Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against and , Two Emerging Human Pathogens.

Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections.

Enhanced Synergistic Efficacy Against Breast Cancer Cells Promoted by Co-Encapsulation of Piplartine and Paclitaxel in Acetalated Dextran Nanoparticles.

Malignant breast tumors constitute the most frequent cancer diagnosis among women. Notwithstanding the progress in treatments, this condition persists as a major public health issue. Paclitaxel (PTX) is a first-line classical chemotherapeutic drug used as a single active pharmaceutical ingredient (API) or in combination therapy for breast cancer (BC) treatment.

Furoxan-piplartine hybrids as effective NO donors and ROS inducers in PC3 cancer cells: design, synthesis, and biological evaluation.

Conjugation of the naturally occurring product piplartine (PPT, 1), which is a potent cytotoxic compound and ROS inducer, with a diphenyl sulfonyl-substituted furoxan moiety (namely, 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide), an important type of NO donor, an ether linker of different chain lengths is described, characterized and screened for the anticancer potential. The cytotoxicity of the new hybrids was evaluated on a panel of human cancer cell lines (MCF-7, PC3 and OVCAR-3) and two non-cancer human cells (MCF10A and PNT2). In general, the synthesized hybrids were more cytotoxic and selective compared to their furoxan precursors 4-6 and PPT in the above cancer cells.

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.

Electrochemical Multicomponent Synthesis of Alkyl Alkenesulfonates using Styrenes, SO and Alcohols.

A novel electrochemical approach to access alkyl alkenesulfonates via a multicomponent reaction was developed. The metal-free method features easy-to-use SO stock solution forming monoalkylsulfites from alcohols with an auxiliary base in-situ. These intermediates serve a dual role as starting materials and as supporting electrolyte enabling conductivity.

Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues.

Two routes to the antimalarial diaminopyrimidine were developed based on the C-6 metalation of suitable 2,4-dichloro-5-alkoxy pyrimidines using (TMP)Zn·2MgCl·2LiCl base. One approach involves a late-stage modification of the C-6 position, while the other allows for tail fragment modification of . Both routes have proven reliable in synthesizing , as well as eight analogues.

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.

Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics.

This contribution describes the design and synthesis of multifunctional micelles based on amphiphilic brush block copolymers (BBCPs) for imaging and selective drug delivery of natural anticancer compounds. Well-defined BBCPs were synthesized via one-pot multi-step sequential grafting-through ring-opening metathesis polymerization (ROMP) of norbornene-based macroinitiators. The norbornenes employed contain a poly(ethylene glycol) methyl ether chain, an alkyl bromide chain, and/or a near-infrared (NIR) fluorescent cyanine dye.

Hybrids of 4-hydroxy derivatives of goniothalamin and piplartine bearing a diester or a 1,2,3-triazole linker as antiproliferative agents.

A library of nine hybrids of 4-hydroxygoniothalamin (2), 4-hydroxypiplartine (4), monastrol (5) and oxo-monastrol (6) was prepared via a modular synthetic route with a diester or a 1,2,3-triazole as linkers. The compounds were assayed against a panel of human cancer cell lines, including MCF-7 (breast adenocarcinoma), HeLa (cervical adenocarcinoma), Caco-2 (colorectal adenocarcinoma) and PC3 (prostate adenocarcinoma), as well as against normal breast (MCF10A) and prostate (PNT2) cells. In general, hybrids with an ester linker containing 4-hydroxypiplartine (4) were more potent than the corresponding hybrids with 4-hydroxygoniothalamin (2).

Enhancing the Anticancer Activity and Selectivity of Goniothalamin Using pH-Sensitive Acetalated Dextran (Ac-Dex) Nanoparticles: A Promising Platform for Delivery of Natural Compounds.

Goniothalamin (GTN), a natural compound isolated from species, has previously demonstrated cytotoxic activity against several cancer cell lines. However, similarly to many natural and synthetic anticancer compounds, GTN presents toxicity toward some healthy cells and low aqueous solubility, decreasing its bioavailability and precluding its application as an antineoplastic drug. In our efforts to improve the pharmacokinetic behavior and selectivity of GTN against cancer cells, we developed a polymeric nanosystem, in which -GTN was encapsulated in pH-responsive acetalated dextran (Ac-Dex) nanoparticles (NPs) with high loadings of the bioactive compound.

Total Synthesis of (+)-Raputindole A: An Iridium-Catalyzed Cyclization Approach.

This work describes the total synthesis of raputindole A () through a convergent approach that features (1) an iridium-catalyzed cyclization to assemble the tricyclic core of the northern part, (2) enzymatic resolution to secure the preparation of an enantiomerically pure benzylic alcohol intermediate, and (3) the installation of the isobutenyl side chain via methallylation of the corresponding benzylic carbocation and coupling of the northern and southern parts via the Heck reaction. (+)-Raputindole A () was prepared in 10 steps (longest linear sequence) in 3.3% overall yield.

Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin.

An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. The synthetic route hinges upon a telescoped continuous flow Grignard addition followed by an acylation reaction capable of delivering a racemic goniothalamin precursor () (20.9 g prepared over 3 h), with a productivity of 7 g·h.

Antiproliferative Flavanoid Dimers Isolated from Brazilian Red Propolis.

Herein reported are results of the chemical and biological investigation of red propolis collected at the Brazilian Northeast coastline. New propolones A-D (-), with a 3-{3-[(2-phenylbenzofuran-3-yl)methyl]phenyl}chromane skeleton; propolonones A-C (-), with a 3-[3-(3-benzylbenzofuran-2-yl)phenyl]chromane skeleton; and propolol A (), with a 6-(3-benzylbenzofuran-2-yl)-3-phenylchromane skeleton, were isolated as constituents of Brazilian red propolis by cytotoxicity-guided assays and structurally identified by analysis of their spectroscopic data. Propolone B () and propolonone A () display significant cytotoxic activities against an ovarian cancer cell line expressing a multiple drug resistance phenotype when compared with doxorubicin.

Modular Synthesis of Di- and Trisubstituted Imidazoles from Ketones and Aldehydes: A Route to Kinase Inhibitors.

A one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes. This methodology afforded twenty-nine disubstituted -imidazoles (23%-85% yield). A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation-condensation protocol, followed by bromination and Suzuki coupling in the imidazole ring to yield trisubstituted -imidazoles (23%-69%, three steps).

Total Synthesis and Structural Validation of Phosdiecin A via Asymmetric Alcohol-Mediated Carbonyl Reductive Coupling.

The first total synthesis and structural validation of phosdiecin A was accomplished in 13 steps through asymmetric iridium-catalyzed alcohol-mediated carbonyl reductive coupling. The present route is the shortest among >30 total and formal syntheses of fostriecin family members.

Synthesis of Nitrogen-Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells.

Two series of racemic goniothalamin analogues displaying nitrogen-containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against a panel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity. Among them, goniothalamin chloroacrylamide 13 e displayed the lowest IC values for both MCF-7 (0.

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.

Synthesis of novel perillyl-dihydropyrimidinone hybrids designed for antiproliferative activity.

A series of fifteen novel dihydropyrimidinone hybrid compounds were synthesized in good yields a multicomponent reaction combined with the Huisgen reaction. The antiproliferative activity was investigated against nine tumor cell lines, and four hybrid compounds (TGI < 10 μM) showed promising antiproliferative activity against the tumor cell lines OVCAR-3 (ovarian), UACC-62 (melanoma) and U251 (glioma). Several hybrid compounds assayed have high TGI values (TGI 147.

Visible-Light-Activated Catalytic Enantioselective β-Alkylation of α,β-Unsaturated 2-Acyl Imidazoles Using Hantzsch Esters as Radical Reservoirs.

An efficient and practical method for the enantioselective β-functionalization of α,β-unsaturated 2-acyl imidazoles is described. The method uses a previously devised chiral-at-metal rhodium catalyst (Λ-RhS, 4 mol %) along with Hantzsch ester derivatives as alkyl radical sources. The rhodium complex exerts a dual role as the visible-light-absorbing unit upon substrate binding and as the asymmetric catalyst.

Preferential Mitochondrial Localization of a Goniothalamin Fluorescent Derivative.

A fluorescent 2,1,3-benzothiadiazole-containing goniothalamin derivative, BTD-GTN (), has been synthesized and successfully tested in bioimaging experiments in live cells. The fluorescent compound proved to be capable of transposing the cell membranes, indicating its subcellular localization. The use of the benzothiadiazole core as the fluorophore revealed the favored localization of the GTN analogue in the cytoplasm of live cells, preferentially in the mitochondria, in line with previous results that indicated the loss of mitochondrial transmembrane potential upon treatment with GTN.

Catalytic Enantioselective Allylations of Acetylenic Aldehydes via 2-Propanol-Mediated Reductive Coupling.

Cyclometalated π-allyliridium C,O-benzoates modified by ( S)-SEGPHOS or ( S)-Cl,OMe-BIPHEP catalyze enantioselective 2-propanol-mediated reductive couplings of diverse nonmetallic allyl pronucleophiles with the acetylenic aldehyde TIPSC≡CCHO. Absolute stereochemistries of the resulting secondary homoallylic-propargylic alcohols were assigned using Rychnovsky's competing enantioselective conversion method.

Organic Synthesis: New Vistas in the Brazilian Landscape.

In this overview, we present our analysis of the future of organic synthesis in Brazil, a highly innovative and strategic area of research which underpins our social and economical progress. Several different topics (automation, catalysis, green chemistry, scalability, methodological studies and total syntheses) were considered to hold promise for the future advance of chemical sciences in Brazil. In order to put it in perspective, contributions from Brazilian laboratories were selected by the citations received and importance for the field and were benchmarked against some of the most important results disclosed by authors worldwide.

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).

Catalytic Asymmetric Synthesis and Stereochemical Revision of (+)-Cryptoconcatone H.

The total synthesis and structural revision of (+)-cryptoconcatone H are described. Guided by computational studies for the final structure assignment, the stereogenic centers at the tetrahydropyran moiety of (+)-cryptoconcatone H were assembled through catalytic asymmetric methodologies: Krische allylation, cross-metathesis reaction, and THP formation via Pd(II)-catalyzed cyclization. Finally, a Krische allylation reaction established the last stereocenter, and the lactone moiety was formed by ring-closing metathesis.