DNA Damage-Inducing 10-Methoxy-canthin-6-one (Mtx-C) Promotes Cell Cycle Arrest in G/M and Myeloid Differentiation of Acute Myeloid Leukemias and Leukemic Stem Cells.

Synthetic 10-methoxy-canthin-6-one (Mtx-C), an alkaloid derivative, exhibits cytotoxic effects against acute myeloid cells (AMLs) and leukemic stem cells (LSCs) at a concentration of approximately 60 μM. However, the antitumor mechanism of Mtx-C in AMLs and LSCs remains elusive. Using Mtx-C at concentrations with low cytotoxicity (2-4 μM) for 72 h, we observed cell arrest with the accumulation of cells in the G/M phase of the cell cycle.

The phosphate ester group in secondary metabolites.

Covering: 2000 to mid-2021The phosphate ester is a versatile, widespread functional group involved in a plethora of biological activities. Its presence in secondary metabolites, however, is relatively rare compared to other functionalities and thus is part of a rather unexplored chemical space. Herein, the chemistry of secondary metabolites containing the phosphate ester group is discussed.

A canthin-6-one derivative induces cell death by apoptosis/necroptosis-like with DNA damage in acute myeloid cells.

Natural products have long been considered a relevant source of new antitumor agents. Despite advances in the treatment of younger patients with acute myeloid leukemia (AML), the prognosis of elderly patients remains poor, with a high frequency of relapse. The cytotoxicity of canthin-6-one alkaloids has been extensively studied in different cell types, including leukemic strains.

Goniothalamin-Related Styryl Lactones: Isolation, Synthesis, Biological Activity and Mode of Action.

This review covers the chemistry and biological aspects of goniothalamin-related styryl lactones isolated from natural sources. This family of secondary metabolites has been reported to display diverse uses in folk medicine, but only a limited number of these compounds have been throughly investigated regarding their biological profile. Herein, we cover the goniothalamin-related styryl lactones having a C6-C3-C4 framework which appeared in the literature for the first time in the period 2000-2017, and the reports on the synthesis, biological activity and mechanism of action which were published from 2007-2017.

Steroidal hormone and morphological responses in the prostate anterior lobe in different cancer grades after Celecoxib and Goniothalamin treatments in TRAMP mice.

Prostate cancer is the second most diagnosed cancer in the world, and alternative methods to prevent and treat different lesion grades need to be evaluated. The objective was to evaluate the morphological, hormonal, and inflammatory responses in the prostate anterior lobe in transgenic adenocarcinoma of the mouse prostate (TRAMP), following Celecoxib and Goniothalamin (GTN) treatments. All animals were treated for 4 weeks, from 8 weeks of age and euthanized either immediately after treatment (12-week-old mice: immediate response) or later (22-week-old mice: late response).

Goniothalamin and Celecoxib Effects During Aging: Targeting Pro-Inflammatory Mediators in Chemoprevention of Prostatic Disorders.

Background: Prostate is highly affected by aging, which lead to inflammatory disorders that can predispose to cancer development. Chemoprevention has emerged as a new therapeutic approach, intensifying studies evaluating the biological properties of new compounds. The aim of this study was to characterize the inflammatory responses in the prostate ventral lobe from senile mice treated with Goniothalamin (GTN), a promising natural compound with anti-inflammatory and antiproliferative properties.

Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis.

The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities.

Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line.

Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects.

Anti-inflammatory therapies in TRAMP mice: delay in PCa progression.

The aim of this study was to characterize the structural and molecular biology as well as evaluate the immediate and late responses of prostatic cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model after treatment with goniothalamin (GTN) and celecoxib. The treated mice received GTN (150 mg/kg, gavage) or celecoxib (10 mg/kg, gavage) from 8 to 12 weeks of age. They were killed at different ages: the immediate-response groups at 12 weeks and the late-response groups at 22 weeks.

(-)-Tarchonanthuslactone: Design of New Analogues, Evaluation of their Antiproliferative Activity on Cancer Cell Lines, and Preliminary Mechanistic Studies.

Natural products containing the α,β-unsaturated δ-lactone skeleton have been shown to possess a variety of biological activities. The natural product (-)-tarchonanthuslactone (1) possessing this privileged scaffold is a popular synthetic target, but its biological activity remains underexplored. Herein, the total syntheses of dihydropyran-2-ones modeled on the structure of 1 were undertaken.

Anti-inflammatory and antinociceptive effects of racemic goniothalamin, a styryl lactone.

Aims: The present study aimed to further investigate the anti-inflammatory activity of goniothalamin (GTN), a styryl lactone, as well as its antinociceptive effects.

Main Methods: The anti-inflammatory activity was evaluated in models of paw edema induced by different mediators in mice and carrageenan-induced peritonitis. Evaluation of the antinociceptive effect was performed through acetic acid-induced writhing test and formalin test.

Gastroprotective effects of goniothalamin against ethanol and indomethacin-induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds.

Goniothalamin (GTN), a styryl-lactone, is a secondary metabolite naturally found in its enantiomeric form (R) in plants of the genus Goniothalamus (Annonaceae). The antiproliferative activity against human tumor cell lines reported in several studies suggest that the α,β-unsaturated δ-lactone moiety emerges as a key Michael acceptor for cysteine residues or other nucleophilic biological molecules. Our group reported on the in vivo activity of (R)- and (S)-GTN as well as its racemic form (rac-GTN) in both Ehrlich solid tumor and carrageenan-induced paw edema in mice, without side effects in the effective doses.

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).

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.

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.

The present work describes the preparation of a novel series of compounds based on the structure of goniothalamin (1), a natural styryl lactone with known cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 17 goniothalamin analogues displaying the 5-methyl-2,5-dihydrofuran-2-one motif were prepared, and their cytotoxicity evaluated. While the analogues bearing methoxy and/or hydroxy groups on the aromatic moiety usually were at least three times less potent than the lead compound (1), ortho and para-trifluoromethyl analogues 10 and 11 exhibited levels of cytotoxicity similar to goniothalamin (1) against most cancer cell lines evaluated.

Knocking down low molecular weight protein tyrosine phosphatase (LMW-PTP) reverts chemoresistance through inactivation of Src and Bcr-Abl proteins.

The development of multidrug resistance (MDR) limits the efficacy of continuous chemotherapeutic treatment in chronic myelogenous leukemia (CML). Low molecular weight protein tyrosine phosphatase (LMW-PTP) is up-regulated in several cancers and has been associated to poor prognosis. This prompted us to investigate the involvement of LMW-PTP in MDR.

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.

Effect of goniothalamin on the development of Ehrlich solid tumor in mice.

In this work the antiproliferative activity of goniothalamin (1), both in racemic and in its enantiomeric pure forms, in a solid tumor experimental model using laboratory animals is described. The antiedematogenic activity displayed by racemic 1 in the carrageenan edema model in mice together with the reduction of Ehrlich solid tumor model suggest a relationship between anticancer and antiinflammatory activities with the antiinflammatory activity favoring the antiproliferative activity itself.

Trypanocidal activity of 5,6-dihydropyran-2-ones against free trypomastigotes forms of Trypanosoma cruzi.

Sixteen 5,6-dihydro-2H-pyran-2-ones were evaluated in in vitro assay against trypomastigotes forms of Trypanosoma cruzi, the causative agent of Chagas' disease. A structure-activity relationship study (SAR) allowed us to establish the relevant structural features for the trypanocidal activity of goniothalamin analogues against T. cruzi.

(R)-Goniothalamin: total syntheses and cytotoxic activity against cancer cell lines.

The total syntheses of (R)-goniothalamin (1), a styryl lactone isolated from several Goniothalamus species, via catalytic asymmetric allylation of alpha-benzyloxyacetaldehyde (2), followed by ring-closing metathesis and Wittig olefination and via catalytic asymmetric allylation of trans-cinnamaldehyde (12), followed by ring-closing metathesis are reported. The antiproliferative activities of (R)-1 and its Z-isomer 10 as well as of the synthetic dihydropyranone intermediates 7 and 8 against eight different cancer cell lines are also described.

Enantioselective syntheses of (R)- and (S)-argentilactone and their cytotoxic activities against cancer cell lines.

Concise total syntheses of (R)- and (S)-argentilactone have been developed via enantioselective catalytic allylation (ECA) and ring-closing metathesis pathways (four steps, 39% overall yield and 82-84% ee) from 2-octynal and their in vitro activity against cancer cells is described.

Probing the mechanism of the Petasis olefination reaction by atmospheric pressure chemical ionization mass and tandem mass spectrometry.

Atmospheric pressure chemical ionization mass (APCI-MS) and tandem mass spectrometry (APCI-MS/MS) is used to probe the mechanism of the Petasis olefination reaction. Oxatitanacycle intermediates 4 were transferred from solution to the gas phase, detected as 4H+ by APCI-MS with characteristic Ti-isotopic patterns, and structurally characterized by APCI-MS/MS. Detection of 4H+, which upon collision activation dissociates to both 3H+ and Cp(2)TiOH+, fully supports the Hughes mechanism as depicted above.