Strongly ROS-Correlated, Time-Dependent, and Selective Antiproliferative Effects of Synthesized Nano Vesicles on BRAF Mutant Melanoma Cells and Their Hyaluronic Acid-Based Hydrogel Formulation.

Cutaneous metastatic melanoma (CMM) is the most aggressive form of skin cancer with a poor prognosis. Drug-induced secondary tumorigenesis and the emergency of drug resistance worsen an already worrying scenario, thus rendering urgent the development of new treatments not dealing with mutable cellular processes. Triphenyl phosphonium salts (TPPSs), in addiction to acting as cytoplasmic membrane disruptors, are reported to be mitochondria-targeting compounds, exerting anticancer effects mainly by damaging their membranes and causing depolarization, impairing mitochondria functions and their DNA, triggering oxidative stress (OS), and priming primarily apoptotic cell death.

The Remarkable and Selective In Vitro Cytotoxicity of Synthesized Bola-Amphiphilic Nanovesicles on Etoposide-Sensitive and -Resistant Neuroblastoma Cells.

Neuroblastoma (NB) is a solid tumor occurring in infancy and childhood. Its high-risk form has currently a survival rate <50%, despite aggressive treatments. This worrying scenario is worsened by drug-induced secondary tumorigenesis and the emergency of drug resistance, calling for the urgent development of new extra-genomic treatments.

Chemical Modification of Pactamycin Leads to New Compounds with Retained Antimicrobial Activity and Reduced Toxicity.

Pactamycin (PCT), an antibiotic produced by , is a five-membered ring aminocyclitol that is active against a variety of Gram-positive and Gram-negative microorganisms, as well as several animal tumor lines in culture and in vivo. Pactamycin targets the small ribosomal subunit and inhibits protein synthesis in bacteria, archaea, and eukaryotes, but due to its toxicity is used only as a tool for biochemical research. Prompted by the successful and well-established procedure for the derivatization of antibiotics, we modified pactamycin by tethering basic amino acids to the free primary amino group of the aminocyclitol ring.

Synthesized -Triphenyl Phosphonium-Based Nano Vesicles Have Potent and Selective Antibacterial Effects on Several Clinically Relevant Superbugs.

The increasing emergence of multidrug-resistant (MDR) pathogens due to antibiotic misuse translates into obstinate infections with high morbidity and high-cost hospitalizations. To oppose these MDR superbugs, new antimicrobial options are necessary. Although both quaternary ammonium salts (QASs) and phosphonium salts (QPSs) possess antimicrobial effects, QPSs have been studied to a lesser extent.

Synthesis of Novel Artemisinin, Ciprofloxacin, and Norfloxacin Hybrids with Potent Antiplasmodial Activity.

The synthesis and antiplasmodial evaluation of new hybrids combining the pharmacophore structures of artemisinin, ciprofloxacin or norfloxacin, and 7-chloroquinoline are reported in this study. The first step for all of the syntheses is the obtainment of key piperazine esters intermediates bearing the drugs ciprofloxacin and norfloxacin. Using these platforms, 18 final compounds were synthesized through a multistep procedure with overall yields ranging between 8 and 20%.

Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein.

Chemotherapy is a powerful means of cancer treatment but its efficacy is compromised by the emergence of multidrug resistance (MDR), mainly linked to the efflux transporter ABCB1/P-glycoprotein (P-gp). Based on the chemical structure of betulin, identified in our previous work as an effective modulator of the P-gp function, a series of analogs were designed, synthesized and evaluated as a source of novel inhibitors. Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.

Mitochondriotropic agents conjugated with NSAIDs through metal ions against breast cancer cells.

Two copper(I) polymorphs of formula [Cu(SALH)(TPP)] (1a and 1b) were prepared by the conjugation of the Non-Steroidal Anti-Inflammatory Drug (NSAID) salicylic acid (SALH) with the mitochondriotropic agent triphenylphosphine (TPP) via metal ion. For comparison, the isomorph [Ag(SALH)(TPP)] (2) was prepared. The conjugates 1a, 1b and 2 were characterized by melting point (m.

Tetraphenylethylene-Based Photoluminescent Self-Assembled Nanoparticles: Preparation and Biological Evaluation.

The conjugation of tetraphenylethylene (TPE) with podophyllotoxin, -desacetylthiocolchicine, and cabazitaxel through a sebacic acid linker led to the formation of fluorescent nanoparticles. Dynamic light scattering (DLS) and photoluminescence spectroscopy were used for the identification and characterization of the fluorescent nanoparticles. The biological evaluation was determined in three human ovarian (KURAMOCHI, OVCAR3, OVSAHO) and three human breast (MCF7, SKBR 3, and MDA-MB231) cancer cell lines.

Chloramphenicol Derivatization in Its Primary Hydroxyl Group with Basic Amino Acids Leads to New Pharmacophores with High Antimicrobial Activity.

In a previous study published by our group, successful modification of the antibiotic chloramphenicol (CHL) was reported, which was achieved by replacing the dichloroacetyl tail with alpha and beta amino acids, resulting in promising new antibacterial pharmacophores. In this study, CHL was further modified by linking the basic amino acids lysine, ornithine, and histidine to the primary hydroxyl group of CHL via triazole, carbamate, or amide bonding. Our results showed that while linking the basic amino acids retained antibacterial activity, it was somewhat reduced compared to CHL.

Histone deacetylase-based dual targeted inhibition in multiple myeloma.

Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM.

Entinostat-Bortezomib Hybrids against Multiple Myeloma.

Although proteasome inhibitors have emerged as the therapeutic backbone of multiple myeloma treatment, patients often relapse and become drug refractory. The combination between proteasome and histone deacetylase inhibitors has shown to be more efficient compared to monotherapy by enhancing the anti-myeloma activity and improving the patient's lifetime expectancy. Hybrid molecules, combining two drugs/pharmacophores in a single molecular entity, offer improved effectiveness by modulating more than one target and circumventing differences in the pharmacokinetic and pharmacodynamic profiles, which are the main disadvantages of combination therapy.

Synthesis and Antiproliferative Activity of Novel Dehydroabietic Acid-Chalcone Hybrids.

Dehydroabietic Acid (DHA, ) derivatives are known for their antiproliferative properties, among others. In the context of this work, DHA was initially modified to two key intermediates bearing a C18 methyl ester, a phenol moiety at C12, and an acetyl or formyl group at C13 position. These derivatives allowed us to synthesize a series of DHA-chalcone hybrids, suitable for structure-activity relationship studies (SARS), following their condensation with a variety of aryl-aldehydes and methyl ketones.

New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity.

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs , , and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using and as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC values of 2.

Inhibition of MurA Enzyme from and by Diterpenes from and Their Synthetic Analogs.

Enzymes MurA and MurF, involved in bacterial cell wall synthesis, have been validated as targets for the discovery of novel antibiotics. A panel of plant-origin antibacterial diterpenes and synthetic analogs derived therefrom were investigated for their inhibitory properties on these enzymes from and . Six compounds were proven to be effective for inhibiting MurA from both bacteria, with IC values ranging from 1.

Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in : Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria.

Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways.

Design and Synthesis of Piperazine-Based Compounds Conjugated to Humanized Ferritin as Delivery System of siRNA in Cancer Cells.

Gene expression regulation by small interfering RNA (siRNA) holds promise in treating a wide range of diseases through selective gene silencing. However, successful clinical application of nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient delivery of negatively charged siRNA duplexes, the internal cavity of "humanized" chimeric Archaeal ferritin (HumAfFt) was specifically decorated with novel cationic piperazine-based compounds (PAs).

New Chloramphenicol Derivatives with a Modified Dichloroacetyl Tail as Potential Antimicrobial Agents.

To combat the dangerously increasing pathogenic resistance to antibiotics, we developed new pharmacophores by chemically modifying a known antibiotic, which remains to this day the most familiar and productive way for novel antibiotic development. We used as a starting material the chloramphenicol base, which is the free amine group counterpart of the known chloramphenicol molecule antibiotic upon removal of its dichloroacetyl tail. To this free amine group, we tethered alpha- and beta-amino acids, mainly glycine, lysine, histidine, ornithine and/or beta-alanine.

Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline.

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.

Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity.

A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant FcB1/Colombia strain. The ART-GMeP hybrid and compounds and which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC values of 2.6, 8.

2,3-Diaminopropanols Obtained from d-Serine as Intermediates in the Synthesis of Protected 2,3-l-Diaminopropanoic Acid (l-Dap) Methyl Esters.

A synthetic strategy for the preparation of two orthogonally protected methyl esters of the non-proteinogenic amino acid 2,3-l-diaminopropanoic acid (l-Dap) was developed. In these structures, the base-labile protecting group 9-fluorenylmethyloxycarbonyl (Fmoc) was paired to the -toluensulfonyl (tosyl, Ts) or acid-labile -butyloxycarbonyl (Boc) moieties. The synthetic approach to protected l-Dap methyl esters uses appropriately masked 2,3-diaminopropanols, which are obtained via reductive amination of an aldehyde prepared from the commercial amino acid -Fmoc---butyl-d-serine, used as the starting material.

Synthesis and structure-activity relationships of novel abietane diterpenoids with activity against .

To find alternative compounds against methicillin-resistant (MRSA) and methicillin-susceptible (MSSA), novel derivatives from dehydroabietic acid were synthesized. Compound was the most effective against 15 MRSA and 11 MSSA with minimum inhibitory concentration values ranging from 3.9 to 15.

General Approach for the Liquid-Phase Fragment Synthesis of Orthogonally Protected Naturally Occurring Polyamines and Applications Thereof.

Orthogonally protected polyamines (PAs) have been synthesized using α,ω-diamines and ω-aminoalcohols as N-C-N and N-C synthons, respectively, and the Mitsunobu reaction as the key reaction for the assembly of the PA skeleta. The Trt, Dde, and Phth groups have been employed for protecting the primary amino functions and the Ns group for activating the primary amino functions toward alkylation and secondary amino function protection. The approach has been readily extended to accommodate the total synthesis of the spider toxins Agel 416 and HO-416b, incorporating the 3-4-3-3 and the 3-3-3-4 PA skeleton, respectively.

A rapid MALDI MS/MS based method for assessing saffron (Crocus sativus L.) adulteration.

We report on a sensitive and fast quantitative MALDI-MS/MS method used to assess saffron authenticity by direct analysis through the determination of picrocrocin as the saffron authenticity marker, and using curcumin as the non-isotopic isobaric internal standard. The internal standard curcumin yielded good linearity (R = 0.994), and with confidence intervals at 95% for intercept.