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Di(hetero) aryl and alicyclic amine derivatives of thieno[2,3-b]pyridine were synthesized in good to high yields (45–76%) via palladium-catalyzed Buchwald–Hartwig amination. The reactions were performed using methyl 5-bromothieno[2,3-b]pyridine-2-carboxylate, prepared in this work, and a variety of substituted anilines bearing either electron-donating groups (EDGs) or electron-withdrawing groups (EWGs), as well as pyridinyl amines, and saturated heterocyclic amines such as morpholine and piperidine. For most substrates, the optimal conditions involved Pd(OAc)2, rac-BINAP, and Cs2CO3 in toluene at 100 °C under argon. Substrate bearing EWGs and electron-deficient pyridinyl amines required Xantphos as the ligand, while reactions with piperidine were only successful using Pd2(dba)3 as a palladium (0) source. The antiparasitic activity of the synthesized compounds was evaluated against Trypanosoma brucei (T. brucei) and Leishmania infantum (L. infantum) in both promastigote and amastigote forms. Most compounds exhibited no significant cytotoxicity (CC50 > 100 μM) in PMA-differentiated THP-1 derived macrophage cells. Analysis of substituent effects focusing on the nature of amino substitution at position C(5) revealed distinct trends in antiparasitic activity. Notably, one compound exhibited activity against Leishmania infantum promastigotes that was nearly four times higher than that of the reference drug miltefosine, and its selectivity index was also approximately fourfold higher.

Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using Et3N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI50 < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC50 < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages.

Small peptides with aromatic nuclei at the N-terminus have been shown to form bioactive, biocompatible, and biodegradable supramolecular peptide hydrogels. Novel heterocycle–dipeptide conjugates with potential biological activity or application as drug carriers were synthesized by using S-(benzo[b]thiophene) and N,S-(thieno [2,3-b]pyridine and thieno[2,3-b]quinoline) heterocycles as N-protective groups for dipeptides l-Phe-l-Phe and l-Phe-l-Leu. The synthesis involved coupling heterocyclic carboxylic acids with trifluoroacetate salts of ethyl l-phenylalanyl-l-phenylalaninate and ethyl l-phenylalanyl- l-leucinate using HBTU and Et3N, producing the corresponding six N-heterocycle–dipeptide ester conjugates, which were then hydrolyzed to the carboxylic acids. These conjugates were subjected to gelation tests in water starting from 0.4 wt% concentration of the conjugates, using a pH-lowering method with GdL. Among them, only the conjugate of benzo[b]thiophene with l-Phe-l-Phe-OH formed a hydrogel, with a gelation critical concentration of 0.15 wt% (GdL 0.6%) and a final pH of 6.8, which is important for biological applications. The hydrogel was characterized by STEM, revealing nanofibers with an average thickness of 17 nm that assemble into a 3D network capable of trapping water. Further rheological analysis demonstrated its viscoelastic behavior (G′ = 3.03 × 103 Pa; G″ = 3.28 × 102 Pa), comparable to the extracellular matrix of certain human tissues, crucial for biomedical applications.

Multicore magnetic nanoparticles of manganese ferrite were prepared using carboxymethyl dextran as an agglutinating compound or by an innovative method using melamine as a cross-coupling agent. The nanoparticles prepared using melamine exhibited a flower-shape structure, a saturation magnetization of 6.16 emu/g and good capabilities for magnetic hyperthermia, with a specific absorption rate (SAR) of 0.14 W/g. Magnetoliposome-like structures containing the multicore nanoparticles were prepared, and their bilayer structure was confirmed by FRET (Förster Resonance Energy Transfer) assays. The nanosystems exhibited sizes in the range of 250–400 nm and a low polydispersity index. A new antitumor thienopyridine derivative, 7-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]thieno[3,2-b]pyridine, active against HeLa (cervical carcinoma), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small-cell lung carcinoma) and HepG2 (hepatocellular carcinoma) cell lines, was loaded in these nanocarriers, obtaining a high encapsulation efficiency of 98 ± 2.6%. The results indicate that the new magnetoliposomes can be suitable for dual cancer therapy (combined magnetic hyperthermia and chemotherapy).

With a complex chemical composition rich in phenolic compounds, propolis (resinous substance collected by Apis mellifera from various tree buds) exhibits a broad spectrum of biological activities. Recently, in vitro and in vivo data suggest that propolis has anticancer properties, but is the cytoxicity of propolis specific for tumor cells? To answer this question, the cytotoxicity of phenolic extracts from Portuguese propolis of different origins was evaluated using human tumor cell lines (MCF7—breast adenocarcinoma, NCI-H460—non-small cell lung carcinoma, HCT15—colon carcinoma, HeLa—cervical carcinoma, and HepG2—hepatocellular carcinoma), and non-tumor primary cells (PLP2). The studied propolis presented high cytotoxic potential for human tumor cell lines, mostly for HCT15. Nevertheless, excluding HCT15 cell line, the extracts at the GI50 obtained for tumor cell lines showed, in general, cytotoxicity for normal cells (PLP2). Propolis phenolic extracts comprise phytochemicals that should be further studied for their bioactive properties against human colon carcinoma. In the other cases, the proximity of the in vitro cytotoxic doses for tumor and normal cell lines should be confirmed by in vivo tests and may highlight the need for selection of specific compounds within the propolis extract.

Multifunctional liposomes containing manganese ferrite/gold core/shell nanoparticles were developed. These magnetic/plasmonic nanoparticles were covered by a lipid bilayer or entrapped in liposomes, which form solid or aqueous magnetoliposomes as nanocarriers for simultaneous chemotherapy and phototherapy. The core/shell nanoparticles were characterized by UV/Visible absorption, X-Ray Diffraction (XRD), Transmission Electron Microscopy (TEM), and Superconducting Quantum Interference Device (SQUID). The magnetoliposomes were characterized by Dynamic Light Scattering (DLS) and TEM. Fluorescence-based techniques (FRET, steady-state emission, and anisotropy) investigated the incorporation of a potential anti-tumor drug (a thienopyridine derivative) in these nanosystems. The core/shell nanoparticles exhibit sizes of 25 ± 2 nm (from TEM), a plasmonic absorption band (λmax = 550 nm), and keep magnetic character. XRD measurements allowed for the estimation of 13.3 nm diameter for manganese ferrite core and 11.7 nm due to the gold shell. Aqueous magnetoliposomes, with hydrodynamic diameters of 152 ± 18 nm, interact with model membranes by fusion and are able to transport the anti-tumor compound in the lipid membrane, with a high encapsulation efficiency (EE (%) = 98.4 ± 0.8). Solid magnetoliposomes exhibit hydrodynamic diameters around 140 nm and also carry successfully the anticancer drug (with EE (%) = 91.2 ± 5.2), while also being promising as agents for phototherapy. The developed multifunctional liposomes can be promising as therapeutic agents for combined chemo/phototherapy.

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines—MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 μM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.

The development of stimuli-sensitive drug delivery systems is a very attractive area of current research in cancer therapy. The deep knowledge on the microenvironment of tumors has supported the progress of nanosystems’ ability for controlled and local fusion as well as drug release. Temperature and pH are two of the most promising triggers in the development of sensitive formulations to improve the efficacy of anticancer agents. Herein, magnetic liposomes with fusogenic sensitivity to pH and temperature were developed aiming at dual cancer therapy (by chemotherapy and magnetic hyperthermia). Magnetic nanoparticles of mixed calcium/manganese ferrite were synthesized by co-precipitation with citrate and by sol–gel method, and characterized by X-ray diffraction (XRD), scanning electron microscopy in transmission mode (STEM), and superconducting quantum interference device (SQUID). The citrate-stabilized nanoparticles showed a small-sized population (around 8 nm, determined by XRD) and suitable magnetic properties, with a low coercivity and high saturation magnetization (~54 emu/g). The nanoparticles were incorporated into liposomes of dipalmitoylphosphatidylcholine/cholesteryl hemisuccinate (DPPC:CHEMS) and of the same components with a PEGylated lipid (DPPC:CHEMS:DSPE-PEG), resulting in magnetoliposomes with sizes around 100 nm. Dynamic light scattering (DLS) and electrophoretic light scattering (ELS) measurements were performed to investigate the pH-sensitivity of the magnetoliposomes’ fusogenic ability. Two new antitumor thienopyridine derivatives were efficiently encapsulated in the magnetic liposomes and the drug delivery capability of the loaded nanosystems was evaluated, under different pH and temperature conditions.

Several novel methyl 7-[(hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C–N Buchwald–Hartwig cross-coupling of either methyl 7-aminothieno[3,2-b]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-b]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure–activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI50 ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI50 values. The effects of the methoxylated compounds 2b (2-OMeC6H4), 2f and 2g (3,4- or 3,5-diOMeC6H3, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI50 = 7.8 µM) and selective compound (2g) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition.

Magnetoliposomes containing calcium ferrite (CaFe2O4) nanoparticles were developed and characterized for the first time. CaFe2O4 nanoparticles were covered by a lipid bilayer or entrapped in liposomes forming, respectively, solid or aqueous magnetoliposomes as nanocarriers for new antitumor drugs. The magnetic nanoparticles were characterized by UV/Visible absorption, XRD, HR-TEM, and SQUID, exhibiting sizes of 5.2 ± 1.2 nm (from TEM) and a superparamagnetic behavior. The magnetoliposomes were characterized by DLS and TEM. The incorporation of two new potential antitumor drugs (thienopyridine derivatives) specifically active against breast cancer in these nanosystems was investigated by fluorescence emission and anisotropy. Aqueous magnetoliposomes, with hydrodynamic diameters around 130 nm, and solid magnetoliposomes with sizes of ca. 170 nm, interact with biomembranes by fusion and are able to transport the antitumor drugs with generally high encapsulation efficiencies (70%). These fully biocompatible drug-loaded magnetoliposomes can be promising as therapeutic agents in future applications of combined breast cancer therapy.