in vitro and in vivo cancer cell death. MATERIALS AND METHODS: The effect of TN-16 on cancer cell proliferation, cell division, autophagic process and apoptotic signalling was assessed by various biochemical (Western blot and SRB assay), morphological (TEM, SEM, confocal microscopy) and flowcytometric assays. In vivo anti-tumour efficacy of TN-16 was investigated in syngeneic mouse model of breast cancer. RESULTS: TN-16 inhibited cancer cell proliferation by impairing late-stage autophagy and induction of apoptosis. Inhibition of autophagic flux was demonstrated by accumulation of autophagy-specific substrate p62 and lack of additional LC3-II turnover in the presence of lysosomotropic agent. The effect was validated by confocal micrographs showing diminished autophagosome-lysosome fusion. Further studies revealed that TN-16-mediated inhibition of autophagic flux promotes apoptotic cell death. Consistent with in vitro data, results of our in vivo study revealed that TN-16-mediated tumour growth suppression is associated with blockade of autophagic flux and enhanced apoptosis. CONCLUSIONS: Our data signify that TN-16 is a potent autophagy flux inhibitor and might be suitable for (pre-) clinical use as standard inhibitor of autophagy with anti-cancer activity.

3-Arylindanones and related compounds as antiproliferative agents against colorectal cancer.

Diverse benzylidene indanones and their derivatives were synthesized as anticancer agents. Two of the analogues, that is 7 and 22, exhibited significant antiproliferative activity against several human cancer cell lines. Both the compounds possessed antimitotic activity and induced apoptosis in DLD1 colorectal adenocarcinoma cells through activation of caspase pathways. In cell cycle analysis, both the compounds induced predominantly G2/M phase arrest in DLD1 cells. Molecular docking studies revealed that compound 7 occupies colchicine binding pocket of ß-tubulin. Both the compounds were safe in acute oral toxicity in rodents. Both the compounds are further being optimized for better efficacy.

Ormeloxifene-induced unfolded protein response contributes to autophagy-associated apoptosis via disruption of Akt/mTOR and activation of JNK.

Autophagy, a regulated nutrient recycling program can affect both cell survival and cell death. Here, we show that Ormeloxifene (ORM), a selective estrogen receptor modulator approved for oral contraceptive use induces autophagic flux in ovarian cancer cells, which is activated by an ER stress response upstream of autophagy. The ER stress response is characterized by activation of IRE1α, PERK and ATF6 and is under regulation of JNK. Pharmacological inhibition of either autophagy or ER stress increased cell survival, as did silencing of autophagy proteins LC3 and Beclin 1, implying that ORM-induced autophagy is pro-death in nature. Ultrastructural observations of treated cells confirmed stages of autophagic maturation. Caspase-dependent apoptosis succeeded these events and was characterized by generation of reactive oxygen species and disruption of mitochondrial membrane potential. A concomitant inhibition of the Akt/mTOR axis was also observed with possible regulation of Akt by ORM. ORM inhibited tumor growth in ovarian xenograft model and displayed autophagic activity. In summary, in vitro and in vivo results reveal that ORM induces autophagy-associated cell death to attenuate proliferation of ovarian cancer cells. Our results demonstrate that using ORM in combination with ER stress and autophagy modulators could offer better therapeutic outcome in ovarian cancer.

Antiproliferative efficacy of curcumin mimics through microtubule destabilization.

Curcumin possesses an attractive chemical structure with highly conjugated diferuloylmethane core. Curcumin mimics have been designed and prepared with an additional bridged phenyl ring in conjugation. Fourteen diverse analogues were evaluated against a panel of human cancer cell lines. The best analogue of the series i.e. compound 6a exhibited potent cytotoxicity against A431, epidermoid carcinoma cell line (IC50 = 1.5 µM) and DLD1, colorectal adenocarcinoma cell line (IC50 = 6.9 µM). In tubulin kinetics experiment, compound 6a destabilized polymerisation process (IC50 = 4.68 µM). In cell cycle analysis, compound 6a exerted G2/M phase arrest in A431 cells and induced apoptosis. In Ehrlich Ascites Carcinoma in Swiss-albino mice, compound 6a showed 78.6% tumour reduction at 80 mg/kg dose and 57% solid tumour reduction at 150 mg/kg dose. Further, in acute-oral toxicity experiment in rodent model, compound 6a was given in three different oral doses to Swiss albino mice. There were non-significant changes in various biochemical parameters and major body organs studied, including their absolute and relative weights. It was tolerable up to 300 mg/kg dose in Swiss-albino mice. The present study shows that the novel curcumin mimic 6a is a safe and efficacious anticancer compound. However, it needs to be optimized for better efficacy.

Coumarin-chalcone hybrid instigates DNA damage by minor groove binding and stabilizes p53 through post translational modifications.

S009-131, a coumarin-chalcone hybrid, had been shown to possess anti-proliferative and anti-tumour effect by triggering apoptosis. In this report, we investigated role of DNA damage signalling pathway in S009-131 induced cancer cell death. Here we show that S009-131 causes DNA damage by potential binding to the minor groove which led to the phosphorylation and activation of ATM and DNA-PK, but not ATR, at earlier time points in order to initiate repair process. S009-131 induced DNA damage response triggered activation of p53 through phosphorylation at its key residues. Pharmacological inhibition of PIKKs abrogated S009-131 induced phosphorylation of p53 at Ser 15. DNA damage induced phosphorylation resulted in reduced proteasomal degradation of p53 by disrupting p53-MDM2 interaction. Additionally, our docking studies revealed that S009-131 might also contribute to increased cellular p53 level by occupying p53 binding pocket of MDM2. Posttranslational modifications of p53 upon S009-131 treatment led to enhanced affinity of p53 towards responsive elements (p53-RE) in the promoter regions of target genes and increased transcriptional efficiency. Together, the results suggest that S009-131 cleaves DNA through minor groove binding and eventually activates PIKKs associated DNA damage response signalling to promote stabilization and enhanced transcriptional activity of p53 through posttranslational modifications at key residues.

Rapid screening and quantitative determination of bioactive compounds from fruit extracts of Myristica species and their in vitro antiproliferative activity.

Efficient and sensitive LC-MS/MS methods have been developed for the rapid screening and determination of bioactive compounds in different fruit parts of four Myristica species, viz., Myristica beddomeii, Myristica fragrans, Myristica fatua and Myristica malabarica. Twenty-one compounds were identified and characterized on the basis of their accurate mass and MS/MS fragmentation pattern using HPLC-QTOF-MS/MS and NMR analysis. Quantitative determination of five major bioactive compounds was performed using multiple-reaction monitoring mode with continuous polarity switching by UHPLC-QqQLIT-MS/MS. Moreover, in vitro antiproliferative activity of these Myristica species was evaluated against five human cancer cell lines A549, DLD-1, DU145, FaDu and MCF-7 using SRB assay. Seventeen phytoconstituents were identified and reported for the first time from M. beddomeii and sixteen from M. fatua. Quantification result showed highest total content of five major bioactive compounds in mace of M. fragrans. Evaluation of in vitro antiproliferative activity revealed potent activity in all investigated species except M. fragrans.

Recent Advances in chemistry and pharmacology of 2-methoxyestradiol: An anticancer investigational drug.

2-Methoxyestradiol (2ME2), an estrogen hormone metabolite is a potential cancer chemotherapeutic agent. Presently, it is an investigational drug under various phases of clinical trials alone or in combination therapy. Its anticancer activity has been attributed to its antitubulin, antiangiogenic, pro-apoptotic and ROS induction properties. This anticancer drug candidate has been explored extensively in last twenty years for its detailed chemistry and pharmacology. Present review is an update of its chemistry and biological activity. It also extends an assessment of potential of 2ME2 and its analogues as possible anticancer drug in future.

Induction of targeted osteogenesis with 3-aryl-2H-benzopyrans and 3-aryl-3H-benzopyrans: Novel osteogenic agents.

Development of target oriented chemotherapeutics for treatment of chronic diseases have been considered as an important approach in drug development. Following this approach, in our efforts for exploration of new osteogenic leads, substituted 3-aryl-2H-benzopyran and 3-aryl-3H-benzopyran derivatives (19, 20a-e, 21, 22a-e, 26, 27, 28a-e, 29, 31a-b, 32 and 33) have been characterized as estrogen receptor-ß selective osteogenic (bone forming) agents. The synthesized compounds were evaluated for osteogenic activity using mouse calvarial osteoblast cells. Four compounds viz20b, 22a, 27and 32 showed significant osteogenic activity at EC50 values 1.35, 34.5, 407 and 29.5pM respectively. Out of these, 20b and 32 were analyzed for their bone mineralization efficacy and osteogenic gene expression by qPCR. The results showed that 20b and 32 significantly increased mineral nodule formation and the transcript levels of BMP-2, RUNX-2 and osteocalcin at 100pM concentrations respectively. Further mechanistic studies of 20b and 32 using transiently knocked down expression of ER-α and ß in mouse osteoblast (MOBs) showed that 20b and 32 exerts osteogenic efficacy via activation of estrogen receptor-ß preferentially. Additionally, compounds showed significant anticancer activity in a panel of cancer cell lines within the range of (IC50) 6.54-27.79µM. The most active molecule, 22b inhibited proliferation of cells by inducing apoptosis and arresting cell cycle at sub-G0 phase with concomitant decrease in cells at S phase.

Anticancer activity and toxicity profiles of 2-benzylidene indanone lead molecule.

3-(3',4',5'-Trimethoxyphenyl)-4,5,6-trimethoxy,2-(3″,4″-methylenedioxybenzylidene)-indan-1-one (1) is an optimized anti-cancer lead molecule obtained on modification of gallic acid, a plant phenolic acid. It exhibited potent cytotoxicities (IC50=0.010-14.76µM) against various human carcinoma cells. In cell cycle analysis, benzylidene indanone 1 induced G2/M phase arrest in both MCF-7 and MDA-MB-231 cells. It also induced apoptosis in DU145 cells which was evident by cleavage of PARP. In Ehrlich ascites carcinoma, benzylidene indanone 1 showed 45.48% inhibition of tumour growth at 20mg/kg dose in Swiss albino mice. Further, in sub-acute toxicity experiment in Swiss-albino mice, it was found to be non-toxic up to 100mg/kg dose for 28days. The lead compound benzylidene indanone 1 can further be optimized for better anti-cancer activity.