C2 Substituent Research Articles

Novel Nontoxic 5,9-Disubstituted SN38 Derivatives: Characterization of Their Pharmacological Properties and Interactions with DNA Oligomers.

Novel nontoxic derivatives of SN38 with favorable antineoplastic properties were characterized in water solution using NMR. The phenomena observed by NMR were linked to basic pharmacological properties, such as solubility, bioavailability, chemical and stereochemical stability, and binding to natural DNA oligomers through the terminal G-C base pair, which is commonly considered a biological target of Topo I inhibitors. Compound 1, with bulky substituents at both C5(R) and C20(S) on the same side of a camptothecin core, manifests self-association, whereas diastereomers 2, with bulky C5(S) and C20(S) substituents are mostly monomeric in solution. The stereogenic center at C5 is stable in water solution at pH 5–6. The compound with an (N-azetidinyl)methyl substituent at C9 can undergo the retro Mannich reaction after a prolonged time in water solution. Both diastereomers exhibit different abilities in terms of binding to DNA oligomers: compound 1 is strongly bound, whereas the binding of compound 2 is rather weak. Molecular modeling produced results consistent with NMR experiments. These complementary data allow linking of the observed phenomena in NMR experiments to basic preliminary information on the pharmacodynamic character of compounds and are essential for planning further development research.

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Deazapurine Nucleoside Analogues for the Treatment of Trichomonas vaginalis.

Trichomoniasis is the most common nonviral sexually transmitted disease in humans, but treatment options are limited. Here, we report a resorufin-based drug sensitivity assay for high-throughput microplate-based screening under hypoxic conditions. A 5203-compound enamine kinase library and several specialized compound series were tested for the inhibition of Trichomonas growth at 10 μM with Z' values of >0.5. Hits were rescreened in serial dilution to establish an IC50 concentration. A series of 7-substituted 7-deazaadenosine analogues emerged as highly potent anti-T. vaginalis agents, with EC50 values in the low double digit nanomolar range. These analogues exhibited excellent selectivity indices. Follow-up medicinal chemistry efforts identified an optimal ribofuranose and C7 substituent. Several nucleosides rapidly cleared cultures of T. vaginalis at a concentrations of just 2 × EC50. Preliminary in vivo evaluation in a murine trichomoniasis model (Tritrichomonas foetus) revealed promising activity upon topical administration, validating purine nucleoside analogues as a new class of antitrichomonal agents.

Synthesis of the Core Structure of Palhinine A

AbstractWe present a strategy to the core structure of the alkaloid palhinine A passing through a 2,5‐difunctionalized cyclohexenone. This enone was prepared by a domino Michael/aldol condensation sequence. An allylation reaction on the cyclohexenone followed by oxy‐Cope rearrangement introduced an allyl group at C3. After the generation of an aldehyde function on the terminus of the C5 substituent, an intramolecular aldol reaction led to a bicyclo[2.2.2]octanone. The five‐membered ring of the core structure could be established by an intramolecular nitrile oxide‐alkene [3+2]‐cycloaddition. Prior to this key transformation, the keto function was converted to an alkene and the allyl group to an oxime.

Evolution of Routes for Asymmetric Total Synthesis of Cyclocitrinol Enabled by Type II [5+2] Cycloaddition†

Main observation and conclusionThe asymmetric total synthesis of an unusual C25 steroid containing a unique bicyclo[4.4.1]undecene A/B ring system, resulting in the synthesis of cyclocitrinol (1) and its isomer Δ8,14‐cyclocitrinol (38), is reported. Initial attempts to construct the synthetically challenging bicyclo[4.4.1]undecene A/B ring system using a type II [5+2] cycloaddition showed that a chiral substituent at the allylic position of the alkene (C6, cyclocitrinol numbering) controlled the stereoselective outcome of the cycloaddition reaction. Late‐stage migration of the tetrasubstituted C8–C14 double bond in Δ8,14‐cyclocitrinol (38) to obtain cyclocitrinol (1) proved challenging, inspiring an alternative approach. The chiral β‐CH2OR group on the allylic substituent at C6 played a pivotal role both in controlling the diastereoselectivity of the type II [5+2] cycloaddition and retaining the C6 substituent under lithium–amine conditions.

CuI-Catalyzed Ullmann-Type Coupling of Phenols and Thiophenols with 5-Substituted 1,2,3-Triiodobenzenes: Facile Synthesis of Mammary Carcinoma Inhibitor BTO-956 in One Step

AbstractA facile and unprecedented synthesis of 2,3-diiodinated or 2,6-diiodinated diaryl ether/thioether derivatives through regioselective Ullmann-type cross couplings of 5-substituted 1,2,3-triiodobenzenes and phenols/thiophenols is described. Remarkably, the coupling reactions are simply controlled by the type of nucleophiles and the nature of C5 substituent at 1,2,3-triiodoarenes providing the internal or terminal coupling products in high regioselectivity and good isolated yields. Noticeable steric and electronic effects were clearly observed on both 1,2,3-triiodoarenes and nucleophiles. The highest yields were isolated from a combination between either electron-poor 1,2,3-triiodoarenes and phenols or electron-rich 1,2,3-triiodoarenes and thiophenols. The optimized conditions were found to be suitable for several functional groups. Using this methodology, mammary carcinoma inhibitor BTO-956 is prepared in only one step with excellent regioselectivity and good isolated yield. This report discloses the first method to prepare 2,3-diiodinated and 2,6-diiodinated diaryl ethers/thioethers in one step that is efficient, regioselective, and general in scope. The products are truly remarkable precursors for other transformations.

6-Morpholino- and 6-amino-9-sulfonylpurine derivatives. Synthesis, computational analysis, and biological activity

The synthesis of novel 6-chloro/morpholino/amino/-9-sulfonylpurine derivatives was accomplished in two ways, either (i) involving the condensation reaction of 6-chloropurine with commercially available arylsulfonyl chlorides in acetone and the presence of aqueous KOH at 0 °C, followed by the substitution of C6-chlorine with morpholine, or (ii) employing a reversed synthetic approach where 6-morpholinopurine and commercially available adenine bases were reacted with the corresponding alkyl, 2-arylethene and arylsulfonyl chlorides giving the N9 sulfonylated products, the latter particularly used where prior nonselective sulfonylation was observed. In both approaches, the sulfonylation reaction occurred regioselectively at the purine N9 position lacking any concurrent N7 derivatives, except in the case of a smaller methyl substituent on SO2 and the free amino group at C6 of the purine ring. The tautomeric features of initial N9 unsubstituted purines, as well as stability trends among the prepared N-9-sulfonylpurine derivates, were investigated using DFT calculations with an important conclusion that electron-donating C6 substituents are beneficial for the synthesis as they both promote the predominance of the desired N9 tautomers and help to assure the stability of the final products. The newly synthesized 6-morpholino and 6-amino-9-sulfonylpurine derivatives showed antiproliferative activity on human carcinoma, lymphoma, and leukemia cells. Among the tested compounds, 6-morpholino 17 and 6-amino 22 derivatives, with trans-β-styrenesulfonyl group attached at the N9 position of purine, proved to be the most effective antiproliferative agents, causing accumulation of leukemia cells in subG0 cell cycle phase.

Structure—Activity Relationship of Local Anesthetics Based on Alkynylpiperidine Derivatives

The influence of the nature of the acyl (propionyl and benzoyl) moiety and the piperidine ring C4 substituent on the activity of several alkynylpiperidine derivatives was studied. The presence of an alkyl (hexyl) radical on the triple bond of the piperidine ring C4 substituent in the infiltration anesthesia model had a positive effect on the anesthesia index and the duration of both total and general anesthesia as compared to lidocaine, novocaine, and trimecaine taken as reference drugs. The ester of 4-(octyn-1-yl)piperidol-1-propionic acid was the most active anesthetic among the studied compounds. Modification of the triple bond (exhaustive hydrogenation and hydration) led to a decrease in the duration of anesthesia. The activity of the benzoate was greater than that of the propionate in the propionate-benzoate pair.

General Method for the Synthesis of α- or β-Deoxyaminoglycosides Bearing Basic Nitrogen.

The introduction of glycosides bearing basic nitrogen is challenging using conventional Lewis acid-promoted pathways owing to competitive coordination of the amine to the Lewis acid promoter. Additionally, because many aminoglycosides lack a C2 substituent, diastereomeric mixtures of O-glycosides are often produced. Herein, we present a method for the synthesis of α- or β- 2,3,6-trideoxy-3-amino- and 2,4,6-trideoxy-4-amino O-glycosides from a common precursor. Our strategy proceeds by the reductive lithiation of thiophenyl glycoside donors and trapping of the resulting anomeric anions with 2-methyltetrahydropyranyl peroxides. We apply this strategy to the synthesis of α- and β-forosamine, pyrrolosamine, acosamine, and ristosamine derivatives using primary and secondary peroxides as electrophiles. α-Linked products are obtained in 60-96% yield and with >50:1 selectivity. β-Linked products are obtained in 45-94% yield and with 1.7->50:1 stereoselectivity. Contrary to donors bearing an equatorial amine substituent, donors bearing an axial amine substituent favored β-products at low temperatures. This work establishes a general strategy to synthesize O-glycosides bearing a basic nitrogen.

An accurate prediction of oxidation potential for a series of phenylthiophene derivatives

The high-level composite G4 method is used to calculate the gas phase standard molar enthalpies of formation (ΔHf,298) for a series of 3-(para-X-phenyl)thiophenes (PTs), in which X is referred to as the -CH3, -OCH3, -H, -F, and -C1 substituents. The accurate oxidation potential (Eox) values are also calculated with respect to the Ag/AgCl reference electrode in acetonitrile. The results show that the theoretical and experimental Eox values are in excellent agreement with each other; these quantities successfully reveal a linear correlation with various electronic characteristics of PTs. A linear dependence behavior on the Hammett constants of the substitutions can be seen for the Eox values. Analysis of the HOMO-LUMO band gap and the UV–visible spectral properties demonstrate the facility of hole transport for the PTs as a potential candidate for conducting polymers.

Discovery of novel HIV-1 integrase-LEDGF/p75 allosteric inhibitors based on a pyridine scaffold forming an intramolecular hydrogen bond

We have discovered HIV-1 novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a pyridine scaffold forming an intramolecular hydrogen bond. Scaffolds containing a pyridine moiety have been studied extensively and we have already reported that substituents extending from the C1 position contributed to the antiviral potency. In this study, we designed a new pyridine scaffold 2 with a substituent at the C1 position. Interestingly, during attempts at optimization, we found that the direction of the C1 substituents with an intramolecular hydrogen bond contributed to the antiviral potency. Compound 34f exhibited better antiviral potency against WT and the T174I mutant (EC50 (WT) = 6.6 nM, EC50 (T174I) = 270 nM) than BI 224436 (EC50 (WT) = 22 nM, EC50 (T174I) > 5000 nM).

Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.

Синтез 5-арил-3-гидрокси-1-(2-гидроксипропил)-4-(фурил-2-карбонил)-3-пирролин-2-онов и 5-арил-3-гидрокси-1-(3-гидроксипропил)-4-(фурил-2-карбонил)-3-пирролин-2-онов

In this work, pyrrolidin-2-ones and their derivatives are considered as a promising class of non-aromatic heterocyclic compounds. Their structure is found in the nuclei of many natural products and biologically active molecules. In pharmacy the possibility of introducing various substituents into the nucleus of pyrrolidin-2-ones is a great importance for the synthesis of new medicinal molecules with improved biological activity. Nowadays the synthesis of new active compounds by introducing various substituents at the C1-, C4- and C5-position of 3-hydroxy-3-pyrrolin-2-one has been little studied and it is of great interest to study the conditions of their synthesis, chemical properties and biological activity. In this research work the corresponding 5-aryl-3-hydroxy-1-(2-hydroxypropyl)-4-(furyl-2-carbonyl)-3-pyrrolin-2-ones and 5-aryl-3-hydroxy-1-(3-hydroxypropyl)-4-(furyl-2-carbonyl)-3-pyrrolin-2-ones were synthesized by the reaction of methyl ester of furyl-2-carbonylpyruvic acid with a mixture of aromatic aldehyde and 1-amino-2-hydroxypropane or 3-amino 1-hydroxypropane when heated in dioxane. The results of the study of the structure of the new synthesized compounds are presented. The structure was proved using 1H NMR spectroscopy and IR spectrometry. It was shown that the IR spectra of the compounds contain bands of the corresponding stretching vibrations of the alcoholic hydroxyl group, enol hydroxyl, amide and ketone groups. In the 1H NMR spectra of the compounds, along with the signals of aromatic protons in the C5 substituent and related groups, characteristic peaks are observed, indicating the formation of the corresponding derivatives of 3-hydroxy-3-pyrrolin-2-ones. It was noted that in the case of the synthesis of 5-aryl-3-hydroxy-1-(2-hydroxypropyl)-4-(furyl-2-carbonyl)-3-pyrrolin-2-ones, the signal of the methine proton at the C5 position of the heterocycle is cleaved in 1H NMR spectra compounds as a result of the appearance of a second chiral center in the 2-hydroxypropyl radical. Elemental analysis was performed for the synthesized compounds.

Optimization of Insecticidal Triterpene Derivatives by Biomimetic Oxidations with Hydrogen Peroxide and Iodosobenzene Catalyzed by MnIII and FeIII Porphyrin Complexes.

Semisynthetic functionalized triterpenes (4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3β-yl acetate; 4α,14-dimethyl-5α-cholest-8-ene-3,7,11-trione; 4α,14-dimethyl-5α-cholesta-7,9(11)-dien-3-one and 4α,14-dimethyl-5α-cholest-8-en-3β-yl acetate), previously prepared from 31-norlanostenol, a natural insecticide isolated from the latex of Euphorbia officinarum, have been subjected to oxidation with hydrogen peroxide (H2 O2 ) and iodosobenzene (PhIO) catalyzed by porphyrin complexes (cytochrome P-450 models) in order to obtain optimized derivatives with high regioselectivity. The main transformations were epoxidation of the double bonds and hydroxylations of non-activated C-H groups and the reaction products were 25-hydroxy-4α,14-dimethyl-5α-cholesta-7,9(11)-dien-3β-yl acetate (59 %), 25-hydroxy-4α,14-dimethyl-5α-cholest-8-ene-3,7,11-trione (60 %), 4α,14-dimethyl-5α,7β-7,8-epoxycholest-9(11)-en-3-one (22 %), 8-hydroxy-4α,14-dimethyl-5α-cholest-9(11)-ene-3,7-dione (16 %), 12α-hydroxy-4α,14-dimethyl-5α,7β-7,8-epoxycholest-9(11)-en-3-one (16 %), and 4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3β-yl acetate (26 %), respectively. We also investigated the insect (Myzus persicae, Rhopalosiphum padi and Spodoptera littoralis) antifeedant and postingestive effects of these terpenoid derivatives. None of the compounds tested had significant antifeedant effects, however, all were more effective postingestive toxicants on S. littoralis larvae than the natural compound 31-norlanostenol, with 4α,14-dimethyl-5α,8α-8,9-epoxycholestan-3β-yl acetate being the most active. The study of their structure-activity relationships points out at the importance of C3 and C7 substituents.

Axially chiral hemiaminals from nonracemic α-amino acid derivatives (thiohydantoins): Synthesis and isomer identification.

Stable, nonracemic axially chiral hemiaminals (O,N-hemiacetals) have been synthesized stereoselectively from lithium aluminum hydride (LiAlH4 ) reductions of nonracemic 5-methyl- and 5-isopropyl-3-(o-aryl)-2-thioydantoins in tetrahydrofuran (THF) at room temperature in 10 min. Predominantly S-configured hemiaminals at C-4 of the heterocyclic ring were produced from the S-configured thiohydantoins at C-5 (by 80% when the C5 substituent is methyl and by 97% when it is isopropyl). The configuration at C-5 was retained during the reduction reaction. The stereochemical outcome of the axially chiral hemiaminals resulted from their conformational preferences.

Strategic Diastereoselective C1 Functionalization in the Aza-Rocaglamide Scaffold toward Natural Product-Inspired eIF4A Inhibitors.

Rocaglates, rocaglamides, and related flavagline natural products exert their remarkable anticancer activity through inhibition of eukaryotic initiation factor 4A (eIF4A) but generally display suboptimal drug-like properties. In our efforts to identify potent drug-like eIF4A inhibitors, we developed synthetic strategies for diastereoselectively functionalizing the C1 position of aza-rocaglamide scaffolds (cf. 14 and 18), which proceed via retention or inversion of configuration at C1 depending on the C2 substituent (cf. 15 and 21) and ultimately enabled the discovery of novel and potent eIF4A inhibitors such as 25.

Facile Reduction of β-Enamino Oxopyrrolidine Carboxylates Mediated by Heterogeneous Palladium Catalyst

The synthesis of diastereoisomers via diastereoselective hydrogenation of unreactive endocyclic enamine system of ethyl 4-hydrazinyl- and 4-(2-hydroxyethylamino)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylates using palladium-based catalyst was developed. The steric and electronic properties of substituents, especially of the C2 substituent, influenced both the yield and diastereoselectivity. Despite the reaction generated three chiral centers, the reduced compounds had either cis–trans or all-trans configuration which was successfully determined by means of 1D and 2D NMR experiments.

Discovery of full color emissive thiazole fluorophores in solution and solid states: The core is central and regulating torsional barrier does the trick!

The rare class of full color tunable molecules from 5-(hetero-2-yl)-1,3-thiazole core with solid and solution state emissions were designed. Stable conformers were predicted computationally and C4 substituent on the 1,3-thiazole ring emerged crucial as multifunctional stacking modulator in the multidirectional charge transfer donor-acceptor systems. Seven novel molecules were synthesized, and their emissions with very good quantum yield both in solution and solid states were reported along with very rare full color dual emission (solution:469–672 nm, solid:466–614 nm). These full color dual state emissive (FCDSE) molecules also displayed solvatochromism and large Stokes shift (solution: 78–210 nm, solid: 90–106 nm). Further, absorption and emission wavelengths were calculated using TDDFT-PBE0/6-31G(d,p) by accounting the solvent effects using Poisson Boltzmann solvation model and the experimental results were well reproduced. The accurate prediction of absorption-emission trend in this homologous series is expected to guide the design of custom-emissive fluorophores and the facile synthetic route can provide diverse compounds for desired technological applications.

Thermal properties of novel oligoether-substituted ionic liquids and the influence of alkyl-substituent isomery

This paper is a continuation of a study focused on thermodynamic properties of isomeric and quasi-isomeric ionic liquids. In this work 5 novel ionic liquids were synthesized, namely 1-(2-(2-ethoxyethoxy)ethyl)-3-alkylimidazolium bis(trifluoromethylsulfonyl)imides, where alkyl stands for different C5 substituents. These species were characterized as to their isobaric molar heat capacity and thermal stability. The results are discussed with respect to different substituent isomerism and compared with data from our previous work (Rotrekl, Fluid Phase Equilib. 2017) that reported on a similar group of isomeric ionic liquids, namely 1-butyl-3-alkylimidazolium bis(trifluoromethylsulfonyl)imides. Data analysis of the experimental heat capacites was carried out using a non-statistical approach of the mathematical gnostics. The conclusions drawn from the present work bring an insight into the fine structure-property relationship which is useful in the development of predictive tools as well as it direct applications such as in energy storage or thermal fluids development.

DFT Study on the Deglycosylation of Methylated, Oxidized, and Canonical Pyrimidine Nucleosides in Water: Implications for Epigenetic Regulation and DNA Repair.

Density functional theory (B3LYP) was used to characterize the kinetics and thermodynamics of the (nonenzymatic) deglycosylation in water for a variety of 2'-deoxycytidine (dC) and 2'-deoxyuridine (dU) nucleoside derivatives that differ in methylation and subsequent oxidation of the C5 substituent. A range of computational models are considered that combine implicit and explicit solvation of the nucleophile and nucleobase. Regardless of the model implemented, our calculations reveal that the glycosidic bond in dC is inherently more stable than that in dU. Furthermore, C5 methylation of either pyrimidine and subsequent oxidation of the methyl group yield overall small changes to the Gibbs reaction energy profiles and thereby preserve lower deglycosylation barriers for the dC compared to those for the dU nucleoside derivatives. However, hydrolytic deglycosylation becomes significantly more energetically favorable when 5-methyl-dC (5m-dC) undergoes two or three rounds of oxidation, with the Gibbs energy barrier decreasing and the reaction becoming more exergonic by up to 40 kJ/mol. In fact, two or three oxidation reactions from 5m-dC result in a deglycosylation barrier similar to that for dU, as well as those for the associated C5-methylated (2'-deoxythymidine) and oxidized (5-hydroxymethyl-dU) derivatives. These predicted trends in the inherent deglycosylation energetics in water directly correlate with the previously reported activity of thymine DNA glycosylase (TDG), which cleaves the glycosidic bond in select dC nucleosides as part of epigenetic regulation and in dU variants as part of DNA repair. Thus, our data suggests that fundamental differences in the intrinsic reactivity of the pyrimidine nucleosides help regulate the function of human enzymes that maintain cellular integrity.