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1.
Chem Sci ; 10(14): 4107-4115, 2019 Apr 14.
Article in English | MEDLINE | ID: mdl-31015949

ABSTRACT

In this study, we report a highly stereoselective and versatile synthesis of spiro pyrazolones, promising motifs that are being employed as pharmacophores. The new synthetic strategy merges organocatalysis and metal catalysis to create a synergistic catalysis using proline derivatives and Pd catalysts. This protocol is suitable for late-stage functionalization, which is very important in drug discovery. Additionally, a thorough computational study proved to be very useful to elucidate the function of the different catalysts along the reaction, showing a peculiar feature: the -CPh2OSiMe3 group of the proline catalyst switches its role during the reaction. In the initial Michael reaction, this group plays its commonly-assumed role of bulky blocking group, but the same group generates π-Pd interactions and acts as a directing group in the subsequent Pd-catalyzed Conia-ene reaction. This finding might be very relevant especially for processes with many steps, such as cascade reactions, in which functional groups are assumed to play the same role during all reaction steps.

2.
Nanomedicine ; 12(7): 1973-1985, 2016 10.
Article in English | MEDLINE | ID: mdl-27133192

ABSTRACT

Triple negative breast cancer (TNBC) is one of the most common invasive malignancies among women, associated with poor prognosis. Standard chemotherapy targets all dividing cells, resulting in dose-limiting toxicities. In this study, we demonstrated a strategy of encapsulating a hydrophobic synthetic compound, nifetepimine, having anticancer properties, in poly (lactic-co-glycolic acid) nanoparticles to increase selectivity of drug to cancerous cells with minimum toxicity towards normal cells. Nanoencapsulated nifetepimine (30-100nm) having loading and encapsulation efficiency of 7.45% and 75% respectively, was successfully internalized inside TNBC cells upon sustained release resulting in apoptosis. An in vivo bio-distribution study indicated that nanonifetepimine selectively accumulated into breast tumor sites of mice, primarily due to prolonged blood circulation time and binding of nifetepimine to epidermal growth factor receptor that remains overexpressed in most of the TNBC tumors. Moreover, we observed significant reduction in breast tumor volume with improved survival implying high tumor targetability of nanonifetepimine.


Subject(s)
Antineoplastic Agents/administration & dosage , Pyrimidinones/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast , Cell Line, Tumor , Female , Humans , Mice , Nanoparticles , Pyrimidinones/pharmacology , Tissue Distribution
3.
J Biol Chem ; 290(7): 3936-49, 2015 Feb 13.
Article in English | MEDLINE | ID: mdl-25527500

ABSTRACT

Triple negative breast cancers (TNBC) are among the most aggressive and therapy-resistant breast tumors and currently possess almost no molecular targets for therapeutic options in this horizon. In the present study we discerned the molecular mechanisms of potential interaction between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway in inducing apoptosis in TNBC cells. Here we observed that induction of ER stress alone was not sufficient to trigger significant apoptosis but simultaneous inhibition of the MEK/ERK pathway enhanced ER stress-induced apoptosis via a caspase-dependent mechanism. Our study also demonstrated nifetepimine, a dihydropyrimidone derivative as a potent anti-cancer agent in TNBC cells. Nifetepimine down-regulated the MEK/ERK pathway in MDAMB-231 and MDAMB-468 cells and resulted in blockage of ER stress-mediated GRP78 up-regulation. Detailed mechanistic studies also revealed that nifetepimine by down-regulating pERK expression also declined the promoter binding activity of TFII-I to the GRP78 promoter and in turn regulated GRP78 transcription. Studies further extended to in vivo Swiss albino and SCID mice models also revalidated the anti-carcinogenic property of nifetepimine. Thus our findings cumulatively suggest that nifetepimine couples two distinct signaling pathways to induce the apoptotic death cascade in TNBC cells and raises the possibility for the use of nifetepimine as a potent anti-cancer agent with strong immune-restoring properties for therapeutic intervention for this group of cancer bearers.


Subject(s)
Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , MAP Kinase Kinase Kinases/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Pyrimidinones/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Animals , Blotting, Western , Cell Cycle/drug effects , Cell Proliferation/drug effects , Endoplasmic Reticulum Chaperone BiP , Female , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Humans , Immunoenzyme Techniques , MAP Kinase Kinase Kinases/genetics , Male , Mice , Mice, Nude , Mice, SCID , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 3/genetics , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Triple Negative Breast Neoplasms/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
4.
J Biol Chem ; 287(39): 32881-96, 2012 Sep 21.
Article in English | MEDLINE | ID: mdl-22851172

ABSTRACT

Multiple mechanisms have been proposed by which tumors induce T cell apoptosis to circumvent tumor immune-surveillance. Although sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) have long been known to regulate intracellular Ca(2+) homeostasis, few studies have examined the role of SERCA in processes of T lymphocyte survival and activation. In this context it remains largely unexplored as to how tumors jeopardize SERCA function to disable T cell-mediated anti-tumor immunity. Here, we show that human CD4(+) T cells in the presence of tumor conditions manifested an up-regulation of SERCA3 expression that resulted in development of endoplasmic reticulum stress leading to CD4(+) T cell apoptosis. Prostaglandin E(2) produced by the tumor cell plays a critical role in up-regulating SERCA3 by enhancing the binding of its transcription factor Sp1. Gene manipulation and pharmacological approaches further established that an increase in SERCA expression also resulted in subsequent inhibition of PKCα and -θ and retention of NFκB in the cytosol; however, down-modulation of SERCA3 expression by a dihydropyrimidone derivative, ethyl-4-(3-nitro)-phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylate (nifetepimine), protected the CD4(+) T cells from tumor-induced apoptosis. In fact, nifetepimine-mediated restoration of PKC activity resulted in nuclear translocation of p65NFκB, thereby ensuring its survival. Studies further undertaken in a tumor-bearing mice model revalidated the immunoprotective role of nifetepimine. Our present study thus strongly suggests that imbalance in cellular calcium homeostasis is an important factor leading to CD4(+) T cell death during cancer and holds promise that nifetepimine may have the potential to be used as an immunorestoring agent in cancer bearers.


Subject(s)
Breast Neoplasms/enzymology , CD4-Positive T-Lymphocytes/metabolism , Calcium/metabolism , Immunologic Factors/pharmacology , Neoplasm Proteins/metabolism , Pyrimidinones/pharmacology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/biosynthesis , Tumor Microenvironment/drug effects , Animals , Breast Neoplasms/genetics , Breast Neoplasms/immunology , CD4-Positive T-Lymphocytes/immunology , Cell Survival/drug effects , Cell Survival/genetics , Cell Survival/immunology , Dinoprostone/genetics , Dinoprostone/immunology , Dinoprostone/metabolism , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/genetics , Endoplasmic Reticulum Stress/immunology , Female , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Enzymologic/genetics , Gene Expression Regulation, Enzymologic/immunology , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/immunology , Humans , Lymphocyte Activation/drug effects , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Male , Mice , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Neoplasm Transplantation , Protein Kinase C-alpha/genetics , Protein Kinase C-alpha/immunology , Protein Kinase C-alpha/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics , Sarcoplasmic Reticulum Calcium-Transporting ATPases/immunology , Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/immunology , Sp1 Transcription Factor/metabolism , Transplantation, Heterologous , Tumor Microenvironment/genetics , Up-Regulation/drug effects , Up-Regulation/genetics , Up-Regulation/immunology
5.
Eur J Med Chem ; 54: 223-31, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22658336

ABSTRACT

A regioselective N1-alkylation of 3,4-dihydropyrimidin-2(1H)-ones using a very efficient mild base Cs(2)CO(3) and alkyl halides at room temperature has been reported. The selectivity of this methodology is excellent and the yields of the alkylated products are very good. Furthermore inhibitory action of both the 3,4-dihydropyrimidin-2(1H)-ones and the N1-alkylated derivatives were tested on Ca(2+)-ATPase, which revealed that the parent compounds can act as Ca(2+)-ATPase inhibitors whereas the N1-alkylated derivatives are inefficient for this purpose.


Subject(s)
Calcium-Transporting ATPases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Alkylation , Animals , Calcium-Transporting ATPases/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Conformation , Pyrimidinones/chemistry , Stereoisomerism , Substrate Specificity
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