Currently, prostate specific membrane antigen ligands are one of the most widely used platforms for creating compounds targeting prostate cancer tumor cells. In this mini-review, we have collected and systematized existing approaches to the synthesis of PSMA ligands based on DCL urea, as the most widely used vector platform. The main approaches to each stage of the synthesis of PSMA inhibitors of various structures are considered in detail, and existing synthetic techniques are collected and analyzed.

Three novel 2-thio-4H-imidazol-4-ones containing conjugated five, six- or seven-membered S,N-heterocycle and pyridin-2-ylmethylidene moiety (L) were synthesized by two-step reaction sequence starting from 2-thiohydantion. The ligand structures were confirmed by H-1 NMR, C-13 NMR and HRMS. The reactions of the ligands L with copper chloride dihydrate give the complexes of LCuCl2 composition. Copper coordination compounds with 6-(pyridin-2-ylmethylidene)-2,3-dihydroimidazo[2,1-b][1,3]thiazol-5(6H)-one (L1) and 2-(pyridin-2-ylmethylidene)-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one (L2) were characterized by the X-ray data, demonstrating the distorted tetrahedral copper coordination environment. It was shown that the presence in the ligand L1 of a five-membered thiazolidine ring fused with imidazolone leads to a significant change in the geometric characteristics of the complex: an increase in the Cu-S distance and the flattening of copper coordination polyhedron. Both synthesized complexes were evaluated using cyclic voltammetry and demonstrated the quasi-reversible reduction of Cu(II) at similar to -0.25 V. Testing of the antibacterial activity on the reporter strains E. coli Delta tolC pDualrep2 (AmpR) and E. coli lptDmut pDualrep2 (KanR) showed a lower activity of the synthesized copper-containing complexes compared to the complexes of similar ligand that did not have an additional condensed ring in its structure.

The electrophilic halogenation of spirocyclic olefins containing an imidazolone fragment were studied using techniques of dropwise addition of halogen and diffusion mixing with halogen vapor. The bromination reactions providing the formation of trans-1,2-dihalogenation products (when reactions with bridging olefin are carried out in chloroform) or skeletal rearrangements (reactions in acetonitrile or methanol) are most chemo- and stereoselective. Chlorination is nonselective with the formation of mixtures of products, and success of iodination is determined by the choice of the substrate and reaction 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.

The electrophilic halogenation and chalcogenation (sulfenylation and selenenylation) of endo and exo isomers of ethyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates bearing electron-withdrawing substituents at the nitrogen atoms with different reagents were studied. Halogenation of both endo and exo isomers gave exclusively the rearranged products. Chalcogenation of endo isomer resulted in the rearranged products, while chalcogenation of exo isomer afforded the rearranged products and 1,2-trans and 1,2-cis addition products.

Two series of novel Cu (II) (4a–e) and Ni (II) (5a–e) complexes bearing 1-(N-phenylthiocarbamoyl)-pyrazoline ligands (3a–e) were synthesized and characterized. The structures of Ni (II) complexes 5a, c were confirmed by X-ray crystallography; both complexes have a distorted octahedral coordination environment of the Ni (II); metal atoms are coordinated by pyridyl and pyrazoline nitrogen atoms and thiocarbonyl sulfur of two ligand moiety, with two chloride anions in the outer sphere. The Cu (II) complex 4a derived from ligand 3a demonstrate a non-typical electrochemical behavior indicating Cu (I) complex formation which can be explained either by pyrazoline ligand ring opening in DMF solution or by a non-innocent nature of 3a. All of the synthesized complexes were cytotoxic against HCT116 and К562 cell lines; the most cytotoxic ligand was 3d, which is structurally related to combretastatin A4.

Methods for the synthesis of new ditopic organic ligands containing coordinating fragments of two types, terpyridine and thiohydantoin, have been developed. The complex formation reactions of the synthesized ligands with copper(II) chloride were studied. As a result, two types of coordination compounds were isolated and characterized by electron spectroscopy, elemental analysis, and cyclic voltammetry: copper(I,II) bis-ligand tetranuclear mixed-valent complexes and a monoligand binuclear complex containing two copper(II) ions. The cytotoxic activity of the obtained coordination compounds with respect to the MCF7, A549, and HEK293 cell lines was studied.

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. It was demonstrated that ZnI2 is an effective catalyst in the Diels-Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2Cl or Boc(2)O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2.

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. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors.

A convenient one-pot synthesis of α-bromoacrylic acid esters followed by their conversion into α-bromo-substituted β-amino acid esters via Michael addition with secondary cyclic amines is proposed. Among the amines, morpholine turned most suitable.

A method for the synthesis of 4-methyl-2-oxo-9-phenyl-2 H -furo[2,3- h ]chromene-8-carboxylic acid amides combining in the structure the angelicin core with heterocyclic fragments at the amide nitrogen atom was developed. The cytotoxic activity of the obtained amides against the MCF7 (breast adenocarcinoma), A549 (non-small cell lung cancer), VA-13 (embryonic lung fibroblast cells) and HEK293T (embryonic kidney cells) cell lines was studied. In contrast to the previously described highly toxic angelicin derivatives with aryl- and hetarylcarbonyl substituents at position 8, the synthesized amides demonstrated in in vitro experiments in these cell lines the IC 50abs values ranging within 2–100 µmol L −1 . The cytotoxicity and selectivity of the action of this group of derivatives were found to be significantly affected by the substituent at position 5′ of the angelicin moiety.

Three groups of bile acid derivatives with acetylenic moieties, such as propargyl, hex-5-ynoyl, and 4,7,10,13-tetraoxahexadec-15-ynoyl ones, were obtained. The cytotoxic activity of the synthesized compounds against hepatocellular carcinoma (HepG2, Huh7), prostate cancer (PC3), and human embryonic kidney (HEK293) cell lines was studied. The parameters enabling estimation of the total lipophilicity of the synthesized bile acid derivatives (log P , TPSA) were calculated. The correlation between the cytotoxic activity and hydrophilic-lipophilic balance of the synthesized compounds was determined. A physicochemical mechanism for the cytotoxic action of bile acid derivatives is proposed.

A method for the synthesis of a conjugate of 4-substituted phenylterpyridine and lipoic acid, containing a triethylene glycol linker group between the terpyridine and sulfur-containing fragments, has been developed. A coordination compound of the resulting terpyridine with Rh(III) was obtained. Cyclic voltammetry was used to explore the ability of the synthesized ligand and its rhodium complex to be chemisorbed on the surface of gold electrodes to form an Au–S bond.

We synthesized substituted phenylterpyridines containing one or two terminal disulfide groups and triazole-containing fragments in the linker between the terpyridine and sulfur-containing functional groups, as well as coordination compounds of the obtained terpyridines with RhIII. The possibility of the ligands and complexes under study to be chemisorbed on the surface of gold electrodes with the formation of an Au-S bond was shown.

1,3-Dipolar cycloaddition of azomethine ylide, generated from isatin and sarcosine, with 5-arylidene-2-thiohydantoins equipped with various chiral substituents at the N3 atom occurs diastereoselectively. The highest selectivity with dr = 5 : 1 was observed for the 2-thiohydantoin bearing 1,2-diphenylethyl substituent.

A synthesis of dispiro derivatives from 5-methylidene-2-chalcogenimidazolones and azomethine ylides generated from isatins and N-substituted α-amino acids has been developed.

The reaction of 2-azanorbornene derivatives with nitrile oxides (generated in situ by dehydrohalogenation of N-hydroxyimoyl halides) affords two regioisomers with the exo-arrangement of the isoxazoline ring.

A convenient procedure has been proposed for the isolation of R and S enantiomers of 1-(2,4-di­methoxyphenyl)ethan-1-amine from the racemate using di-O-benzoyltartaric acids as chiral auxiliaries. The pure enantiomers were converted into the corresponding chiral thioureas and 2-thiohydantoins by reaction with ethyl 2-isothiocyanatoacetate.

3-Aryl-5-methylidenethiohydantoins and 3-aryl-5-methylidene-selenohydantoins were obtained by one-pot reaction of aryl isothiocyanates or isoselenocyanates with l-serine in NaOH–H2O–Py mixture followed by room temperature HCl-promoted dehydration.

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against E. coli strain LPTD.