Julio C. Pastre

Flow chemistry syntheses of natural products.

The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.

Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells.

The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the γ-pyrones and the aza-goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin (1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds.

Synthesis of novel room temperature chiral ionic liquids: application as reaction media for the heck arylation of aza-endocyclic acrylates

New achiral and chiral RTILs were prepared using novel and/or optimized synthetic routes. These new series of imidazolinium, imidazolium, pyridinium and nicotine-derived ionic liquids were fully characterized including differential scanning calorimetry (DSC) analysis. The performance of these achiral and chiral room temperature ionic liquids (RTILs) was demonstrated by means of the Heck arylation of endocyclic acrylates employing arenediazonium salts and aryl iodides. The Heck arylations performed in the presence of these ionic entities, either as a solvent or as an additive, were effective leading to complete conversion of the substrate and good to excellent yield of the Heck adduct. In spite of the good performances, no asymmetric induction was observed in any of the cases studied. Two new diastereoisomeric NHC-palladium complexes were prepared in good yields from a chiral imidazolium salt and their structure characterized by X-ray diffraction. Overall, the Heck arylations employing arenediazonium tetrafluoroborates in RTILs were more effective than the traditional protocols employing aryl iodides in terms of reactivity and yields.

A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness

In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 μM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 μM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment.

Design and Synthesis of N-Acylated Aza-Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin (1) and the evaluation of the potential antitumor activity of the compounds. N‐Acylation of aza‐goniothalamin (2) restored the in vitro antiproliferative activity of this family of compounds. 1‐(E)‐But‐2‐enoyl‐6‐styryl‐5,6‐dihydropyridin‐2(1H)‐one (18) displayed enhanced antiproliferative activity. Both goniothalamin (1) and derivative 18 led to reactive oxygen species generation in PC‐3 cells, which was probably a signal for caspase‐dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7‐aminoactinomycin D double staining, which indicated apoptosis, and also led to G2/M cell‐cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin (1), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza‐goniothalamin (2) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.

Catalisadores contendo carbenos n-heterocíclicos como ligantes: propriedades, sínteses, aplicações e comparação com outros ligantes

N-heterocyclic carbenes (NHCs) have become of considerable importance in modern organometallic chemistry and homogeneous catalysis. There are several advantages in the use NHCs over their phosphorus analogues, which explains the enormous development of NHC ligands in the field of organometallic catalysis in the past few years. In this article, we present an overview of the importance of the catalysts containing NHC ligands, their synthesis, some pertinent synthetic applications, and a brief comparison with other catalysts.

Formal Total Synthesis of Actinoranone and Asymmetric Synthesis of Labda-7,13-(E)-dien-15-ol

The syntheses of the polyketide and terpenoid fragments of actinoranone are reported in a concise fashion, relying on catalytic methods. Minimization on the use of protecting groups and redox reactions allowed the synthesis of the carbon backbone of actinoranone in 20 steps (11 steps for LLS). The asymmetric synthesis of labda-7,13-(E)-dien-15-ol is also disclosed.

Formal Total Synthesis of Actinoranone: Synthesis Approaches and Cytotoxic Studies

This article describes our efforts toward the total synthesis of actinoranone. Our synthesis strategies rely on a convergent route to connect the terpenoid and polyketide fragments, employing catalysis and powerful classical reactions for the assembly of these key fragments. A new transformation was disclosed during this work, a domino ring-opening and esterification. Initial cytotoxic studies for the selected synthesis intermediates are also presented.

Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients

We present a comprehensive review of the advent and impact of continuous flow chemistry with regard to the synthesis of natural products and drugs, important pharmaceutical products and definitely responsible for a revolution in modern healthcare. We detail the beginnings of modern drugs and the large scale batch mode of production, both chemical and microbiological. The introduction of modern continuous flow chemistry is then presented, both as a technological tool for enabling organic chemistry, and as a fundamental research endeavor. This part details the syntheses of bioactive natural products and commercial drugs.

Produção de 5-(Hidroximetil)furfural a partir de Biomassa: Desafios Sintéticos e Aplicações como Bloco de Construção na Produção de Polímeros e Combustíveis Líquidos

A producao de compostos conhecidos como blocos de construcao a partir de recursos renovaveis tem despertado muito interesse da comunidade cientifica nos ultimos anos. Blocos de construcao sao moleculas que apresentam, na grande maioria das vezes, multiplos grupos funcionais e oferecem excelentes oportunidades para serem quimicamente ou biologicamente transformadas em compostos com alto valor agregado. Alguns exemplos de compostos com alto valor agregado incluem bio-polimeros, bio-combustiveis, bio-solventes e os compostos de quimica de base. Entre os exemplos que podemos citar como blocos construtores, o 5-(hidroximetil)furfural (5-HMF) apresenta-se como um dos mais estudados nos ultimos anos devido ao seu potencial como materia-prima para preparacao de insumos quimicos. Nesse contexto, este artigo de revisao tem por objetivo apresentar as recentes metodologias sinteticas para preparacao de 5-HMF a partir de recursos renovaveis, bem como a aplicacao de 5-HMF na producao de biocombustiveis liquidos e biopolimeros.