Potential Anti-breast Cancer Research Articles

Abstract 3: Discovery and optimization of small molecule Bax activators for cancer therapy

Abstract Bax, an indispensable executioner protein of B-cell lymphoma 2 (Bcl-2) family, plays a pivotal role in controlling the mitochondrial dysfunction and apoptosis in normal and cancer cells. High throughput screening to combat the nicotine-induced Bax phosphorylation at serine 184 (S184) to activate the proapoptotic function of Bax has revealed compound SMBA1 as a promising Bax direct activator as we previously reported. Initial medicinal chemistry campaign by choosing SMBA1 as a lead compound for breast cancer treatment resulted in the identification of compound CYD-2-11 with low micromolar IC50 values against MDA-MB-231 and MCF-7 as well as in vivo inhibitory effects against MDA-MB-231 xenograft tumor growth. Herein, we report the comprehensive structural optimization based on CYD-2-11 as the lead by introducing various alkylamino side chains to have a deeper access to S184 pocket and replacing carbon atoms with nitrogen as well as reducing the nitro group of 9H-fluorene scaffold to construct diverse derivatives for enhanced drug properties. CYD-4-61 and GL0385 have been discovered as the most potent anti-breast cancer agents with submicromolar IC50 values of 0.34 and 0.33 µM against MDA-MB-231 as well as 0.65 and 0.26 µM against MCF-7, respectively. More importantly, these drug candidates exhibited significant in vivo efficacy suppressing xenograft tumor growth by activating Bax to induce cancer cell apoptosis with the potential to overcome resistance against Adriamycin (ADR) in breast cancer. This work was supported by Breast Cancer Research Program (BCRP) Breakthrough Award BC160038 (to J.Z.) and BC160038P1 (to Q.S.) from the Department of Defense (DoD). Citation Format: Gang Liu, Hyejin Kim, Chunyong Ding, Zhuo Yu, Hong Wang, Haiying Chen, Qiang Shen, Jia Zhou. Discovery and optimization of small molecule Bax activators for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3.

Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil.

Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

Design, Synthesis and Cytotoxicity of Novel Coumarin-1,2,3-triazole-1,2,4- Oxadiazole Hybrids as Potent Anti-breast Cancer Agents

Background: This work reports design, synthesis, and in vitro cytotoxicity of novel coumarin-1,2,3-triazole-1,2,4-oxadiazole hybrids against three breast cancer cell lines MCF-7, MDA-MB-231, and T-47D. Methods: Synthetic procedure for the preparation of desired compounds was started from the reaction of coumarins or with propargyl bromide to give O-propargylated coumarins or 5. Then, click reaction between the later compounds and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles afforded the desired products in good yields. Results: Among the synthesized compounds, 4-((1-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (9a) showed the best cytotoxicity against breast cancer cell lines. Conclusion: Compound 9a depicted the most activity toward MDA-MB-231 and T-47D cells while compounds 8a and 8c were the most potent compounds against MCF-7.

Synthesis and antitumor activity of three novel ginsenoside M1 derivatives with 3′-ester modifications

Ginsenoside M1 (M1) was considered to be the main antitumor component of ginsenoside metabolites in the body. In order to enhance its potency on antitumor effect, three novel M1 3′–ester derivatives (1c, 2c, 3c) were synthesized and evaluated. The yield of these derivatives was between 41% and 69%. Compared with M1, 2c and 3c can improve the efficacy of the inhibition on breast cancer MCF–7 and MDA–MB–231 cells, especially for MCF–7 (fold: 0.7–4.2, p < 0.0001). Further study suggested that 2c and 3c may cause cell autophagy and promote apoptosis in MCF–7 cells. The results indicated the 3′–ester modified M1 derivatives 2c and 3c possess higher abilities of inhibition growth towards triple–positive breast cancer and provided a new source for synthesis of potential anti-breast cancer drugs.

Design, Synthesis, In vitro Cytotoxic Activity Evaluation, and Study of Apoptosis Inducing Effect of New Styrylimidazo[1,2-a]Pyridines as Potent Anti-Breast Cancer Agents.

This paper reports synthesis, cytotoxic activity, and apoptosis inducing effect of a novel series of styrylimidazo[1,2-a]pyridine derivatives. In this study, anti-cancer activity of novel styrylimidazo[1,2-a]pyridines was evaluated. Styrylimidazo[1,2-a]pyridine derivatives 4a-o were synthesized through a one-pot three-component reaction of 2-aminopyridines, cinnamaldehydes, and isocyanides in high yield. All synthesized compounds 4a-o were evaluated against breast cancer cell lines including MDA-MB-231, MCF-7, and T-47D using MTT assay. Apoptosis was evaluated by acridine orange/ethidium bromide staining, cell cycle analysis, and TUNEL assay as the mechanism of cell death. Most of the synthesized compounds exhibited more potent cytotoxicity than standard drug, etoposide. Induction of apoptosis by the most cytotoxic compounds 4f, 4g, 4j, 4n, and 4m was confirmed through mentioned methods. In conclusion, these results confirmed the potency of styrylimidazo[1,2-a]pyridines for further drug discovery developments in the field of anti-cancer agents.

RETRACTED: Development of two Cu(II) and Cd(II) coordination complexes based on mixed-ligand approach and application of their nanostructures as potential anti-breast cancer agents

Abstract We report herein the fabrication and structural characterization of two new coordination complexes [Cu3(μ3-O)(pz)3(Hpz)(Hpdc)(H2O)2](H2O)4 (1, H2pdc = pyridine-3,5-dicarboxylic acid, Hpz = pyrazol) and [Cd(phen)(bdc)](H2O) (2, phen = 1,10-phenanthroline, H2bdc = 1,2- acidic benzenedicarboxylic) through the application of acidic carboxylic and the N-containing linkers as the co-ligands. The molecular arrangement for the constructed CPs were probed by the structural solution and refinement based on the singe crystal X-ray data and their phase purities was confirmed via a comparison between the simulated profile from the crystal data with the measured profile using the powder X-ray diffraction. Furthermore, an ultrasonic treatment method was used to produce the nano particles of CPs 1 and 2 with good water dispersibility and framework integrality. Moreover, the in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method were administered on the breast cancer cell line BT474 with rising aggregations of the nanostructures 1 and 2, the cell apoptosis and ROS production level was also performed on BT474 cell line. This study suggested both nanostructures 1 and 2 have promising anticancer properties.

Ginsenoside Rk1 induces cell death through ROS-mediated PTEN/PI3K/Akt/mTOR signaling pathway in MCF-7 cells

Abstract Ginsenosides have been reported to possess pharmacological effects, such as antioxidative, anti-inflammatory and antitumor effects. Nevertheless, little has been reported about the anti-breast cancer effects of ginsenoside Rk1 (Rk1). In this work, we explored the anti-breast cancer effects of Rk1. The results suggested that Rk1 suppressed cell growth, colony formation, and triggered S phase arrest. Rk1 also triggered ROS overproduction, reduced mitochondrial membrane potential and induced apoptosis. Moreover, the PTEN/PI3K/Akt/mTOR pathway was involved in Rk1-induced apoptosis. Treatment with Z-VAD-FMK, LY294002 and N-acetylcysteine further illustrated that Rk1 induced apoptosis in MCF-7 cells through ROS-mediated PTEN/PI3K/Akt/mTOR signaling pathway. Furthermore, in xenograft nude mice model, Rk1 treatment dramatically suppressed tumor growth and caused no obvious injuries to major organs. Taken together, the results of this study demonstrated, for the first time, the anticancer efficacy and mechanism of Rk1 in MCF-7 cells, providing basic evidence supporting Rk1 as a potential anti-breast cancer agent.

Recombinant human lactoferrin induces apoptosis, disruption of F-actin structure and cell cycle arrest with selective cytotoxicity on human triple negative breast cancer cells.

Breast cancer is the most frequently diagnosed cancer among women worldwide. Here, recombinant human lactoferrin (rhLf) expressed in Pichia pastoris was tested for its potential cytotoxic activity on a panel of six human breast cancer cell lines. The rhLf cytotoxic effect was determined via a live-cell HTS imaging assay. Also, confocal microscopy and flow cytometry protocols were employed to investigate the rhLf mode of action. The rhLf revealed an effective CC50 of 91.4 and 109.46µg/ml on non-metastatic and metastatic MDA-MB-231 cells, with favorable selective cytotoxicity index values, 11.68 and 13.99, respectively. Moreover, rhLf displayed satisfactory SCI values on four additional cell lines, MDA-MB-468, HCC70, MCF-7 and T-47D (1.55-3.34). Also, rhLf provoked plasma membrane blebbing, chromatin condensation and cell shrinkage in MDA-MB-231 cells, being all three apoptosis-related morphological changes. Also, rhLf was able to shrink the microfilaments, forming a punctuated cytoplasmic pattern in both the MDA-MB-231 and Hs-27 cells, as visualized in confocal photomicrographs. Moreover, performing flow cytometric analysis, rhLf provoked significant phosphatidylserine externalization, cell cycle arrest in the S phase and apoptosis-induced DNA fragmentation in MDA-MB-231 cells. Hence, rhLf possesses selective cytotoxicity on breast cancer cells. Also, rhLf caused apoptosis-associated morphologic changes, disruption of F-actin cytoskeleton organization, phosphatidylserine externalization, DNA fragmentation, and arrest of the cell cycle progression on triple-negative breast cancer MDA-MB-231 cells. Overall results suggest that rhLf is using the apoptosis pathway as its mechanism to inflict cell death. Findings warranty further evaluation of rhLf as a potential anti-breast cancer drug option.

Design and Synthesis of Novel Thiosemicarbazones as Potent Anti-breast Cancer Agents

Background: Thiosemicarbazones and its derivatives received a great pharmaceutical importance due to their prominent biological activities. Methods: A series of disubstituted thiosemicarbazone derivatives (1-12) were designed and synthesized as pure compounds in good yield. All the synthesized compounds were analyzed by spectral data. The anticancer activity of all the compounds was performed against breast cancer MCF-7 and MDA-MB-231 cell lines. Results: Most of the compounds showed activity against breast cancer MCF-7 and MDA-MB-231 cell lines with (IC50 = 12.25 &amp;#181;M ‒ 185.35 &amp;#181;M) and (IC50 = 12.97 &amp;#181;M ‒ 107.33 &amp;#181;M), respectively. Compound 9 presented (IC50 = 12.76 &amp;#181;M and 12.97 &amp;#181;M) against MCF-7 and MDA-MB-231 cell lines, respectively. Conclusion: Compound 9, was found to exhibit significant anti-breast cancer activity. This compound was further evaluated for side population percent inhibition assay on the breast cancer cell line MCF-7 at 5 and 10 &amp;#181;M concentration. It showed superiority to block side population by more than 80% at 5 μM concentration compared to the reference drug verapamil.

Abstract P1-06-03: A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity

Abstract Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) are Ser/Thr protein kinase members of the CDK family. CDKs are regulated by cyclins and members of the family are key regulators of the cell cycle. Other members of this family—CDK7, CDK8, CDK9, CDK12 and CDK13—have been described as transcription-regulating kinases. CDK12 and CDK13 phosphorylate the C-terminal domain (CTD) of rpb1 the largest subunit of RNA polymerase II and interact with RNA processing factors, playing pivotal roles controlling transcription initiation and elongation, as well as posttranscriptional RNA processing. Specifically, CDK12 acts as the limiting factor for the transcription of a small subset of genes that are involved in the DNA damage response pathway and CDK13 affects expression of genes involved in growth signaling pathways. Importantly, like their cell cycle family members CDK12 and CDK13 have also been shown to be promising therapeutic targets for several cancer types. We have generated a novel, selective, and orally bioavailable, small molecule inhibitor of CDK12 and CDK13. Our lead molecule downregulates key DNA damage repair proteins including ATM, ATR, Brca1 and Rad51 leading to induction of apoptotic cell death in all triple negative breast cancer (TNBC) cell lines tested. We have confirmed the selectivity of our compound by kinase profiling and by comparing the gene expression profile by RNA-seq of cells treated with compound or infected with CRISPR sgRNA targeting Cdk12 and/or Cdk13. Importantly, our compound acts in synergy with the chemotherapeutic agents Cisplatin, Irinotecan and Olaparib. Finally, in preclinical efficacy studies, our lead compound blocked tumor progression in two different PDX models of TNBC and demonstrated tumor regression and enhanced efficacy over single treatment when dosed in combination with selected chemotherapeutic agents. Citation Format: Quereda V, Bayle S, Francesca V, Andrii M, William R, Derek D. A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-03.

The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells

The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.

Synthesis, Characterization and In-vitro Evaluation of Novel Naphthoquinone Derivatives and Related Imines: Identification of New Anticancer Leads.

Quinones such as 1,4-naphthoquinones are abundant in nature and naphthoquinone based natural products are known to possess anticancer activity. This pharmacophore is known to convey anticancer activity to some drugs such as streptonigrin, mitomycin A, etc. We synthesized and characterized different classes of naphthoquinone derivatives including bis naphthoquinone, 2-arylaminonaphthoquinone, benzoxantene-6,11-dione and benzoacridine-5,6-dione derivatives instead of the expected 2-hydroxy-3-(substituted phenyl(aryl amino)methyl)naphthalene-1,4-dione derivatives from the reaction of 2-hydroxy1,4-naphthoquinone (lawson) with different benzaldehydes and aryl amines. Benzoacridine-5,6-dione derivatives and related imines showed potent anti-breast cancer activity in MCF-7 cancer cells. The in-vitro results revealed that five compounds benzoacridinedione derivatives (6b and 7b) and imines (13, 14 and 15) by the IC50 range of 5.4-47.99 μM are the most potent anti-breast cancer structures.

Assessment of the Inhibitory Effects of Ficin-hydrolyzed Gelatin Derived from Squid (Uroteuthis duvauceli) on Breast Cancer Cell Lines and Animal Model

Marine novel natural products have been applied for cancer therapy. Enzyme-digested gelatin hydrolysates have proven to serve as promising sources of potent biologically active peptides. Potential anti-breast cancer properties of the extracted Ficin-digesterd gelatin hydrolysate from Indian squid (Uroteuthis duvauceli) was extensively characterized by cellular and animal models. Gelatin was extracted from squid skin, hydrolyzed by Ficin, and characterized by standard physico-chemical methods. Ficin-digested gelatin hydrolysate was used at various doses of 0-0.1 mg/mL for assessment of MCF-7 and MDA-MB-231 breast cancer cells versus HUVEC normal cells. Cytotoxicity, phase-contrast morphological examination, apoptosis/necrosis, clonal-growth, cell-migration, Matrix-metalloproteinases (MMPs) zymography, and Western blotting were used for cellular assessments. For animal studies, breast tumor-induced BALB/c mice received hydrolyzed gelatin regimen, followed by tumor size/growth and immune-histochemical analyses. Significant inhibition of MCF-7 and MDA-MB-231 with no cytotoxicity on HUVEC cells were detected. Apoptosis was increased in cancer cells, as revealed by elevated ratio of cleaved caspase-3 and PARP. MMP-2 and MMP-9 activities in both cancer cells were diminished. In mice, gelatin hydrolysate prevented weight loss, decreased tumor size, induced p53, and down-regulated Ki67 levels. These findings suggest that Ficin-digested gelatin hydrolysate could be a beneficial candidate for novel breast cancer therapies.

The synergistic effect of 2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside combined with Adriamycin on MCF-7 breast cancer cells.

ObjectiveBreast cancer has been reported to be a serious disease and a threat to women’s health. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG) is a bioactive natural compound originating from Polygonum multiflorum Thunb., which has been shown to possess anti-inflammatory and antitumor properties. Adriamycin (ADM) is a chemotherapy agent used in tumor therapy that is limited by its side effects. However, little is known about the synergistic effect of THSG combined with ADM on breast cancer. This study seeks to investigate the effects of the combination of THSG plus ADM on MCF-7 breast cancer cells and to test the mechanisms involved.Materials and methodsMTT assay was detected to determine cell viability. Furthermore, cell apoptosis was tested by flow cytometry and TUNEL assay. In addition, protein expression was measured by Western blot analysis.ResultsThe individual treatment of THSG and ADM induced cell injury. Moreover, cotreatment further increased it, which the effect may be associated with the elevation of the apoptotic-related protein expression such as Bax/Bcl-2 and cleaved caspase-3/caspase-3. Lastly, our results also show the reduction of vascular endothelial growth factor/phosphatidylinositol 3-kinase/Akt protein expression in the individual or synergistic treatment.ConclusionTaken together, cotreatment of THSG and ADM may exert a synergistic reduction of cell injury via the inhibition of vascular endothelial growth factor/phosphatidylinositol 3-kinase/Akt pathway. Thus, THSG might possess potent anti-breast cancer effect with ADM.

Anti‑breast cancer activity of selected 1,3,5‑triazines via modulation of EGFR‑TK.

The present study investigated the effect of certain 1,3,5-triazine derivatives on epidermal growth factor receptor-tyrosine kinase (EGFR-TK). The results suggested that 1,3,5-triazine derivatives exhibited optimal drug likeness via molinspiration and proved to be effective drug candidates as potential anticancer agents. The molecules were demonstrated to interact with key catalytic residues of EGFR, including Asn818, Lys721, Leu694, Val702 and Met742 as demonstrated in molecular docking experiments. Compound 1d was demonstrated to be the most potent analogue with an inhibitory constant of 0.44 nM, against EGFR-TK in in-vitro enzyme inhibition assay. Compound 1d was further evaluated for its effect on the cellular viability of three breast cancer cell lines, including highly metastatic MDAMB231, human epidermal growth factor receptor 2-positive BT474 and estrogen receptorpositive MCF7 cells, using an MTT assay and apoptosis analysis. Western blot analysis was performed to examine the levels of β-catenin in the control and treated cells. Based on the findings of the current study, the chemical 1,3,5-triazine series are potential novel inhibitors of EGFR-TK and β-catenin signaling, and may be potent anti-breast cancer agents.

Synthesis, Characterization and Evaluation of 1,3-Bisindolyl-2-Propen-1- One Derivatives as Potent Anti-Breast Cancer Agents

Synthesis, Characterization and Evaluation of 1,3-Bisindolyl-2-Propen-1- One Derivatives as Potent Anti-Breast Cancer Agents

Synthesis, antiproliferative activity and mechanism of gallium(III)-thiosemicarbazone complexes as potential anti-breast cancer agents

Five thiosemicarbazone ligands were synthesized and characterized by condensation with different aldehydes or ketones by 4-phenylthiosemicarbazone. The representative dichlorido[2-(Di-2-pyridinylmethylene)-Nphenylhydrazinecarbothioamide-N,N,S]-gallium(III) (Ga4) was characterized by X-ray single crystal diffraction, which was 1:1 ligand/Ga(III) complexes. The structure-activity relationship of these ligands and Ga (III) complexes have been investigated, and the results demonstrate that the formation of Ga (III) complexes have significant antiproliferative activity over the corresponding ligands. The anticancer mechanism of gallium (III) complexes has been studied in detail, which is typical agents that effect on the mitochondrial apoptotic pathway. The ability of gallium (III) complexes to inhibit the cell cycle does not enhanced with the increasing concentrations, whereas the ability to promote apoptosis is concentration-dependent.

Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising Preclinical Antitumor Activity in Breast Cancer

Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer.

Design and synthesis of fluorescent symmetric bis-triazolylated-1,4-dihydropyridines as potent antibreast cancer agents

ABSTRACTHerein, we report the synthesis of fluorescent 1,4-dihydropyridine-linked bis-triazoles (2a–2n) through Hantzsch synthesis by the condensation of o/m-chloro-substituted benzaldehyde, ethyl 3-oxo-4(prop-2-yn-1-yloxy)butanoate, and ammonium acetate in the presence of Ba(NO3)2 as a catalyst followed by the click reaction of resultant Hantzsch product (1) with various aromatic as well as aliphatic azides. All the synthesized compounds were well characterized by 1H-NMR, 13C-NMR, FTIR, and HRMS spectral techniques. Antibreast cancer evaluation of all the synthesized derivatives revealed that the compounds 2f (IC50 = 7 ± 0.02 µM) and 2g (IC50 = 5 ± 0.03 µM) showed better anticancer activity (lower IC50) than the standard drug tamoxifen (IC50 = 11.2 ± 0.01 µM) against breast carcinoma (MDA-MB-231) cell line. The synthesized compounds were also screened against normal human embryonic kidney (HEK-293) cell line and found to be nontoxic. The fluorescent nature and cytotoxicity assay of these newly synthesized hybrids recommend their utility in tumor cell imaging.

Synthesis of Hybrids of Dihydropyrimidine and Pyridazinone as potential Anti-Breast Cancer Agents.

Different 3-aroylpropionic acids and dihydropyrimidine hydrazine derivatives were condensed together to yield a series of dihydropyrimidine and pyridazinone hybrids (5a-u). This was done in order to develop therapeutic agents for the treatment of breast cancer with improved Cycloxygenase-2 (COX-2) selectivity. In-vitro anticancer evaluation for these compounds was done against human breast cancer cell lines (MCF-7, MDA-MB-231) and normal human keratinocytes (HaCaT). Amongst all the developed analogs, compound 5l emerged as the most potent agent against both these cell lines with IC50 values of 3.43 and 2.56 µM respectively. The synthesized compounds were also evaluated for COX-2 selectivity. To observe the binding pattern of the compounds with COX-2, a docking study was performed using PDB ID: 1CX2.