We have developed a convenient approach to the assembly of 1,2,3-triazole-fused quinazolines through the cyclization of 5-iodotriazoles bearing a pendant sulfonamide moiety. The C(sp2)-N bond formation proceeds efficiently as a base-promoted halogen substitution in the triazole ring. The rational choice of base and solvent enables the chemodivergent synthesis of either triazole-fused quinazolines or their dihydro derivatives. The potential applications of the target heterocycles were illustrated by their involvement in Rh-catalyzed denitrogenative amidation.

5-Iodo-1,2,3-triazoles tethered to a formyl group via an ortho-phenylene linker have been shown to be versatile precursors to a plethora of fused heterocyclic systems. The high reactivity of the aldehyde moiety toward nucleophilic addition enables in situ generation of various saturated azaheterocycles, which induces further intramolecular iodine substitution in the triazole ring. The cascade assembly of structures combining triazole, quinazoline, and cyclic aminal units occurs readily under catalyst-free conditions upon heating in ethanol. The use of chiral β-aminoalcohols allows an easy construction of enantiopure polycyclic scaffolds in a diastereoselective fashion. Chemoselective oxidative cleavage of the hemiaminal ether fragment can be performed in a one-pot manner, furnishing triazole-fused lactams.

This study aims to develop dual-responsive delivery systems based on microgel-liposome complexes, capable of controlled and stepwise cargo release in response to distinct physiological stimuli. Stable multiliposomal complexes were constructed by electrostatic adsorption of small anionic liposomes onto large cationic microgels composed of PNIPAM-co-DADMAC. Two types of liposomes were used: conventional anionic liposomes and pH-sensitive ones incorporating an ampholytic molecular switch. Their release behavior was examined under thermal and pH stimuli. It was shown that the two liposome types responded independently to their respective stimuli: conventional liposomes were disrupted upon microgel collapse above the VPTT (similar to 32 degrees C), whereas switch-containing liposomes remained intact under heating but released their cargo upon acidification. The presence of the molecular switch was found to enhance the mechanical stability of the membrane, allowing selective response. Importantly, cytotoxicity assays confirmed that all components-microgels, liposomes, and their complexes-were non-toxic at relevant concentrations. These findings demonstrate that the developed complexes enable two-stage, stimulus-specific release and highlight the potential of microgel-liposome complexes as advanced platforms for smart drug delivery.

A straightforward approach for the attachment of a nitrile moiety to the 1,2,3-triazole core has been developed. The protocol is based on the cyanation of 5-iodo-1,2,3-triazoles which are readily accessible by Cu-catalyzed azide-iodoalkyne cycloaddition. Halogen substitution occurs smoothly with KCN as a cyanide source using a Pd(0)-Dpephos catalytic system. The reaction tolerates a variety of functional groups as well as some sensitive heterocyclic scaffolds and affords the target 5-cyano-1,2,3-triazoles in yields of up to 99%. Further transformations of the nitrile group enable an easy preparation of 1,2,3-triazoles bearing diverse moieties, including amides, amines, and some azaheterocycles.

A new method of the design of stimuli-sensitive multiliposomal containers for encapsulation and controlled drug release is described. Despite quite a wide choice of pH-sensitive containers, there is still a considerable challenge to synthesize those that respond quickly to small variations in pH and release most of the encapsulated drug in a short time. The suggested AMS-containing multiliposomal complexes demonstrated an excellent rate of encapsulated substance release under altering the pH of the outer solution. To improve the efficiency of the delivery of bioactive compounds to target cells and to increase the therapeutic effect, pH-sensitive liposomes were concentrated on the surface of the carrier- PEG-coated cationic liposomes. A pH-sensitive ampholytic derivative of cholan-24-oic acid embedded into the membrane of anionic liposomes allowed the rapid release of the cargo in the areas of low pH, such as tumors, inflammation sites, etc. The diameter of the complexes was optimized for passive targeting and typically ranged from 250 to 400 nm. The biodegradability of liposomes ensured enzymatic destruction of the multiliposomal containers and their elimination from the body after performing their transport function. The multiliposomal complexes and products of their biodegradation demonstrated low cytotoxicity. The composition of multiliposomal complexes, in particular, the amount of PEGylated lipid in the bilayer, was estimated to provide a high speed of the cargo release upon changing the pH. The novel developed pH-sensitive containers show potential for biomedical applications.

A convenient and efficient approach to 3-thiosubstituted androstanes has been developed. The formation of a C(sp(2))-S bond was achieved through the Cu-catalyzed coupling of steroidal iododienes with a variety of S-nucleophiles, such as (het)aryl thiols and dithiocarbamates. A simple catalytic system comprising CuI without auxiliary ligands enabled the preparation of a library of target compounds in good to high yields. A moderate inhibitory activity against hormone-dependent cancer cell lines was demonstrated for representative 3-thiolated steroids.

The review summarizes recent advances in the synthesis of 3-azabicyclo[3.1.0]hexane (3-ABH) derivatives that are heterocyclic systems often present in molecules capable of acting on various biological targets and actively used in drug design. Modern synthetic approaches to 3-ABH derivatives based on transition metal catalysis have been classified and analyzed, and mechanisms of the key processes have been considered. The examined approaches include the synthesis of 3-ABH by three- and five-membered ring fusion, as well as numerous one-pot syntheses from acyclic precursors via tandem cyclizations.

Alumina was found to activate Cu(I) catalysts in hydroboration of alkynes. This allowed to develop a simple and efficient protocol for hydroboration of alkynes with B2Pin2 using inexpensive CuCl/PPh3 catalytic system. The approach does not require moisture-sensitive activators and stepwise preparation of 'activated' Cu complex. The developed conditions were applied to the preparation of beta-styrylboronates from terminal and internal alkynes with excellent regio- and stereoselectivity. The procedure can also be extended to other terminal alkynes by the appropriate choice of ligand.

Divergent access to bicyclo[3.1.0]hexane and cyclopenta[c]pyrazole scaffolds bearing azole and azine units has been developed. The approach involves intramolecular cyclization of 5-iodo-1,2,3-triazoles acting as stable diazoimine precursors with concomitant noncatalytic (3 + 2)-cycloaddition. The choice of solvent allows control of the outcome of the cascade transformation. The developed procedure is simple and cost-efficient and allowed important heterocycles to be obtained in one-pot with various functional groups.

pH-sensitive liposomes have great potential for biomedical applications, in particular as nanocontainers for the delivery of biologically active compounds to specific areas of the human body. In this article, we discuss the possible mechanism of fast cargo release from a new type of pH-sensitive liposomes with embedded ampholytic molecular switch (AMS, 3-(isobutylamino)cholan-24-oic acid) with carboxylic anionic groups and isobutylamino cationic ones attached to the opposite ends of the steroid core. AMS-containing liposomes demonstrated the rapid release of the encapsulated substance when altering the pH of an outer solution, but the exact mechanism of the switch action has not yet been accurately determined. Here, we report on the details of fast cargo release based on the data obtained using ATR-FTIR spectroscopy as well as atomistic molecular modeling. The findings of this study are relevant to the potential application of AMS-containing pH-sensitive liposomes for drug delivery.

Transformation of 11-trifluoroacetate 6α-methylhydrocortisone (11-TFA MHC) by cells of the actinobacteria Arthrobacter (Nocardioides) was carried out in the presence of α-cyclodextrin (α-CD). The composition and dynamics of the accumulation of the transformation products in the culture medium at various pHs and the ratio of the α-CD/substrate were studied. It was shown that the addition of α-CD to the transformation medium at pH 7 promotes an increase in the rate of 1,2-dehydrogenation with the formation of 6 α-methylprednisolone 11-trifluoroacetate (11-TFA MPL). At pH 7, the primary process is the hydrolysis of the 11β-trifluoroacetyloxy group. In this case, the participation of α-CD in these processes as an acceptor of the trifluoroacetyl ion is not excluded.

A novel approach to 2-(1-arylalkyl)benzoxazoles via a reaction of arylboronic acids with 2-(5-iodo-1,2,3-triazolyl)phenols has been developed. The key intermediates of the proposed cascade transformation are 2-(1-diazoalkyl)benzoxazoles, entering reductive C-C-coupling with boronic acids. The reaction proceeds under transition-metal-free conditions and affords target compounds in yields up to 67%.

Divergent approaches to 1,2,3-triazole-fused heterocycles via chemoselective cyclization of 2-(5-iodotriazolyl)benzamides with controllable C–O or C–N bond formation have been developed.

A new method has been developed for the synthesis of 2-(1-arylalkyl)-1,3-benzoxazoles by coupling of arylboronic acids with 2-(5-iodo-1 H -1,2,3-triazol-1-yl)phenols. The proposed cascade process involves intermediate formation of 2-(1-diazoalkyl)-1,3-benzoxazoles and their reductive C–C coupling with arylboronic acids. The procedure requires no transition metal catalysis and provides up to 67% yield of the target products.

The ability of [1,2,3]triazolobenzoxazinones to act as a source of "hidden" diazo group was discovered. These diazo precursors can be easily prepared by the intramolecular cyclization of 2-(5-iodo-1,2,3-triazolyl)benzoic acids. The Cu-catalyzed capture of the hidden diazo group allows for further functionalization through the denitrogenative pathway. The transformations proceed via the formation of either diazoimine or diazoamide intermediates. Novel routes to various anthranilamides as well as thiolated benzoxazinones were developed using the one-pot cyclization/diazo capture procedure.

A convenient Pd- and phosphine-free protocol for assembling internal alkynes from tertiary propargyl alcohols and (het)aryl halides has been developed. The proposed tandem approach includes the base-promoted retro-Favorskii fragmentation followed by Cu-catalyzed C(sp)-C(sp2) cross-coupling. The use of inexpensive reagents (e.g. a catalyst, additives, a base, and a solvent) and good functional group tolerance make the procedure practical and cost-effective. The synthetic utility of the method was demonstrated by a smooth alkynylation of vinyl iodides derived from natural steroidal hormones.

AbstractA convenient approach to assemble 1,2,3-triazole-fused 4H-3,1-benzoxazines has been developed. Diverse alcohol-tethered 5-iodotriazoles, readily accessible by a modified protocol of Cu-catalyzed (3+2)-cycloaddition, were utilized as precursors of the target fused heterocycles. The intramolecular C–O coupling proceeded efficiently under base-mediated transition-metal-free conditions, furnishing cyclization products in yields up to 96%. Suppression of the competing reductive cleavage of the C–I bond was achieved by the use of Na2CO3 in acetonitrile at 100 °C. This practical and cost-effective procedure features a broad substrate scope and valuable functional group tolerance.

In vitro and in cell cultures, succinyl phosphonate (SP) and adipoyl phosphonate (AP) selectively target dehydrogenases of 2-oxoglutarate (OGDH, encoded by OGDH/OGDHL) and 2-oxoadipate (OADH, encoded by DHTKD1), respectively. To assess the selectivity in animals, the effects of SP, AP, and their membrane-penetrating triethyl esters (TESP and TEAP) on the rat brain metabolism and animal physiology are compared. Opposite effects of the OGDH and OADH inhibitors on activities of OGDH, malate dehydrogenase, glutamine synthetase, and levels of glutamate, lysine, citrulline, and carnosine are shown to result in distinct physiological responses. ECG is changed by AP/TEAP, whereas anxiety is increased by SP/TESP. The potential role of the ester moiety in the uncharged precursors of the 2-oxo acid dehydrogenase inhibitors is estimated. TMAP is shown to be less efficient than TEAP, in agreement with lower lipophilicity of TMAP vs. TEAP. Non-monotonous metabolic and physiological impacts of increasing OADH inhibition are revealed. Compared to the non-treated animals, strong inhibition of OADH decreases levels of tryptophan and beta-aminoisobutyrate and activities of malate dehydrogenase and pyruvate dehydrogenase, increasing the R-R interval of ECG. Thus, both metabolic and physiological actions of the OADH-directed inhibitors AP/TEAP are different from those of the OGDH-directed inhibitors SP/TESP, with the ethyl ester being more efficient than methyl ester.

Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for brain glucose and neurotransmitter metabolism, which is dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (AcPMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine, and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. A comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in freezing time are most pronounced after administration of methyl acetylphosphinate and dimethyl acetylphosphonate. The PDHC inhibitors do not significantly change the levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation, but increase total protein succinylation and glutarylation, affecting sirtuin 5 expression. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compensated by increased degradation of amino acids through the activated OGDHC, increasing total protein succinylation/glutarylation. Simultaneously, parasympathetic activity and anxiety indicators decrease.

An efficient domino approach to assemble benzoxazoles and anthranilamides bearing dithiocarbamate moieties has been developed. The proposed route represents a Cu-catalyzed three-component reaction between readily available 5-iodo-1,2,3-triazoles, amines, and CS2. The cascade transformation is based on a denitrogenative coupling of in situ formed dithiocarbamic acids with diazo intermediates, generated via annulation-triggered triazole ring-opening. This method is applicable to nucleophilic secondary amines and features good functional group compatibility.