Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions.

A diffusion mixing technique with a volatile reagent was successfully used to generate crotonic condensation adducts of active methylene compounds and formaldehyde at room temperature in the absence of strong acids and bases. The formed adducts were highly reactive intermediates capable of reacting with dienes in a three-component reaction, leading to the formation of Diels-Alder main reaction products.

Green Light Activated Dual-Action Pt(IV) Prodrug with Enhanced PDT Activity.

Light induced release of cisplatin from Pt(IV) prodrugs is a promising tool for precise spatiotemporal control over the antiproliferative activity of Pt-based chemotherapeutic drugs. A combination of light-controlled chemotherapy (PACT) and photodynamic therapy (PDT) in one molecule has the potential to overcome crucial drawbacks of both Pt-based chemotherapy and PDT via a synergetic effect. Herein we report green-light-activated Pt(IV) prodrug GreenPt with BODIPY-based photosentitizer in the axial position with an incredible high light response and singlet oxygen generation ability.

Pentamethine cyanine dyes with alkynyl group as perspective structure for conjugation with targeting moiety.

We report a modified carbocyanine-based asymmetric fluorescent dye, suitable for the azide-alkyne cycloaddition reaction, that possesses promising photochemical properties (Φ = 0,49). As an example of usage of the new fluorophore, it was conjugated to a ligand targeting prostate-specific membrane antigen (PSMA), one of the widely utilized prostate cancer markers.

1,3-Dipolar Cycloaddition of Nitrile Oxides and Nitrilimines to (-)-β-Caryophyllene: Stereoselective Synthesis of Polycyclic Derivatives and Their Biological Testing.

The cycloaddition of nitrile oxides and nitrilimines to one or both of the C=C double bonds of caryophyllene is described. The possibility of introducing five-membered fused and spiro-linked heterocycles into the structure of sesquiterpenes by the 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrilimines to caryophyllene was demonstrated. As a result of these reactions, pharmacophore fragments of isoxazoline and pyrazoline are introduced into the structure of caryophyllene, which leads to an increase in the conformational rigidity of the molecule.

Bifunctional Copper Chelators Capable of Reducing Aβ Aggregation and Aβ-Induced Oxidative Stress.

Five bifunctional copper chelating agents, , designed to prevent beta-amyloid (Aβ) aggregation, were synthesized, and the leader compound () was chosen. acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity. Reactive oxygen species measurements provided by the Pt-nanoelectrode technique in single Aβ-affected human neuroblastoma SH-SY5Y cells revealed significant antioxidant activity of .

BODIPY in Alzheimer's disease diagnostics: A review.

Timely diagnosis and therapy of Alzheimer's disease remains one of the greatest questions in medicinal chemistry of neurodegenerative disease. The lack of low-cost sensors capable of reliable detection of structural changes in AD-related proteins is the driving factor for the development of novel molecules with affinity for AD hallmarks. The development of cheap, safe diagnostic methods is a highly sought-after area of research.

Light-Responsive Pt(IV) Prodrugs with Controlled Photoactivation and Low Dark Toxicity.

Light-induced release of cisplatin from Pt(IV) prodrugs represents a promising approach for precise control over the antiproliferative activity of Pt-based chemotherapeutic drugs. This method has the potential to overcome crucial drawbacks of conventional cisplatin therapy, such as high general toxicity toward healthy organs and tissues. Herein, we report two Pt(IV) prodrugs with BODIPY-based photoactive ligands and , which were designed using carbamate and triazole linkers, respectively.

Structure-activity relationship study of mesyl and busyl phosphoramidate antisense oligonucleotides for unaided and PSMA-mediated uptake into prostate cancer cells.

Phosphorothioate (PS) group is a key component of a majority of FDA approved oligonucleotide drugs that increase stability to nucleases whilst maintaining interactions with many proteins, including RNase H in the case of antisense oligonucleotides (ASOs). At the same time, uniform PS modification increases nonspecific protein binding that can trigger toxicity and pro-inflammatory effects, so discovery and characterization of alternative phosphate mimics for RNA therapeutics is an actual task. Here we evaluated the effects of the introduction of several -alkane sulfonyl phosphoramidate groups such as mesyl (methanesulfonyl) or busyl (1-butanesulfonyl) phosphoramidates into gapmer ASOs on the efficiency and pattern of RNase H cleavage, cellular uptake , and intracellular localization.

The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.

Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu to Cu triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with -acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins.

[3+2]-Cycloaddition of Nitrile Imines to Parabanic Acid Derivatives-An Approach to Novel Spiroimidazolidinediones.

Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop» or using the recently proposed diffusion mixing technique, which led to ~5-15% increases in target compound yields.

Small Molecules with Spiro-Conjugated Cycles: Advances in Synthesis and Applications.

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Fluorescent Conjugates Based on Prostate-Specific Membrane Antigen Ligands as an Effective Visualization Tool for Prostate Cancer.

Fluorescent dyes are widely used in histological studies and in intraoperative imaging, including surgical treatment of prostate cancer (PC), which is one of the most common types of cancerous tumors among men today. Targeted delivery of fluorescent conjugates greatly improves diagnostic efficiency and allows for timely correct diagnosis. In the case of PC, the protein marker is a prostate-specific membrane antigen (PSMA).

Synthesis, I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures.

Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [I]PSMA-m-IB and [I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches.

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates.

Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. studies of the affinity of the synthesized compounds to the protein target have been carried out.

Recent Advances in Cu/Cu-Based Radiopharmaceuticals.

Copper-64 (T = 12.7 h) is a positron and beta-emitting isotope, with decay characteristics suitable for both positron emission tomography (PET) imaging and radiotherapy of cancer. Copper-67 (T = 61.

[4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones.

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels-Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids.

Photoinduced Reduction of Novel Dual-Action Riboplatin Pt(IV) Prodrug.

Controlled photoreduction of Pt(IV) prodrugs is a challenging task due to the possibility of targeted light-controlled activation of anticancer agents without affecting healthy tissues. Also, a conjugation of photosensitizers and clinically used platinum drugs into one Pt(IV) prodrug allows combining photodynamic therapy and chemotherapy approaches into one molecule. Herein, we designed the cisplatin-based Pt(IV) prodrug Riboplatin with tetraacetylriboflavin in the axial position.

New Titanocene (IV) Dicarboxylates with Potential Cytotoxicity: Synthesis, Structure, Stability and Electrochemistry.

The search for new anticancer drugs based on biogenic metals, which have weaker side effects compared to platinum-based drugs, remains an urgent task in medicinal chemistry. Titanocene dichloride, a coordination compound of fully biocompatible titanium, has failed in pre-clinical trials but continues to attract the attention of researchers as a structural framework for the development of new cytotoxic compounds. In this study, a series of titanocene (IV) carboxylate complexes, both new and those known from the literature, was synthesized, and their structures were confirmed by a complex of physicochemical methods and X-ray diffraction analysis (including one previously unknown structure based on perfluorinated benzoic acid).

Synthesis and Biological Evaluation of Novel -Indolinones with Anticancer Activity.

Novel variously substituted thiohydantoin-based -indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCT, and HCT. Several compounds demonstrated a relatively high cytotoxic activity vs.

Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stability.

Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease treatment. Statins' side effects are generally attributed to poor bioavailability and hepatoselectivity, which are closely related to their high lipophilicity. Targeted delivery of statins to the liver is considered as a way to reduce unwanted side effects.

Tacrine-Based Hybrids: Past, Present, and Future.

Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the "one drug-multiple targets" strategy is of current interest.

Regioselective Cycloaddition of Nitrile Imines to 5-Methylidene-3-phenyl-hydantoin: Synthesis and DFT Calculations.

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring.

Biotinylated Pt(IV) prodrugs with elevated lipophilicity and cytotoxicity.

A design of Pt(IV) prodrugs with tumor cell targeting moieties leading to increased selectivity is of interest. Herein, we designed a novel Pt(IV) prodrugs with COX-inhibitor naproxen, long-chain hydrophobic stearic acid moiety and biotin as axial ligands. We have established that for Pt(IV) prodrugs with biotin and naproxen or stearate in axial position, the lipophilicity rather than biotin receptors expression is the main factor of cytotoxicity.