An Overview of Cancer Biology, Pathophysiological Development and It's Treatment Modalities: Current Challenges of Cancer anti-Angiogenic Therapy.

A number of conditions and factors can cause the transformation of normal cells in the body into malignant tissue by changing the normal functions of a wide range of regulatory, apoptotic, and signal transduction pathways. Despite the current deficiency in fully understanding the mechanism of cancer action accurately and clearly, numerous genes and proteins that are causally involved in the initiation, progression, and metastasis of cancer have been identified. But due to the lack of space and the abundance of details on this complex topic, we have emphasized here more recent advances in our understanding of the principles implied tumor cell transformation, development, invasion, angiogenesis, and metastasis. Inhibition of angiogenesis is a significant strategy for the treatment of various solid tumors, that essentially depend on cutting or at least limiting the supply of blood to micro-regions of tumors, leading to pan-hypoxia and pan-necrosis inside solid tumor tissues. Researchers have continued to enhance the efficiency of anti-angiogenic drugs over the past two decades, to identify their potential in the drug interaction, and to discover reasonable interpretations for possible resistance to treatment. In this review, we have discussed an overview of cancer history and recent methods use in cancer therapy, focusing on anti-angiogenic inhibitors targeting angiogenesis formation. Further, this review has explained the molecular mechanism of action of these anti-angiogenic inhibitors in various tumor types and their limitations use. In addition, we described the synergistic mechanisms of immunotherapy and anti-angiogenic therapy and summarizes current clinical trials of these combinations. Many phase III trials found that combining immunotherapy and anti-angiogenic therapy improved survival. Therefore, targeting the source supply of cancer cells to grow and spread with new anti-angiogenic agents in combination with different conventional therapy is a novel method to reduce cancer progression. The aim of this paper is to overview the varying concepts of cancer focusing on mechanisms involved in tumor angiogenesis and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy.

Synthesis of a Family of Pd(II) Complexes Using Pyridyl-Ketone Ligands: Crystal Structure, Thermal, Physicochemical, XRD/HSA, Docking, and Heck Reaction Application.

Four Pd(II) complexes, (dpk)PdCl2 (complex-1), and (dpk)Pd(OAc)2 (complex-2) have been prepared using di(2-pyridyl) ketone as the chelate ligand (dpk). The (dpk·EtOH)PdCl2 (complex-3) and (dpk·EtOH)Pd(OAc)2 (complex-4) were synthesized by selectively introducing complex-1 and complex-2 to an EtOH in situ nucleophilic addition reaction on the O=C of the dpk ligand, respectively. All complexes were characterized using CHN-EA, UV-vis, FT-IR, FAB-MS, EDX, TGA, and NMR physicochemical tools. The XRD-crystallography technique was employed to ascertain the structure of complex-3. The analysis revealed a monoclinic/P21/c crystal system characterized by a square planar structure oriented in the cis direction around the Pd center. Several C-H···Cl and O-H···O H-bonds constructing 2D-S12 and S7 synthons were confirmed via XRD/HSA interactions. The influence of EtOH addition to the O=C group of dpk in (dpk)PdCl2 was documented by using UV-vis/FT-IR spectra and TGA analysis. As catalysts, all complexes have demonstrated a notable catalytic function in the Heck reaction, resulting in a high yield under gentle conditions using iodobenzene and methyl acrylate as model reactions. Moreover, the complex-1 and complex-3 docking activity was evaluated against 1BNA-DNA.

Synthesis, molecular docking, analgesic, anti-inflammatory, and ulcerogenic evaluation of thiophene-pyrazole candidates as COX, 5-LOX, and TNF-α inhibitors.

The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using 1H NMR, 13C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series. The compounds (7f and 7g) with effective in vitro potentials were further analyzed for analgesic, anti-inflammatory, and ulcerogenic evaluations. Also, to ascertain the binding affinities of compounds (7a-j), docking assessments were carried out and the ligand (7f) with the highest binding affinity was docked to know the interactions of the ligand with amino acids of target proteins.

Synthesis, crystal structure, Hirshfeld surface analysis, energy frameworks and computational studies of Schiff base derivative.

The compound (E)-ethyl 3-(2-(2,4-dinitrophenyl)hydrazono)butanoate (3) was synthesised and crystallized using ethanol as a solvent. The compound was characterized by 1H NMR, and single crystal X-ray diffraction. The compound crystallizes in the monoclinic crystal system with the space group P21/c. The intermolecular interactions and the interaction energies responsible for the stabilization of the molecules were determined by Hirshfeld surface analysis and energy framework calculations. The structure of the compound was optimized by Density Functional Theory calculations and HOMO-LUMO energy gap was calculated. The non-covalent interactions were revealed by reduced density gradient analysis. The Mulliken atomic charges and natural atomic charges were calculated by density functional theory calculations. The reactive sites present in the molecule are shown by molecular electrostatic potential map. The inter and intra molecular charge transfer were investigated by NBO analysis.

Discovery of novel benzophenone integrated derivatives as anti-Alzheimer's agents targeting presenilin-1 and presenilin-2 inhibition: A computational approach.

The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aß42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aß. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer's potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.

Antiproliferative pharmacophore azo-hydrazone analogue BT-1F exerts death signalling pathway targeting STAT3 in solid tumour.

BACKGROUND: Anomalous activation of intra-cellular signalling cascades confers neoplastic properties on malignant cells. The JAK2/STAT3 proteins play a pivotal role in the pathogenesis of most of the solid malignancies. The over expression of STAT3 in these tumours results in an evasion of apoptosis and thereby pathogenesis. Hence, strategy to target STAT3 to regress tumour development is an emerging new concept. As an approach, anti-neoplastic drug, Azo-hydrozone analogue, BT-1F with potential anti-proliferative effect was evaluated to demonstrate its capacity to counteract STAT3 signal with mechanistic approach. METHODS: Cell based screening for cytotoxicity was performed through MTT, LDH and Trypan blue. The BT-1F induced anti-clonogenic property by clonogenic assay. The apoptotic capacity was examined by crystal violet staining, flow cytometry, Annexin-FITC, DAPI and TUNEL assay. The altered signalling events were studied using immunoblot. The drug-induced anti-tumour effect was evaluated in an in-vivo solid tumour model and molecular interaction was further validated by in-silico studies. RESULTS: The BT-1F exerts chemo-sensitivity specifically against EAC and A549 cells without altering its normal counterpart. The anti-proliferative/anti-clonogenic effect was due to the induction of apoptosis through inhibition of STAT3Tyr705 signal. Eventually downstream signalling proteins p53, Bax, Bad and Bcl-xL were significantly altered. Further in-vivo experimental results validated  in-vitro findings. The computational approaches assures the BT-1F efficiency in binding with STAT3. CONCLUSION: Systemic validation of STAT3 target drug, BT-1F in in-vitro, in-silico and in-vivo models has promising strategy for solid cancer treatment.

Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer.

Reigning of the abnormal gene activation associated with survival signalling in lung cancer leads to the anomalous growth and therapeutic failure. Targeting specific cell survival signalling like JAK2/STAT3 nexus has become a major focus of investigation to establish a target specific treatment. The 2-bromobenzoyl-4-methylphenoxy-acetyl hydra acetyl Coumarin (BP-1C), is new anti-neoplastic agent with apoptosis inducing capacity. The current study was aimed to develop antitumor phramacophore, BP-1C as JAK2 specific inhibitor against lung neoplastic progression. The study validates and identifies the molecular targets of BP-1C induced cell death. Cell based screening against multiple cancer cell lines identified, lung adenocarcinoma as its specific target through promotion of apoptosis. The BP-1C is able to induce, specific hall marks of apoptosis and there by conferring anti-neoplastic activity. Validation of its molecular mechanism, identified, BP-1C specifically targets JAK2Tyr1007/1008 phosphorylation, and inhibits its downstream STAT3Tyr705 signalling pathway to induce cell death. As a consequence, modulation in Akt/Src survival signal and altered expression of interwoven apoptotic genes were evident. The results were reproducible in an in-vivo LLC tumor model and in-ovo xenograft studies. The computational approaches viz, drug finger printing confers, BP-1C as novel class JAK2 inhibitor and molecular simulations studies assures its efficiency in binding with JAK2. Overall, BP-1C is a novel JAK2 inhibitor with experimental evidence and could be effectively developed into a promising drug for lung cancer treatment.

Design, Synthesis, Characterization, and Analysis of Antimicrobial Property of Novel Benzophenone Fused Azetidinone Derivatives through In Vitro and In Silico Approach.

A sequence of novel 2-(4-benzoyl-2-methyl-phenoxy)-N-(3-chloro-2-oxo-4-phenyl-azetidin-1-yl)-acetamide analogues 9(a−n) were synthesized by multistep synthesis. The newly synthesized compounds were well characterized, and their antimicrobial activities were carried out by disc diffusion and broth dilution methods. Further, all the novel series of compounds (9a−n), were tested against a variety of bacterial and fungal strains in comparison to Ketoconazole, Chloramphenicol, and Amoxicillin as standard drugs, respectively. Compounds 9a, 9e, and 9g as a lead molecule demonstrated a good inhibition against tested strains. Further, molecular docking studies have been performed for the potent compounds to check the three-dimensional geometrical view of the ligand binding to the targeted proteins.

Tumor angiogenesis: Current challenges and therapeutic opportunities.

Angiogenesis plays an important role in the development of cancer since it allows for the delivery of oxygen, nutrients, and growth factors as well as tumor dissemination to distant organs. Inhibition of angiogenesis is an important strategy for the prevention of multiple solid tumors that depend on cutting or at least reducing the blood supply to tumor micro-regions, resulting in pan-hypoxia and pan-necrosis within solid tumor tissues. These drugs are an important part of treatment for some types of cancer. As a stand-alone therapy, inhibition of tumor angiogenesis can arrest or halt tumor growth, but will not eliminate the tumor. Therefore, anti-angiogenic drugs in combinations with another anti-cancer treatment method, like chemotherapy, lead to being critical for optimum cancer patient outcomes. Over the last two decades, investigations have been made to improve the efficacy of anti-angiogenic drugs, recognize their potential in drug interactions, and come up with plausible explanations for possible treatment resistance. This review will offer an overview of the varying concepts of tumor angiogenesis, several important angiogenic factors; focus on the role of anti-angiogenesis strategies in cancer treatment.

Design, synthesis, docking, Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein from Staphylococcus aureus.

It is of interest to document the design, synthesis, docking, Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein (PDB ID: 3VOB) from Staphylococcus aureus for antimicrobial applications. We report the quantitative structure function data in this context.

Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs to induce anti-neoplasia.

BACKGROUND: Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression. METHODS: A new series of DPA (7a-t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches. RESULTS: Initial in vitro anti-proliferative screening of Compounds DPA (7a-t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC50 value of 4.3 µM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways. CONCLUSIONS: Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity.

Synthesis, structural characterization, and DFT studies of anti-cancer drug N-(2-Aminophenyl)-2-(4-bromophenoxy)acetamide.

Drug design is an integrated and developing system that portends an era of a novel and safe tailored drugs. It involves studying the effects of biologically active synthetic, semi-synthetic, and natural compounds based on molecular interactions in terms of molecular structure with activated functional groups or its unique physicochemical properties involved. The title compound, N-(2-aminophenyl)-2-(4-bromophenoxy) acetamide (c), was synthesized in a good yield and characterized by different spectroscopic techniques (1H, 13CNMR, and LC-MS) and finally, the structure was confirmed by X-ray diffraction (XRD) studies. The XRD data confirms that the cryatal structure is orthorhombic with space group of Pca2 1 . The intermolecular interactions (N-H … O and N-H … Cg) inside the molecule stabilizes the crystal structure. The existence of this intermolecular interactions are computed by the Hirshfeld surfaces (HS) and two-dimensional (2D) fingerprints plot analysis. In addition to this, Energy frame work analysis is performed to quantify the interaction energies between the molecular pairs in a crystal by incorporating new version of CrystalExplorer17 using the energy model of HF/3-21G. Also to calculate the HOMO and LUMO energies, DFT calculations were carried out.

Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression.

BACKGROUND: Hypoxic microenvironment is a common feature of solid tumors, which leads to the promotion of cancer. The transcription factor, HIF-1α, expressed under hypoxic conditions stimulates tumor angiogenesis, favoring HIF-1α as a promising anticancer agent. On the other hand, synthetic Indolephenoxyacetamide derivatives are known for their pharmacological potentiality. With this background here, we have synthesized, characterized, and validated the new IPA (8a-n) analogs for anti-tumor activity. METHODS: The new series of IPA (8a-n) were synthesized through a multi-step reaction sequence and characterized based on the different spectroscopic analysis FT-IR, 1H, 13C NMR, mass spectra, and elemental analyses. Cell-based screening of IPA (8a-n) was assessed by MTT assay. Anti-angiogenic efficacy of IPA (8k) validated through CAM, Rat corneal, tube formation and migration assay. The underlying molecular mechanism is validated through zymogram and IB studies. The in vivo anti-tumor activity was measured in the DLA solid tumor model. RESULTS: Screening for anti-proliferative studies inferred, IPA (8k) is a lead molecule with an IC50 value of ˜5 µM. Anti-angiogenic assays revealed the angiopreventive activity through inhibition of HIF-1α and modulation downstream regulatory genes, VEGF, MMPs, and P53. The results are confirmative in an in vivo solid tumor model. CONCLUSION: The IPA (8k) is a potent anti-proliferative molecule with anti-angiogenic activity and specifically targets HIF1α, thereby modulates its downstream regulatory genes both in vitro and in vivo. The study provides scope for new target-specific drug development against HIF-1α for the treatment of solid tumors.

Design, synthesis and molecular docking of benzophenone conjugated with oxadiazole sulphur bridge pyrazole pharmacophores as anti inflammatory and analgesic agents.

The prostaglandins (PG) a group of physiologically active lipid compounds having diverse hormone like effects are important mediators of the body's response to pain and inflammation, and are formed from essential fatty acids found in cell membranes. This reaction is catalyzed by cyclooxygenase, a membrane associated enzyme occurring in two isoforms, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of COX. In view of this, a series of novel benzophenones conjugated with oxadiazole sulphur bridge pyrazole moiety 8a-l were designed, synthesized, characterized and subsequently evaluated for anti-inflammatory and analgesic property. The investigation of novel analogues 8a-l for potential anti-inflammatory activity showed high levels of COX-1 and COX-2 inhibitory activity. Among the series, compound 8i with electron withdrawing fluoro group at the para position of the benzoyl ring of benzophenone was characterized by highest IC50 values for both COX-1 and COX-2 inhibition, which is comparable to the standard drug. Further, molecular docking studies have been performed for the potent compound.

Synthesis of coumarin analogs appended with quinoline and thiazole moiety and their apoptogenic role against murine ascitic carcinoma.

The synthesis and antiproliferative effect of a series of quinoline and thiazole containing coumarin analogs 12a-d and 13a-f respectively, on mice leukemic cells was performed. The chemical structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. The result indicates that, 7-methoxy-2-oxo-2H-chromene-3-carboxylic acid [4-(4-methoxy-phenyl)-thiazol-2-yl]-amide (13f) showed potent activity against EAC and DLA cells in MTT (15.3 µM), tryphan blue (15.6 µM) and LDH (14.2 µM) leak assay with 5-fluorouracil as a standard. Further, the anti-neoplastic effect of the compound 13f was verified against Ehrlich ascites tumour by BrdU incorporation, TUNEL, FACS and DNA fragmentation assays. Experimental data showed that compound 13f induces the apoptotic cell death by activating apoptotic factors such as caspase-8 &-3, CAD, Cleaved PARP, γ-H2AX and by degrading genomic DNA of cancer cells and thereby decreasing the ascitic tumour development in mice. Besides, compound 13f was also subjected for docking studies to approve the in vitro and in vivo studies. The data revealed that the compound 13f has very good interaction with caspase 3 protein by binding with amino acid Arg 207 through hydrogen bond.

Synthesis and amelioration of inflammatory paw edema by novel benzophenone appended oxadiazole derivatives by exhibiting cyclooxygenase-2 antagonist activity.

Ten new 2(4-hydroxy-3-benzoyl) benzamide-5-phenyl-1,3,4-oxadiazole derivatives (10a-j) were synthesized by coupling 3-benzoyl-4-hydroxybenzoic acid (5) with 2-amino-5-phenyl-1,3,4-oxadiazoles (9a-j). The structures of these compounds were confirmed by IR, 1H, 13C NMR, and mass spectra, and also by elemental analyses. The anti-inflammatory activity of the compounds 10a-j were investigated by screening them against human red blood cells (HRBC) in-vitro. The results reveal that among this series, compound 10j with hydroxy substituent, particularly at the ortho position of the phenyl ring attached to the 5th carbon atom of the oxadiazole ring possess significant membrane stabilizing activity in comparison with the control. Further, in-vivo chick chorioallantoic membrane (CAM) and rat corneal anti-angiogenesis assays were performed to assess the effect of compound 10j on endothelial cell migration. This confirmed that compound 10j inhibits the proliferation of endothelial cells. Anti-inflammatory studies detected the amelioration of carrageen induced rat hind paw edema. Further in-vivo and in-silico approaches revealed the inhibition of inflammatory marker enzyme cyclooxygenase-2 (Cox-2) and myleoperoxidase (MPO). The study reports that the compound 10j effectively act against the inflammatory mediated anti-angiogenic disorders which could be translated into a new drug in future.

The Novel 4-Phenyl-2-Phenoxyacetamide Thiazoles modulates the tumor hypoxia leading to the crackdown of neoangiogenesis and evoking the cell death.

Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8a-ab were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC50 value of ˜ 13 µM. The mechanism of cytotoxicity assessed for anti-tumor studies both in ascites and solid tumor models in-vivo inferred the regressed tumor activity. This is due to changes in the cause of tumor microenvironment with crackdown of neovascularization and evoking apoptosis process as assessed by CAM, corneal vascularization and apoptotic hallmarks in 8f treated cells. The molecular gene studies inferred involvement of HIF-1upregulation and stabilization of p53 which are interlinked in signaling as conferred by immunoblot analysis.

Design and synthesis of conjugated azo-hydrazone analogues using nano BF3·SiO2 targeting ROS homeostasis in oncogenic and vascular progression.

Disrupted redox balance is implicated in multiple pathologies including malignant progression and tumor angiogenesis. In this investigation, we report the design and development of novel and effective ROS detoxifying azo-hydrazone molecules targeting malignant pathologies and neoangiogenesis. A series of azo-derivatives conjugated to hydrazones moieties (9a-j) were synthesized using Nano BF3·SiO2. The compounds (9a-j) were screened for in-vitro antioxidant and lipid peroxidation inhibitory activity. Among the series 9a-j, compound 9f potently quenched biologically relevant radicals such as superoxide and hydrogen peroxide which emerged as the lead ROS detoxifying molecules. Compound 9f potently inhibited the proliferative capability of Daltons Lymphoma Ascites (DLA) tumor cells in-vivo in dose dependent manner. Regressed tumor progression was correlated with pronounced endogenous antioxidant enzyme superoxide dismutase and catalase in-vivo. Also, ROS levels were severely suppressed in 9f treated mice as assessed by lapsed lipid peroxidation. Altered enzymic and ROS levels in-vivo by 9f were implicated in suppressed VEGF secretion leading to regressed tumor neovasculature and tumor growth. Considering together, it is evident that the synthetic azo-hydrazone analogue 9f with potent ROS scavenging efficacy inhibits tumor progression and neo-angiogenesis.

The anti-invasive role of novel synthesized pyridazine hydrazide appended phenoxy acetic acid against neoplastic development targeting matrix metallo proteases.

Neoplastic metastasis is a major process where tumor cells migrate from the primary tumor and colonize at other parts of our body to form secondary tumor. Cancer incidences are rising and novel anti-neoplastic compounds with new mechanism of actions are essential for preventing cancer related deaths. In the current examination, a novel series of pyridazine analogues 6a-l was synthesized and evaluated against metastatic neoplastic cells. Experimental data postulated compound 6j has potential cytotoxic efficacy with prolonged activity against various cancer cells, including A549, HepG2, A498, CaSki and SiHa cells. Moreover, compound 6j arrests the A549 migration and invasions markedly by counteracting matrix metalloproteinase (MMP)-2 and MMP-9 expressions. Also, compound 6j proved its potentiality against Dalton's solid lymphoma progression in-vivo by abridging MVD and MMP expressions. Compound 6j interacts with MMP-2 and MMP-9 by H- bond in-silico, thereby down regulates the MMPs action in tumourigenesis. Altogether, we concluded that compound 6j down regulates MMP-2 and MMP-9 and thereby impairs metastatic cancer cell migration and invasions which can be translated into a potent anti-neoplastic agent.

Synthesis of novel morpholine conjugated benzophenone analogues and evaluation of antagonistic role against neoplastic development.

A series of novel 4-benzyl-morpholine-2-carboxylic acid N'-[2-(4-benzoyl-phenoxy)-acetyl]-hydrazide derivatives 8a-j has been synthesized from (4-hydroxy-aryl)-aryl methanones through a multi-step reaction sequence and then evaluated for anti-proliferative activity in vitro against various types of neoplastic cells of mouse and human such as DLA, EAC, MCF-7 and A549 cells. From the cytotoxic studies and structural activity relationship of compounds 8a-j, it is clear that methyl group on the B ring of benzophenone is essential for antiproliferative activity and bromo at ortho position (compound 8b) and methyl at para position (compound 8f) on A ring of benzophenone are significant for extensive anti-mitogenic activity. Investigation on clonogenesis and Fluorescence-activated cell sorting suggests that compounds 8b and 8f have the potency to exhibit the prolonged activity with cell cycle arrest on G2/M phase against cancer progression. Further, the compounds 8b and 8f inhibit murine ascites lymphoma through caspase activated DNase mediated apoptosis.