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Evolution-derived natural compounds have been inspirational for design of numerous pharmaceuticals, e.g., penicillins and tetracyclines. Herein, we present a bioinspired strategy to design peptide dendrimers for the effective therapy of E. coli infections where the selection of appropriate amino acids and the mode of their assembly are based on the information gained from research on membranolytic natural antimicrobial peptides (AMP's). On the molecular level two opposite effects were explored: the effect of multiple positive charges necessary for membrane disintegration was equilibrated by the anchoring role of tryptophanes. Indeed, a series of Trp-terminated dendrimers exhibited high potency against clinical isolates of antibiotic resistant ESBL E. coli strains, stability in human plasma along with very low hemo- and genotoxicity. Investigation of the underlying antimicrobial mechanism indicated that the dendrimers studied at minimal inhibitory concentration showed weak permeability toward membranes. Solid-state 2D NMR studies revealed their presence on and inside the model membranes. Therefore, their biological properties might be explained by targeting of extra- or intracellular receptors. Our results point to a new approach to design novel branched antimicrobials with high therapeutic index.

Background: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS). Neuroblastoma (NB) is one of the most common cancers of childhood derived from the neural crest cells. The survival rate for patients with GBM and high-risk NB is poor, therefore, novel therapeutic approaches are needed. Increasing evidence suggests a dual role of redox-active compounds in both tumorigenesis and cancer treatment. Therefore, in this study, polyfunctional peptide-based dendrimeric molecules of the bola structure carrying residues with antiproliferative potential on one side and the antioxidant residues on the other side were designed. Methods: We synthesized non-symmetric bola dendrimers and assessed their radical scavenging potency as well as redox capability. The influence of dendrimers on viability of rat primary cerebellar neurons (CGC) and normal human astrocytes (NHA) was determined by propidium iodide staining and cell counting. Cytotoxicity against human GBM cell lines, T98G and LN229, and NB cell line SH-SY5Y was assessed by cell counting and colony forming assay. Results: Testing of CGC and NHA viability allowed to establish a range of optimal dendrimers structure and concentration for further evaluation of their impact on two human GBM and one human NB cell lines. According to ABTS, DPPH, FRAP, and CUPRAC antioxidant tests, the most toxic for normal cells were dendrimers with high charge and an excess of antioxidant residues (Trp and PABA) on both sides of the bola structure. At 5 μM concentration, most of the tested dendrimers neither reduced rat CGC viability below 50–40%, nor harmed human neurons (NHA). The same dose of compounds 16 or 22, after 30 min treatment decreased the number of SH-SY5Y and LN229 cells, but did not affect the number of T98G cells 48 h post treatment. However, either compound significantly reduced the number of colonies formed by SH-SY5Y, LN229, and T98G cells measured 14 days after treatment. Conclusions: Peptide dendrimers with non-symmetric bola structure are excellent scaffolds for design of molecules with pro/antioxidant functionality. Design of molecules with an excess of positive charges and antioxidant residues rendered molecules with high neurotoxicity. Single, 30 min exposition of the GBM and NB cell lines to the selected bola dendrimers significantly suppressed their clonogenic potential

An efficient asymmetric ring-opening (ARO) reaction of

A new convenient, mild, one-pot procedure is described for the diastereoselective synthesis of constrained 7,5- and 7,6-fused azabicycloalkanes. Using 2-formyl-L-tryptophan and 2-formyl-l-phenylalanine as bielectrophilic building blocks, T3P-mediated Pictet-Spengler and Meyers lactamization reactions were developed to present chiral and polycyclic aminoindolo- and aminobenzazepinone compounds in excellent yields. The conformationally constrained compounds can serve as templates for peptidomimetic research or polyheterocyclic privileged scaffolds.

Synthesis of new type of the Hoveyda–Grubbs catalysts containing modified N-heterocyclic carbene ligands is described herein. New catalysts bear different in size polyether clamp embracing N,N′-2,4-dimethylphenyl substituents in N-heterocyclic carbene. New complexes were tested in model RCM, enyne and CM reactions. They showed comparable activity to that of commercially available Grubbs second generation and Hoveyda–Grubbs second generation complexes. Complex with larger polyether clamp proved Z-stereoselective in a macrocycle formation and yielded more Z isomers than commercial complexes in CM reactions. The catalysts are stable and easy to purify.

Nucleophilic displacement of chlorides in 3,3′-dichloro-5,5′-bi-1,2,4-triazine with benzenethiolate or 2-pyridinethiolate anion afforded the corresponding symmetrical disulfide of 5,5′-bi-1,2,4-triazine in high yields. These products were transformed into 6,6′-bis(phenylthio)-2,2′-bipyridines and 6,6′-bis(2-pyridylthio)-2,2′-bipyridines by using Diels-Alder reactions. All compounds were fully characterized by spectroscopic methods and the X-ray diffraction analysis.

A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component reaction (Ugi-3CR) was developed to present trisubstituted indoloazepinones in good yields and excellent diastereomeric excess.

Traditional antimicrobial therapy used today at clinics is mainly focused on application of developed several decades ago several classes of small chemically modified organic compounds of natural origin, e.g. penicillins, cephalosporins, macrolides, fluoroquinolones, etc. The efficacy of these drugs is declining due to spreading of antibiotic resistance around the microbial world. Herein, we examine current strategies of designing new antimicrobials as nanotechnology-based pharmaceutical drug delivery platforms. We address several problems like synergistic action of β-lactams and nanoparticles, nanoparticles self-cytotoxicity, perspectives of targeted drug delivery and application of “green” chemistry, vital for the prospective production of β-lactams nanoformulations with enhanced efficacy and low toxicity.

Two new copper metal–organic frameworks containing 2,2′-dihydroxy-1,1′-binaphthalene-5,5′-dicarboxylic acid (5,5′-H2BDA) and 2,2′-dihydroxy-1,1′-binaphthalene-4,4′-dicarboxylic acid (4,4′-H2BDA) ha...

A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced ‘writhing’ and ‘hot plate’ test in mice and at radioligand binding assay. At ‘writhing’ test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED50 values ranging from 0.04 to 11 mg/kg (i.p.) (ED50 for ASA – 39.15 mg/kg). Analgesic effect at the ‘hot plate’ test was observed for three compounds 4c,e,f at the dose 3–5 times higher then that of morphine (ED50-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described.

The present state of knowledge about the preparation, methods of characterization and the prospect of medical applications of dendrimers ― a new class of polymeric compounds ― is presented on the basis of literature review.

A new convenient, mild, one-pot procedure is described for the diastereoselective synthesis of constrained 7,5- and 7,6-fused azabicycloalkanes. Using 2-formyl-L-tryptophan and 2-formyl-l-phenylalanine as bielectrophilic building blocks, T3P-mediated Pictet–Spengler and Meyers lactamization reactions were developed to present chiral and polycyclic aminoindolo- and aminobenzazepinone compounds in excellent yields. The conformationally constrained compounds can serve as templates for peptidomimetic research or polyheterocyclic privileged scaffolds.

Two versatile syntheses of 1 - and 1,2-disubstituted 2-benzazepinones are presented, using N-acyliminium ions as reactive intermediates. The methodology for 1-substitution is based on the synthesis of benzotriazole adducts, which are cyclized upon addition of AlCl 3 . The simultaneous introduction of 1- and 2-substitions is realized by an N-acylation of an imine.

A catalyst bearing a handle prolonged by a CH2-O-CH2-group provides the products with comparable yield and E-selectivity.

Both N-methoxycarbonylmethyl- and N-methoxycarbonylethyl-derivatives of dihydroxy-( d )-homoproline were subjected to the intramolecular ester condensation to yield ketoesters of pyrrolizidine and indolizidine series, respectively. The former ketoester was transformed into derivative related to australine, while the latter were transformed into the natural lentiginosine as well as its 2-epi-, and 7-hydroxy-2-epi-derivatives.

The corresponding allenamides are formed in situ and are directly trapped with furan to give the Diels-Alder products.

Dendrimers, which are highly branched, multivalent and monodisperse polymers, have received continuous interest in recent years because of the global demand for new nanomolecules that are useful in advanced technology and medicine. While dendrimers are advantageous for many highly specialised applications, the high polyvalency of higher-generation dendrimers requires, however, well-controlled, target-tailored regioselective chemical engineering. The structural evolution of dendrimers – from simple, monofunctional molecules to the more complex, multifunctional compounds – is inextricably associated with a continuous improvement in traditional synthetic strategies, as well as the development of new synthetic tools. The purpose of this review is to provide insight into currently available synthetic methods that yield dendrimers with various morphologies, placing emphasis on the evaluation of their advantages and limitations. In particular, we will review current efforts that focus on simplifying and optimising the existing methods and the development of new strategies that permit control over the targeted introduction of various functionalities in one or more selected areas of the molecule.

A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component reaction (Ugi-3CR) was developed to present trisubstituted indoloazepinones in good yields and excellent diastereomeric excess.

Various γ-substituted (2R)-N-(β,γ-enoyl)bornane-10,2-sultams have been examined in diastereoselective OsO4 syn-dihydroxylation. In contrast to the C(α)-atom, the bornane-10,2-sultam auxiliary exerts a very poor influence on the C(β)-carbon. Spontaneous stereoselective hydrolysis of the minor diastereoisomer (3S,4S)-5c opens the way to enantiomerically pure building blocks.

The chiroptical properties of the title compounds bearing various substituents at the N(1) and N(2) nitrogen atoms are discussed. It was found that the sign of the n−π* Cotton effect centered at about the 230−250 nm region can be correlated with the absolute configuration of the stereogenic center at C(5). It was also found that the sign of this Cotton effect is predictable by Weigang's lactam sector rule. MMX calculations, supported by X-ray measurements, showed that substituents at the nitrogen atoms significantly affect the conformation of the five-membered ring. It was additionally concluded that the conformation of the five-membered ring in 5-substituted pyrazolidin-3-ones is the sign-determining factor for an n−π* transition.

Bentley and Hunt’s empirical rule for the determination of the anti/syn relationship of protons attached to C-2 and C-5 atoms in 2-substituted clavams does not predict the correct stereochemistry in a series of 2-substituted clavams synthesised by us. In this paper we propose a simple method for determination of the relative stereochemistry of 2-substituted clavams based on nuclear Overhauser effect (NOE) experiments and assignment of the diastereotopicity of protons attached to the C-3 atom. Circular dichroism (CD) measurements and X-ray crystallography provide stereochemical and spectral assignments.

The anti-aldol products are obtained with high enantioselectivity in comparison to the same reaction in the solution or in neat with traditional magnetic stirring.

6-Hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (6Htc) has been proposed as a rigid mimic of tyrosine conformation in opioid ligand–receptor complex. The significant receptor binding to mu and delta opioid receptors of respective analogues of deltorphin, dermorphin, and endomorphin with d,l -6Htc prove initial prediction.

X-ray diffraction analysis of 10 crystal structures of co-crystals of acyclic diamines (with or without ether functions) and several dicarboxylic acids (maleic, fumaric, succinic and adipic) shows preferred types of intermolecular interactions. These include the formation by a doubly protonated amine molecule of a pattern of six, strong intermolecular hydrogen bonds with carboxy groups from acid molecules surrounding the amine. The folded conformation of the amine molecule is preferred for 2,2′-diaminodiethylether ( 1 ) and 2,2′-(ethylenedioxy)diethylamine ( 2 ). For 1,4-diaminobutane ( 3 ), the folded conformation was only found in the co-crystal with two molecules of adipic acid.

Metal-organic frameworks, obtained from BDA, Cu(NO3)2 and Ph-NMe2, are applied as Lewis acid catalysts in the title reaction.

Novel pyrrolo[3,4-d]pyridazinones (III) and (VII) are tested as potential analgesic agents.

A series of new cationic lipopeptides containing branched, amphiphilic polar head derived from (Lys)Lys(Lys) dendron and C(8) or C(12) chain at C-end were designed, synthesized and characterized. Antimicrobial in vitro activity expressed as minimal inhibitory concentration (MIC) was evaluated against Gram-positive and Gram-negative bacteria and yeasts from the Candida genus. A significant enhancement of antimicrobial potency along with increased selectivity against Candida reference strains was detected for derivatives with the C(12) residue. Several compounds were characterized by a low hemotoxicity. The antifungal activity of branched lipopeptides is multimodal and concentration dependent. Several compounds, studied in detail, induced potassium leakage from fungal cells, caused morphological alterations of fungal cells and inhibited activity of candidal β(1,3)-glucan synthase.

Bentley and Hunt’s empirical rule for the determination of the anti/syn relationship of protons attached to C-2 and C-5 atoms in 2-substituted clavams does not predict the correct stereochemistry in a series of 2-substituted clavams synthesised by us. In this paper we propose a simple method for determination of the relative stereochemistry of 2-substituted clavams based on nuclear Overhauser effect (NOE) experiments and assignment of the diastereotopicity of protons attached to the C-3 atom. Circular dichroism (CD) measurements and X-ray crystallography provide stereochemical and spectral assignments.

The chiroptical properties of the title compounds bearing various substituents at the N(1) and N(2) nitrogen atoms are discussed. It was found that the sign of the n−π* Cotton effect centered at about the 230−250 nm region can be correlated with the absolute configuration of the stereogenic center at C(5). It was also found that the sign of this Cotton effect is predictable by Weigang's lactam sector rule. MMX calculations, supported by X-ray measurements, showed that substituents at the nitrogen atoms significantly affect the conformation of the five-membered ring. It was additionally concluded that the conformation of the five-membered ring in 5-substituted pyrazolidin-3-ones is the sign-determining factor for an n−π* transition.

Various γ-substituted (2R)-N-(β,γ-enoyl)bornane-10,2-sultams have been examined in diastereoselective OsO4 syn-dihydroxylation. In contrast to the C(α)-atom, the bornane-10,2-sultam auxiliary exerts a very poor influence on the C(β)-carbon. Spontaneous stereoselective hydrolysis of the minor diastereoisomer (3S,4S)-5c opens the way to enantiomerically pure building blocks.

Both N-methoxycarbonylmethyl- and N-methoxycarbonylethyl-derivatives of dihydroxy-( d )-homoproline were subjected to the intramolecular ester condensation to yield ketoesters of pyrrolizidine and indolizidine series, respectively. The former ketoester was transformed into derivative related to australine, while the latter were transformed into the natural lentiginosine as well as its 2-epi-, and 7-hydroxy-2-epi-derivatives.

Schiff bases derived from (±)-4-aldehydo-2- -azetidinones react with acid chlorides and triethylamine to produce (±)-bis-β-lactams in a diastereoselective fashion. The steric course of β-lactam fonnation was determined in one case by using chiral HPLC separation of enantiomers. Definitive evidence in support of this enantiospecific course of β-lactam formation was obtained from single crystal X-ray diffraction studies on a racemic bis-β-lactam.