Abstract:

We have investigated the synergistic effect of nitric oxide and singlet oxygen originating from stimulated ruthenium complexes and their photodynamic action against a melanoma cancer cell line. In aqueous solution, the photosensitizer [Ru(NH3)5pz]2+(I; pz = pyrazine) and the nitrosylruthenium complex trans-[RuCl([15]aneN4)NO]2+(II; [15]aneN4= 1,4,8,12-tetrazacyclopentadecane) can produce singlet oxygen and nitric oxide, respectively. The phototoxicity of complex I does not correlate with the singlet oxygen quantum yields unless it is mediated by nitric oxide release from complex II. This effect is around 70 and 50 % higher than the effect prompted by compounds I and II, respectively, in isolation in the presence of light. It was found that the number of hypodiploid cells in the melanoma cancer cells increased, which indicates that a mixture of compounds I and II induces apoptosis of tumorigenic cell lines. Both singlet oxygen and nitric oxide produced by the ruthenium complexes enhance the photodynamic efficacy in melanoma cancer cells.

Author affiliation: Ramos, Loyanne C. B.. Universidade de Sao Paulo; Brasil

Author affiliation: Marchesi, Mario Sérgio Pereira. Universidade de Sao Paulo; Brasil

Author affiliation: Callejon, Daniel. Universidade de Sao Paulo; Brasil

Author affiliation: Baruffi, Marcelo Dias. Universidade de Sao Paulo; Brasil

Author affiliation: Lunardi, Claure N.. Universidade do Brasília; Brasil

Author affiliation: Slep, Leonardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina

Author affiliation: Bendhack, Lusiane M.. Universidade de Sao Paulo; Brasil

Author affiliation: da Silva, Roberto Santana. Universidade de Sao Paulo; Brasil

Abstract:

Twenty N-fatty acylamines from linolenic and arachidonic acids, fifteen of them new compounds, were obtained through Candida antarctica B lipase-catalyzed esterification and aminolysis reactions in very good yields and with high chemoselectivity. The optimal reaction conditions were achieved by studying the reaction parameters (temperature, E/S ratio, alcohol and alkanolamine/fatty acid ratio, time, solvent, free-solvent system, etc.). To identify ideal enzymatic methods for generating the alkanolamides we evaluated enzyme performance in three procedures: i) aminolysis of ethyl ester, ii) direct condensation between the fatty acid and the alkanolamine, and iii) a one-pot/two-step conversion of fatty acids into alkanolamides via in situ formation of the ethyl ester and subsequent aminolysis by the alkanolamine. The advantages noted with the enzymatic methodology, such as mild reaction conditions and low environmental impact, underscore biocatalysis as a convenient way to prepare the reported compounds. The cytotoxic activities of all compounds and mixtures of anandamide and its analogues were evaluated in rat glioma C6 cells. These studies reveal that some anandamide analogues enhance the antitumor effects of anandamide, suggesting their possible application as therapeutic tools in cancer treatment. Twenty N-fatty acylamines from linolenic and arachidonic acids were obtained by one-pot/two-step Candida antarctica B lipase-catalyzed esterification and aminolysis reactions in very good yields with high chemoselectivity. Cytotoxicity assays using rat glioma C6 cells revealed that some analogues enhanced the antitumor effects of anandamide (AEA), suggesting possible anticancer applications.

Author affiliation: Quintana, Paula Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina

Author affiliation: Garcia Liñares, Guadalupe Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina

Author affiliation: Chanquia, Santiago Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina

Author affiliation: Gorojod, Roxana Mayra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina

Author affiliation: Kotler, Monica Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina

Author affiliation: Baldessari, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina

Abstract:

We have previously reported the synthesis of a series of twenty N-fatty acylamines analogs of anandamide, fifteen of them novel, following an enzymatic approach, in very good yield and a chemoselective way. The cytotoxic activity of all compounds and mixtures of anandamide and its analogues was evaluated in rat glioma C6 cells and these studies revealed that some of them greatly enhance the antitumor effect of anandamide, suggesting their possible application as an alternative treatment for cancer. Encouraged by these great results, hereby we present a thorough molecular modeling study of the interaction between seven representative different substrates and the lipase used in the synthesis with the aim of understanding the observed relation between structure and reactivity. Furthermore, this approach can be applied to better understand, and thus improve, innovative biocatalytic processes for the synthesis of new bioactive drugs or precursors.

Author affiliation: Garcia Liñares, Guadalupe Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina

Author affiliation: Chanquia, Santiago Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina

Author affiliation: Baldessari, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina

Abstract:

In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR–BF2 adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized. Computational docking studies were performed to compare binding efficiency to target proteins involved in specific cancers, namely HER2, proteasome, VEGFR, BRAF, and Bcl-2, versus known inhibitor drugs. The majority presented very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole-based CUR–BF2 and CUR compounds and their bis-thiocyanato derivatives exhibited high anti-proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines, more specifically against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI-8226) with significantly lower IC50 values versus healthy PBMC cells; they also exhibited higher anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) than the parent curcumin, while showing notably lower cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).

Author affiliation: Laali, Kenneth K.. University of North Florida. Department of Chemistry; Estados Unidos

Author affiliation: Greves, William J.. University of North Florida. Department of Chemistry; Estados Unidos

Author affiliation: Zwarycz, Angela T.. University of North Florida. Department of Chemistry; Estados Unidos

Author affiliation: Correa-Smits, Sebastian J.. University of North Florida. Department of Chemistry; Estados Unidos

Author affiliation: Troendle, Frederick J.. University of North Florida. Department of Chemistry; Estados Unidos

Author affiliation: Borosky, Gabriela Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina

Author affiliation: Akhtar, Sharoon. Mayo Clinic. Department of Cancer Biology; Estados Unidos

Author affiliation: Manna, Alak. Mayo Clinic. Department of Cancer Biology; Estados Unidos

Author affiliation: Paulus, Aneel. Mayo Clinic. Department of Hematology and Oncology ; Estados Unidos

Author affiliation: Chanan-Khan, Asher. Mayo Clinic. Department of Hematology and Oncology ; Estados Unidos

Author affiliation: Nukaya, Manabu. University of North Florida. Department of Chemistry; Estados Unidos

Author affiliation: Kennedy, Gregory D.. University of North Florida. Department of Chemistry; Estados Unidos