From 2021 to present

Current data shows that, worldwide, more than 18 million new cases of cancer, and approximately 10 million deaths from this disease were reported in 2020. It is estimated that the average number of new cancer cases by 2040 will increase by 47% compared to 2020, and could reach 28.4 million people affected. Currently lung cancer is the leading cause of death, followed by colorectal cancer and liver cancer, however, projections show that pancreatic cancer will occupy the third position in cases of death by 2025 in several countries. Several modalities of treatment for cancer are available, but currently conventional chemotherapy is the most used option, despite the fact that the main chemotherapeutic drugs used, present serious side effects due to their high toxicity by low selectivity, fighting not only the tumor cells, but also the healthy cells. This situation is also aggravated when one considers the cellular resistance observed by the use of traditional chemotherapy drugs. For this reason, the development of therapies directed to targets that play important roles in the growth and/or maintenance of pancreatic cancer is an important strategy to combat and control deaths from this disease. Among the main pathways that act for the evolution of pancreatic cancer, the mitogen-activated protein kinases (MAPKs) stand out. The MAPKs mediate a wide variety of cellular processes in response to various extracellular stimuli. Considering this information, phytochemicals present in Brazilian propolis, and a molecular docking study are performed for the p38 MAPK pathway.

From 2020 to 2021

Funding: FUNADESP

In recent years we can see a considerable increase of in silico computational techniques for the development of pharmacological tests, simulations and hypotheses. These methods include databases, quantitative and qualitative structure-activity relationships, pharmacophore groups, and other molecular modeling approaches. In silico medicinal chemistry, is a rapidly growing area that encompasses the development of techniques for using software and obtaining, analyzing, and integrating biological and chemical data from a variety of sources. More specifically, it uses this information to create models or computer simulations that can be used to make predictions, possibilities, and ultimately provide discoveries or advances in therapeutics. Using qualitative techniques, a new series of push-pull compounds already obtained, characterized and tested against various tumor cell lines in vitro will be analyzed, to establish a relationship between the chemical structure and biological activity of these compounds and also to propose structures that could potentially be more bioactive than the molecules already obtained.

From 2019 to 2020

Funding: FUNADESP

Veterinary antibiotics are constantly used for prophylaxis and treatment of diseases in dairy cattle. The consumption of products from these cattle causes unnecessary exposure of human consumers to residues of these drugs, which can help the development of resistant bacteria, being a risk to public health. Quantification and identification will be performed for the most commonly used β-lactam antibiotics. The samples will first go through a screening, through microbiological screening. The positive samples will have the substances identified by UV-VIS spectroscopy and the quantification of the residues will be performed by two methods: microbiological and spectroscopic (UV-VIS). The method validation will be performed in order to confirm the acceptance criteria of the developed method.

From 2019 to 2020

Taking as reference the compound 3-[3-chloro-3-(4-iodo-phenyl)-alylidene]-pentane-2,4-dione, which exhibited potent antitumor action in in vitro tests against B16F10, 4T1, MCF-7, SCC-9 tumor cells with IC50 result = 1.95 µM, 3.715 µM, 0.6665 µM and 10.86 µM respectively. The same compound was also shown to be non-toxic in toxicity tests with normal cells such as HUVEC and FN-1. Structural analogues to the prototype compound, are planned, and their ability as imaging contrasts will be evaluated.

From 2018 to 2019

Funding: FUNADESP

Natural products have been the source of inspiration for the development of most drugs. More than 80% of the substances used in therapeutics are natural substances or are substances inspired by natural compounds. Among the natural compounds with relevant pharmacological activity is (E,E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione or, curcumin as it is better known. Curcumin has been used in Ayuverdic medicine for over 6000 years, exhibiting various pharmacological properties. In addition to practical results, extensive research over the past decades has indicated that curcumin has great therapeutic potential. Considering this information, the present project proposes to increase the natural production of curcumin, by Curcuma longa L., through the supplementation of its main precursor, ferulic acid, and its analogue, in the form of potassium salt. The exogenous supplementation of a precursor provides, the increase of the production of the next intermediate in the biosynthesis pathway. The use of its derivative, in the form of a potassium salt, aims to encourage the biosynthesis of curcumin, since potassium is the most important cation in plant physiology, highlighting, among others, its role as an activator of enzymatic functions. The possibility of naturally obtaining a greater amount of curcumin, aims to expand the therapeutic studies of this natural product, which presents numerous scientifically proven biological activities, such as anti-inflammatory, antioxidant, antiparasitic, antiviral and antitumor.

From 2012 to 2017

Funding: DAAD/CNPq/CAPES

Doctoral Work

A statistic of IARC (International Agency for Research on Cancer) predicts that 19.5 million people will be affected by the disease in the year 2025th . Different types of cancer are treated by surgery, radiotherapy, chemotherapy or stem cell transplantation. The compound 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4- pentadien-3-one (HB1) has been studied by our working group and exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines and showed very low toxicity rate. Another important compound obtained, was the compound 3-((Z)-3-chloro-3-(4-iodophenyl)allylidene)pentane-2,4-dione (C21), which has shown through in vitro tests also high antitumor activity against tumoral cell B16F10 (IC50 = 0.73 g/mL, in the concentration of 1g/mL after 24 hours) and low toxicity against normal cells. An approach to increase the anti-tumor activity is the combination of carbohydrates with biologically active substances. An example of the effect of associated with carbohydrate compounds are the specific interactions between carbohydrates and lectins on the cell wall, which contribute to many intercellular recognition processes. The first target of this proposal was the synthesis of curcumin analogues linked to C-Glycosidic moieties. It was started with the C-rhamnosylation using the reaction of tetra-O-benzyl-rhamnosyl trichloroacetimidates with electron-rich phenols in the presence of trimethylsilyl triflate (TMSOTf) to get C-glycosidic linkages. Unfortunately the C-Glycosylated compound was not obtained. Through NMR analysis it was possible to observe the formation of the O-Glycosylated compound (15), which seems to be also very interesting. In order to obtain the compound (24) and (25) and subsequently obtaining new C-Glycosylated compounds (28, 30, 35, 43 and 42) were made several synthetic reactions starting from D-Galactose. The first step was the acetylation of all free hydroxyl groups presents and then, the anomeric acetylprotected hydroxy group was replaced by bromo group via hydrogen bromide treatment to obtain the compound (17). Through glycosylation Helferich the brominated glycoside (17) was converted into the galactopyranoside (18) an allylglycoside, which through Zemplén conditions afforded the compound (19), which was subsequently protected by benzylation reaction giving the compound (20). The anomeric dealkylation was performed using palladium (II) chloride-catalyzed, forming the product (21), which was converted into the lactone (22) by Dess-Martin periodinane oxidation. With the Grignard reaction, the hemiacetal (23) was obtained and finally with triethylsilane and BF3.OEt2, the compound (24) was obtained through reduction with significant yield. The total deprotection for benzyls groups was performed by boron trichloride and then de compound (25) was synthesized in one hour with high yield.

Advisor: Prof Dr Anderson Orzari Ribeiro

Advisor: Prof Dr Christian Vogel

Co-Advisor: Prof Dr José Agustín Quincoces Suárez

From 2009 to 2011

Master Work

In this work it was observed that some ortho-substituted chlorinated push-pull butadienes showed better biological action in relation to the para-substituted compounds, which is the case of compound 2-(1-chloro-4-nitro-buta-1,3-dienyl)phenyl benzoate, which showed better activity in relation to its isomer 4-(1-chloro-4-nitro-buta-1,3-dienyl)phenyl benzoate. On the other hand, the compound 2-(1-chloro-4-nitro-buta-1,3-dienyl)phenyl benzoate, for some unknown reason, was not active in the in vivo tests performed. In the cytotoxicity studies all tested compounds showed excellent results. In this group of tested compounds, the isomers 2-(4-acetyl-1-chloro-5-oxo-hexa-1,3-dienyl)phenyl benzoate and the 4-(4-acetyl-1-chloro-5-oxo-hexa-1,3-dienyl)phenyl benzoate, showed no significant difference, having both great cytotoxic capacity. It also appears that the type of substituent is a determinant in the antiproliferative activity exhibited. Note that compound 4-(1-chloro-4-nitro-buta-1,3-dienyl)phenyl benzoate is significantly more active than 4-(1-chloro-4,4-dicyano-buta-1,3-dienyl)phenyl benzoate. This could perhaps be explained by the fact that the nitro group is a stronger electroacceptor substituent than the cyano groups, which could convert the chlorine-bound carbon atom into a stronger electrophilic center and hence the greater ease of being replaced by nucleophilic agents existing in biological receptors. Also noteworthy are phenyl 4-(4-acetyl-1-chloro-5-oxo-hexa-1,3-dienyl)benzoate and phenyl 2-(1-chloro-4,4-dicyano-buta-1,3-dienyl)benzoate, which in in vitro DNA fragmentation studies have been shown to be biologically potent and selective, causing insignificant damage to normal lymphocyte cells.

Advisor: Prof Dr José Agustín Quincoces Suárez

From 2006 to present

Collaborator

The group conducts research with propolis and other natural products, potentially containing flavonoids, tannins and aromatic acids. It uses chemometrics in its studies. It has partnerships with institutions such as: USP, UNICAMP and UNESP. The group leader, Prof Dr Marcucci, has extensive experience in method development using high-performance liquid chromatography as well as separation of chemicals as described above. She also has experience in the validation of chromatographic methods for medicinal plants and herbal medicines. She has several undergraduate students in her research group, some of whom have already received FAPESP scientific initiation grants. He participates in a project with FINEP support for the identity and quality of Brazilian honeys. He is a member of the Technical Chamber of Herbal Medicines of ANVISA.

From 2005 to 2007

Funding: FAPESP

Scientific Initiation Scholarship

This work is based on products with recognized antitumor activity, such as 2-hydroxy-5-(3-methylbut-2-enyl)acetophenone, a component of Brazilian propolis. The transformation of this prototype into an appreciable number of derivatives is planned, employing the reactions of alkylation with 3-chloro-3-methyl-butino-1, followed by catalytic partial hydrogenation reaction and Claisen rearrangement to introduce prenyl groups in ortho position with respect to the OH-phenol groups. To enhance the electronic conjugation, necessary to increase the biological activity of the starting molecules, the Vilsmeier-Haack, Knoevenagel, Claisen-Schmidt, and Aldolic reactions, among others, will be performed. The purity of the products obtained will be verified using the chromatographic techniques of CCD (thin-layer chromatography) and HPLC (high-performance liquid chromatography). Structural characterization will be carried out with the help of quantitative elemental analysis and IR (infrared), NMR (nuclear magnetic resonance) and Mass Spectrometry spectroscopic methods. The predictions made by means of the TOPS-MODE computer programs indicate that several of these derivatives should possess an outstanding antitumor activity. Also these molecules are important raw materials to obtain new prenylated compounds, which may have even greater biological importance.

Advisor: Prof Dr José Agustín Quincoces Suárez

From 2005 to 2020

Collaborator

With funding from FAPESP 2001/03756-1; 2004/11351-0 and 2011/50435-8, among other 21 financial aids granted by this institution, it was possible to synthesize an appreciable number of new families of polyfunctional phenols existing in Brazilian Propolis and in plants, as well as their synthetic derivatives, which exhibited selective antitumor properties, among other relevant biological applications. Also with financial aid from FAPESP and then UNIAN, it was possible for a total of seven patents to be approved abroad: US 7,432,401 B1 07.10.2008; EP 1572614B1 25.12.2013; US 8,859,625 B2 14.10.2014; EP 2054365 B1 24.09.2014; JP 5317290 19.07.2013; JP 5802658 B2 04.09.2015 and US 9,381,169 B2 05.07.2016. All these approved patents are part of a package that is being negotiated through a Tender Protocol prepared by FAPESP/UNIAN/UNICAMP in 2015.