Design, Synthesis, and Evaluation of Trivalent PROTACs Having a Functionalization Site with Controlled Orientation

Trivalent PROTACs having a functionalization site with controlled orientation were designed, synthesized, and evaluated. Based on the X-ray structure of BRD protein degrader MZ1 (1) in complex with human VHL and BRD4BD2, we expected that the 1,2-disubstituted ethyl group near the JQ-1 moiety in MZ1 (1) could be replaced by a planar benzene tether as a platform for further functionalization. To test this hypothesis, we first designed six divalent MZ1 derivatives, 2a-c and 3a-c, by combining three variations of substitution patterns on the benzene ring (1,2-, 1,3-, and 1,4-substitution) and two variations in the number of ethylene glycol units (1 or 2). We then tested the synthesized compounds for the BRD4 degradation activity of each. As expected, we found that 1,2D-EG2-MZ1 (2a), an MZ1 derivative with 1,2-disubstituted benzene possessing two ethylene glycol units, had an activity profile similar to that of MZ1 (1). Based on the structure of 2a, we then synthesized and evaluated four isomeric trivalent MZ1 derivatives, 15a-15d, having a tert-butyl ester unit on the benzene ring as a handle for further functionalization. Among the four isomers, 1,2,5T-EG2-MZ1 (15c) retained a level of BRD4 depletion activity similar to that of 2a without inducing a measurable Hook effect, and its BRD4 depletion kinetics was the same as that of MZ1 (1). Other isomers were also shown to retain BRD4 depletion activity. Thus, the trivalent PROTACs we synthesized here may serve as efficient platforms for further applications.

Design, Synthesis, and Evaluation of Trivalent PROTACs Having a Functionalization Site with Controlled Orientation

Trivalent PROTACs having a functionalization site with controlled orientation were designed, synthesized, and evaluated. Based on the X-ray structure of BRD protein degrader MZ1 (1) in complex with human VHL and BRD4BD2, we expected that the 1,2-disubstituted ethyl group near the JQ-1 moiety in MZ1 (1) could be replaced by a planar benzene tether as a platform for further functionalization. To test this hypothesis, we first designed six divalent MZ1 derivatives, 2a-c and 3a-c, by combining three variations of substitution patterns on the benzene ring (1,2-, 1,3-, and 1,4-substitution) and two variations in the number of ethylene glycol units (1 or 2). We then tested the synthesized compounds for the BRD4 degradation activity of each. As expected, we found that 1,2D-EG2-MZ1 (2a), an MZ1 derivative with 1,2-disubstituted benzene possessing two ethylene glycol units, had an activity profile similar to that of MZ1 (1). Based on the structure of 2a, we then synthesized and evaluated four isomeric trivalent MZ1 derivatives, 15a-15d, having a tert-butyl ester unit on the benzene ring as a handle for further functionalization. Among the four isomers, 1,2,5T-EG2-MZ1 (15c) retained a level of BRD4 depletion activity similar to that of 2a without inducing a measurable Hook effect, and its BRD4 depletion kinetics was the same as that of MZ1 (1). Other isomers were also shown to retain BRD4 depletion activity. Thus, the trivalent PROTACs we synthesized here may serve as efficient platforms for further applications.

Rh(I)-Catalyzed Enantioselective Cyclization of Enyne through Site-Selective C(sp3)-H Bond Activation Triggered by Formation of Rhodacycle

Rh(I)-catalyzed enantioselective cyclization of enyne through C(sp3)-H bond activation was investigated. It was found that the cyclization of enyne having a t-butyl moiety on the alkene afforded a spirocyclic compound (up to 92% ee), while the cyclization of enyne having an i-propyl or an ethyl group on the alkene gave a cyclic diene (up to 98% ee). Furthermore, an intermolecular competition reaction using a deuterium-labeled substrate revealed that C(sp3)-H bond activation was one of the key steps, having a high energy barrier, in this cyclization.

DMT analogues: N-ethyl-N-propyltryptamine and N-allyl-N-methytryptamine as their hydrofumarate salts

The solid-state structures of the hydrofumarate salts of two N,N-dialkyltryptamines, namely N-ethyl-N-propyltryptammonium (EPT) hydrofumarate {systematic name: [2-(1H-indol-3-yl)ethyl](methyl)propylazanium 3-carboxyprop-2-enoate}, C15H23N2 +·C4H3O4 −, and N-allyl-N-methyltryptammonium (MALT) hydrofumarate {systematic name: [2-(1H-indol-3-yl)ethyl](methyl)(prop-2-en-1-yl)azanium 3-carboxyprop-2-enoate}, C14H19N2 +·C4H3O4 −, are reported. Both compounds possess a protonated tryptammonium cation, and a hydrofumarate anion in the asymmetric unit. The ethyl group of the EPT cation is modeled as a two-component disorder with 50% occupancy for each component. In the extended structure, N—H...O and O—H...O hydrogen bonds generate infinite two-dimensional networks parallel to the (001) plane for both compounds.

Kinetics of catalytic oxidation 4-bromethylbenzene by ozone in acetic acid

The kinetic regularities of catalytic oxidation of 4-bromoethylbenzene by ozone to create an eco-logical, low-temperature technology for the synthesis of 4-bromoacetophenone have been studied. The experiment was performed in a glass reactor with a porous membrane under conditions of kinetic regime at a temperature of 293-333 K. The concentration of ozone in the gas phase was determined by spectrophotometric method. Analysis of 4-bromoacetophenone and its oxidation products was performed by gas-liquid chromatography. Oxidation of 4-bromoethylbenzene by ozone in a solution of acetic acid at a temperature of 293 K in the presence of catalytic impurities of manganese (II) ace-tate proceeds mainly on the ethyl group with the formation of a mixture of 4-bromoacetophenone (95.6 %) and 1-(4-bromophenylethanoacetate 4.2 % ). Prevention of destructive oxidation of the ben-zene ring (ozonolysis) with the involvement of the catalyst is explained by the fact that ozone under ca-talysis mainly reacts with a salt of manganese (II) and not with the substrate to form the active form of manganese Mn(IV) which has high substrate selectivity to alkylarenes, directs the oxidation of 4-bromoethylbenzene to the ethyl group. High selectivity of side chain oxidation is achieved only at ele-vated catalyst concentrations, which is largely due to the higher reaction rate of the substrate with ozone than with Mn(IV). The composition of the products of catalytic oxidation of 4-bromoethylbenzene depends on the temperature: at 293 K the reaction stops at the stage of formation of the corresponding ketone and acylated alcohol, increasing the temperature promotes further oxidation of 4-bromoacetophenone to 4-bromobenzoic acid, thus forming a mixture containing 4-bromoacetophenone (82.5 %), 1-(4-bromophenyl)ethanolacetate (4.2 %) and 4-bromo-benzoic acid (11.8 %). The research allowed to formulate general regularities of the reaction of catalytic oxidation of 4-bromomethylbenzene by ozone in acetic acid, to explain the role of the catalyst in the system and to propose a chemical scheme of oxidation corresponding to experimental data.

Antimicrobial properties of half-sandwich Ir(iii) cyclopentadienyl complexes with pyridylbenzimidazole ligands

Ethyl group determined the toxicity of pyridylbenzimidazole Ir(iii) compounds and exchange of the group with sulfonate led to diminishing of the antibacterial activity. Increasing the metal content per complex, 3, gave rise to a compound with no toxicity.