Chemical biology: new natural and synthetic molecular targets against cancer, structural studies, biological evaluation and mode of action

• Grant number: 09/51602-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2009
• End date: March 31, 2015
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Agreement: NSF - American Universities (Chemistry)
• Principal Investigator: Ronaldo Aloise Pilli
• Grantee: Ronaldo Aloise Pilli
• Principal researcher abroad: Sukwon Hong
• Institution abroad: University of Florida, Gainesville (UF) , United States
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas
• Principal investigators: Fernando Antonio Santos Coelho
• Associated scholarship(s): 13/16174-8 - Synthesis and biological evaluation of Brevipolide a and related compounds, BP.DD; 12/24385-6 - Influence of protein phosphatases inhibitors in the expression and / or activity of protein kinases in pancreatic cancer, BP.IC; 10/16990-1 - Synthesis and evaluation of cytotoxic activity of gama-dihydropyrones: goniothalamin and abyssinone II analogues, BP.PD; + associated scholarships 10/15496-3 - Molecular mechanisms involved in the control of pancreatic cancer aggressiveness by protein phosphatases inhibitors, BP.DR; 10/12701-5 - Compounds with furanofurones and piranopirones frameworks from disacharides: synthetic studies, BP.IC; 10/08673-6 - Studies toward the Synthesis of Analogues of Fostriecin and Total Synthesis and Structural Elucidation of Coibacinas A and B, BP.DR; 09/09489-7 - Fluorescence-based probes applied to sulfoxidases activity and phosphatases inhibition, BP.PD; 09/18390-4 - Morita-Baylis-Hillma in synthesis: structural diversity and biological evaluation of spirocyclohexadienones, BP.DR - associated scholarships

Abstract

This research proposal aims the preparation and unambiguous structural characterization of about 100 natural and synthetic organic compounds belonging to the δ-lactone and δ-lactam families (mostly, α, β-unsaturated ones), butenolide diterpenes, 1,4-quinones of the caulibugulone family and (β-hydroxy-α-methylenic esters together with their biological evaluation against: i) a panel of nine human cancer cell lines (lung/NCI-H460; breast/MCF-7; ovary/OVCAR-3; ovary with resistance to adriamycin/NCI-ADR/Res; colon/HT-29; prostate/PC-3; melanoma/UACC-62; kidney/786-0 and leukemia/K-562); ii) as fosfatase inhibitors (CD45, SHP2, LMWPTP, CDC25 and PTP1B, PPl, PP2A e PP2B) and, iii) their effect on the interaction of Hsp70 and Hsp90 human proteins with their client co-chaperones and protein clients and on the ATPase activity. The proposal is based on preliminary biological evaluation of some representatives of the structural classes proposed to be investigated in this study and the research team is composed by investigators with solid background in the areas of Synthetic Organic Chemistry, structural elucidation by X-ray diffraction analysis, pharmacological evaluation and enzimatic activity determination, and more than 10 students, who will contribute with their expertise to acquire a coherent body of information from their experimental work in order to identify lead compounds and their mode of action which will allow the design of new compounds with better profile for further in vivo biological evaluation. (AU)

Scientific publications

(31)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

OLIVEIRA, F. L.; HUBER, P. C.; ALMEIDA, W. P.; SABINO, J. R.; APARICIO, R.. Tris[2-(1,3-thiazol-2-yl-kappa N)-1H-benzimidazole-kappa N-3]zinc(II) dinitrate ethanol hemisolvate monohydrate at 100 K. ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS, v. 69, n. 2, p. 119+, FEB 2013. (10/20861-2, 09/51602-5)

FERNANDES, DANIARA C.; SIMONI, DEBORAH DE ALENCAR; RODRIGUES, JR., MANUEL T.; SANTOS, MARILIA S.; COELHO, FERNANDO. Crystal structure of 3-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrocyclopenta[b]indole-2-car boxylic acid. ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, v. 71, n. 6, p. O395-U248, JUN 2015. (09/51602-5, 13/07600-3)

PILLI, RONALDO ALOISE; TONETO NOVAES, LUIZ FERNANDO; TEIXEIRA CARNEIRO, VANIA MARIA; DREKENER, ROBERTA LOPES; AVILA, CAROLINA MARTINS. Total Synthesis of Natural Dihydropyranones: A Contribution to the Structural Elucidation of Natural Products. Coibacins A and B, Cryptomoscatones D1, D2 and E3. CURRENT ORGANIC SYNTHESIS, v. 12, n. 5, p. 523-529, 2015. (11/00457-5, 09/51602-5, 10/08673-6)

BRITO, GILMAR A.; SAROTTI, ARIEL M.; WIPF, PETER; PILLI, RONALDO A.. Cascade cyclization triggered by imine formation. Formal synthesis of the alkaloid (+/-)-stemoamide and its 9a-epimer. Tetrahedron Letters, v. 56, n. 48, p. 6664-6668, DEC 2 2015. (09/51602-5, 10/00219-4)

RAITZ, ISMAEL; DE SOUZA FILHO, ROBERTO Y.; DE ANDRADE, LORENA P.; CORREA, JOSE R.; NETO, BRENNO A. D.; PILLI, RONALDO A.. Preferential Mitochondrial Localization of a Goniothalamin Fluorescent Derivative. ACS OMEGA, v. 2, n. 7, p. 3774-3784, JUL 2017. (09/51602-5, 16/12541-4, 13/07607-8)

VENDRAMINI-COSTA, DEBORA BARBOSA; SPINDOLA, HUMBERTO MOREIRA; DE MELLO, GLAUCIA COELHO; ANTUNES, EDSON; PILLI, RONALDO ALOISE; DE CARVALHO, JOAO ERNESTO. Anti-inflammatory and antinociceptive effects of racemic goniothalamin, a styryl lactone. Life Sciences, v. 139, p. 83-90, OCT 15 2015. (12/18281-3, 09/51602-5)

FONSECA, EMANUELLA M. B.; TRIVELLA, DANIELA B. B.; SCORSATO, VALERIA; DIAS, MARIANA P.; BAZZO, NATALIA L.; MANDAPATI, KISHORE R.; DE OLIVEIRA, FABIO L.; FERREIRA-HALDER, CARMEN V.; PILLI, RONALDO A.; MIRANDA, PAULO C. M. L.; et al. Crystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates. Bioorganic & Medicinal Chemistry, v. 23, n. 15, p. 4462-4471, AUG 1 2015. (10/17544-5, 11/03054-9, 09/51602-5, 11/15792-4)

MARTINS, LUCIMARA J.; FERREIRA, BRUNO R. V.; ALMEIDA, WANDA P.; LANCELLOTTI, MARCELO; COELHO, FERNANDO. An easy access to halogenated and non-halogenated spiro-hexadienones. Tetrahedron Letters, v. 55, n. 38, p. 5264-5267, SEP 17 2014. (09/51602-5, 09/18390-4, 11/20033-5)

LUNA-FREIRE, KRISTERSON R.; SCARAMAL, JOAO PAULO S.; RESENDE, JACKSON A. L. C.; TORMENA, CLAUDIO F.; OLIVEIRA, FABIO L.; APARICIO, RICARDO; COELHO, FERNANDO. An asymmetric substrate-controlled Morita-Baylis-Hillman reaction as approach for the synthesis of pyrrolizidinones and pyrrolizidines. Tetrahedron, v. 70, n. 20, p. 3319-3326, MAY 20 2014. (09/51602-5, 11/20033-5)

NOVAES, LUIZ F. T.; SAROTTI, ARIEL M.; PILLI, RONALDO A.. Total synthesis and stereochemical assignment of cryptolatifolione. RSC ADVANCES, v. 5, n. 66, p. 53471-53476, 2015. (09/51602-5)

PIROVANI, RODRIGO V.; BRITO, GILMAR A.; BARCELOS, ROSIMEIRE C.; PILLI, RONALDO A.. Enantioselective Total Synthesis of (+)-Lyngbyabellin M. MARINE DRUGS, v. 13, n. 6, p. 3309-3324, JUN 2015. (10/00336-0, 09/51602-5, 13/07607-8, 10/00219-4)

VENDRAMINI-COSTA, DEBORA BARBOSA; FRANCESCONE, RALPH; POSOCCO, DAVID; HOU, VIVIANTY; DMITRIEVA, OXANA; HENSLEY, HARVEY; DE CARVALHO, JOAO ERNESTO; PILLI, RONALDO ALOISE; GRIVENNIKOV, SERGEI I.. Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis. Carcinogenesis, v. 38, n. 1, p. 51-63, JAN 2017. (09/51602-5, 14/05189-7)

MARTINS, LUCIMARA JULIO; SIMONI, DEBORAH DE ALENCAR; APARICIO, RICARDO; COELHO, FERNANDO. Crystal structure of methyl 2-(2H-1,3-benzodioxol-5-yl)-7,9-dibromo-8-oxo1-oxaspiro[4.5]deca-2,6,9-triene-3-carboxylate. ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, v. 70, p. 9-pg., 2014-12-01. (09/51602-5, 09/18390-4)

FERNANDES, DANIARA C.; SIMONI, DEBORAH DE ALENCAR; RODRIGUES, MANUEL T., JR.; SANTOS, MARILIA S.; COELHO, FERNANDO. Crystal structure of 3-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrocyclopenta[b]indole-2-carboxylic acid. ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, v. 71, p. 9-pg., 2015-06-01. (13/07600-3, 09/51602-5)

CARNEIRO, VANIA M. T.; AVILA, CAROLINA M.; BALUNAS, MARCY J.; GERWICK, WILLIAM H.; PILLI, RONALDO A.. Coibacins A and B: Total Synthesis and Stereochemical Revision. Journal of Organic Chemistry, v. 79, n. 2, p. 630-642, JAN 17 2014. (11/00457-5, 09/51602-5, 10/08673-6)

NACIUK, FABRICIO F.; MILAN, JULIO C.; ANDREAO, ALMIR; MIRANDA, PAULO C. M. L.. Exploitation of a Tuned Oxidation with N-Haloimides in the Synthesis of Caulibugulones A-D. Journal of Organic Chemistry, v. 78, n. 10, p. 5026-5030, MAY 17 2013. (09/51602-5)

VENDRAMINI-COSTA, DEBORA BARBOSA; DALTRO DE CASTRO, ILTON BARROS; TASCA GOIS RUIZ, ANA LUCIA; MARQUISSOLO, CILENE; PILLI, RONALDO ALOISE; DE CARVALHO, JOAO ERNESTO. Effect of goniothalamin on the development of Ehrlich solid tumor in mice. Bioorganic & Medicinal Chemistry, v. 18, n. 18, p. 6742-6747, SEP 15 2010. (09/51602-5)

BARCELOS, ROSIMEIRE COURA; PASTRE, JULIO CEZAR; CAIXETA, VANESSA; VENDRAMINI-COSTA, DEBORA BARBOSA; DE CARVALHO, JOAO ERNESTO; PILLI, RONALDO ALOISE. Synthesis of methoxylated goniothalamin, aza-goniothalamin and gamma-pyrones and their in vitro evaluation against human cancer cells. Bioorganic & Medicinal Chemistry, v. 20, n. 11, p. 3635-3651, JUN 1 2012. (09/51602-5, 10/16990-1)

TONETO NOVAES, LUIZ FERNANDO; AVILA, CAROLINA MARTINS; PELIZZARO-ROCHA, KARIN JULIANE; VENDRAMINI-COSTA, DEBORA BARBOSA; DIAS, MARINA PEREIRA; BARBOSA TRIVELLA, DANIELA BARRETO; DE CARVALHO, JOAO ERNESTO; FERREIRA-HALDER, CARMEN VERISSIMA; PILLI, RONALDO ALOISE. (-)-Tarchonanthuslactone: Design of New Analogues, Evaluation of their Antiproliferative Activity on Cancer Cell Lines, and Preliminary Mechanistic Studies. CHEMMEDCHEM, v. 10, n. 10, p. 1687-1699, OCT 2015. (10/17544-5, 12/09254-2, 13/08896-3, 09/51602-5, 12/24385-6, 10/08673-6)

BARCELOS, ROSIMEIRE COURA; PASTRE, JULIO CEZAR; VENDRAMINI-COSTA, DEBORA BARBOSA; CAIXETA, VANESSA; LONGATO, GIOVANNA BARBARINI; MONTEIRO, PAULA ARAUJO; DE CARVALHO, JOAO ERNESTO; PILLI, RONALDO ALOISE. Design and Synthesis of N-Acylated Aza-Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity. CHEMMEDCHEM, v. 9, n. 12, p. 2725-2743, DEC 2014. (12/18281-3, 09/51602-5, 10/16990-1)

TONETO NOVAES, LUIZ FERNANDO; DREKENER, ROBERTA LOPES; AVILA, CAROLINA MARTINS; PILLI, RONALDO ALOISE. Total synthesis of cryptomoscatones D1 and D2: stereochemical assignment of cryptomoscatone D1. Tetrahedron, v. 70, n. 37, p. 6467-6473, SEP 16 2014. (09/51602-5)

BARCELOS, ROSIMEIRE COURA; PELIZZARO-ROCHA, KARIN JULIANE; PASTRE, JULIO CEZAR; DIAS, MARINA PEREIRA; FERREIRA-HALDER, CARMEN VERISSIMA; ALOISE PILLI, RONA IDO. A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 87, p. 745-758, NOV 24 2014. (10/15496-3, 09/51602-5, 10/16990-1, 12/24385-6)

CARNEIRO, VANIA M. T.; TRIVELLA, DANIELA B. B.; SCORSATO, VALERIA; BERALDO, VIVIANE L.; DIAS, MARIANA P.; SOBREIRA, TIAGO J. P.; APARICIO, RICARDO; PILLI, RONALDO A.. Is RK-682 a promiscuous enzyme inhibitor? Synthesis and in vitro evaluation of protein tyrosine phosphatase inhibition of racemic RK-682 and analogues. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 97, p. 42-54, JUN 5 2015. (11/00457-5, 10/17544-5, 09/51602-5, 13/07607-8)

VENDRAMINI-COSTA, DEBORA BARBOSA; ALCAIDE, ANTONIO; PELIZZARO-ROCHA, KARIN JULIANE; TALERO, ELENA; AVILA-ROMAN, JAVIER; GARCIA-MAURINO, SOFIA; PILLI, RONALDO ALOISE; DE CARVALHO, JOAO ERNESTO; MOTILVA, VIRGINIA. Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line. Toxicology and Applied Pharmacology, v. 300, p. 1-12, JUN 1 2016. (12/18281-3, 09/51602-5)

BRUDER, MARJORIE; VENDRAMINI-COSTA, DEBORA BARBOSA; DE CARVALHO, JOAO ERNESTO; PILLI, RONALDO ALOISE. Design, synthesis and in vitro evaluation against human cancer cells of 5-methyl-5-styryl-2,5-dihydrofuran-2-ones, a new series of goniothalamin analogues. Bioorganic & Medicinal Chemistry, v. 21, n. 17, p. 5107-5117, SEP 1 2013. (09/51602-5)

LIRA, LUCAS M.; VASILEV, DIMITAR; PILLI, RONALDO A.; WESSJOHANN, LUDGER A.. One-pot synthesis of organophosphate monoesters from alcohols. Tetrahedron Letters, v. 54, n. 13, p. 1690-1692, MAR 27 2013. (09/51602-5)

NOVAES, LUIZ F. T.; SAROTTI, ARIEL M.; PILLI, RONALDO A.. Total Synthesis and Tentative Structural Elucidation of Cryptomoscatone E3: Interplay of Experimental and Computational Studies. Journal of Organic Chemistry, v. 80, n. 24, p. 12027-12037, DEC 18 2015. (09/51602-5, 13/07607-8)

OLIVEIRA, F. L.; HUBER, P. C.; ALMEIDA, W. P.; SABINO, J. R.; APARICIO, R.. Tris[2-(1,3-thiazol-2-yl-kappa N)-1H-benzimidazole-kappa N-3]zinc(II) dinitrate ethanol hemisolvate monohydrate at 100 K. ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS, v. 69, p. 13-pg., 2013-02-01. (10/20861-2, 09/51602-5)

MARTINS, LUCIMARA JULIO; SIMONI, DEBORAH DE ALENCAR; APARICIO, RICARDO; COELHO, FERNANDO. Crystal structure of 3-methoxycarbonyl-2-(4-methoxypheny1)-8-oxo-1-azaspiro-[4.5]deca-1,6,9-trien-1-ium-1-olate. ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, v. 70, p. 9-pg., 2014-11-01. (09/51602-5, 09/18390-4)

VIVAS, M. G.; GERMINO, J. C.; BARBOZA, C. A.; SIMON, DEBORAH DE A.; VAZQUEZ, P. A. M.; DE BONI, L.; ATVARS, T. D. Z.; MENDONCA, C. R.. Revealing the Dynamic of Excited State Proton Transfer of a pi-Conjugated Salicylidene Compound: An Experimental and Theoretical Study. Journal of Physical Chemistry C, v. 121, n. 2, p. 1283-1290, JAN 19 2017. (09/51602-5, 11/12399-0, 13/16245-2)

VENDRAMINI-COSTA, DEBORA BARBOSA; MONTEIRO, KARIN MAIA; IWAMOTO, LEILANE HESPPORTE; JORGE, MICHELLE PEDROZA; TINTI, SIRLENE VALERIO; PILLI, RONALDO ALOISE; DE CARVALHO, JOAO ERNESTO. Gastroprotective effects of goniothalamin against ethanol and indomethacin-induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds. Chemico-Biological Interactions, v. 224, p. 206-212, DEC 5 2014. (12/18281-3, 09/51602-5)