Design and synthesis of further simplified pyripyropene A based ACAT2 selective inhibitors

Acyl-coenzyme A: cholesterol acyltransferases (ACATs) play the significant role in the formation of cholesterol esters. One form of this enzyme is ACAT2, which not only regulates the balance of cholesterol metabolism in cells but also participates in the “escape” mechanism of hepatocellular carcinoma (HCC) cells. The natural product pyripyropene A (PPPA) and its analogs are the only chemical ACAT2-specific inhibitors. To develop simpler analogs and endeavor to remove a portion of multichiral centers and enrich a variety of analogs, new PPPA analogs are creatively designed and synthesized based on previous work. Among these new analogs, 7a and 9f show better activity and selective inhibition of ACAT2 compared with PPPA. These results will provide a new future for potential therapeutic use in atherosclerosis and HCC.     

2-(4-Oxo-3,4-dihydro-2-quinazolinylmethyl)benzoic Acids

Condensation of 2-cyanomethylbenzoic acid with anthranilic acids gave a series of 2-(4-oxo-3,4-dihydro-2-quinazolinylmethyl)benzoic acids which are structural analogs of the alkaloid glycosminine (2-benzyl-1,2-dihydro-4-quinazolone).     

Novel [D-Arg2]dermorphin(1-4) analogs with mu-opioid receptor antagonist activity

Ten Tyr-D-Arg-Phe-betaAla-NH(2) (YRFB) analogs in which specific amino acid side chains are shifted to the N(alpha)-position were synthesized, and the binding to these analogs to the mu receptor and their in vitro biological properties were evaluated. Some analogs in which a N,N-bis(p-hydroxybenzyl)-Gly residue was substituted for Tyr(1) exhibited mu receptor antagonist activities (pA(2)) between 5.3 and 6.1. Of these analogs, [N,N-bis(p-hydroxybenzyl)-Gly(1)]YRFB was found to be the most potent specific antagonist for the mu-opioid receptor.     

Synthetic Analogs of Marine Alkaloid Aplysinopsin Suppress Anti-Apoptotic Protein BCL2 in Prostate Cancer

Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer.     

2-methylindole analogs as cholinesterases and glutathione S-transferase inhibitors: Synthesis,biological evaluation,molecular docking,and pharmacokinetic studies

In this study, we aimed to (i) synthesize new 2-methylindole analogs containing various amino structures, pyrrolidine, piperidine, morpholine, and substituted phenyl groups through structural and molecular modifications, (ii) evaluate the pharmaceutical potential of 2-methylindole analogs via assessing enzyme inhibitory activity against glutathione S-transferase (GST), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), (iii) predict ADMET and pharmacokinetic properties of the synthesized 2-methylindole analogs, (iv) reveal the possible interactions between the synthesized 2-methylindole analogs with GST, AChE, and BChE enzymes using several molecular docking software. In vitro enzyme inhibition assays showed that the synthesized indole analogs exhibited moderate to good inhibitory activities against GST, AChE, and BChE enzymes. Briefly, the inhibitory activities of the analogs 4b and 4i against AChE, 4a and 4b against BChE, and analogs 1 and 4i against GST were detected to be higher or close to the standard inhibitor compounds. The analog 4b was detected to have the best inhibitory activity against both AChE and BChE enzymes with the lowest IC₅₀ values as 0.648 µM for AChE and 0.745 µM for BChE. The analyses of enzyme inhibition relationship with the synthesized analogs could help to design new analogs for the inhibitors of cholinergic and glutathione pathways based on the indole derivatives.     

Conformational Analysis of 2-Methoxy-2-oxo-1,3,2-dioxaphosphorinane and Its Methylthio and Methylselenyl Analogues

Russian Journal of Physical Chemistry A - This research aimed at exploring the stabilities of the conformers of 2-methoxy-2-oxo-1,3,2-dioxaphosphorinane and its methylthio and methylselenyl analogs...     

Synthesis of enzyme-inhibitory phospholipid analogs II. Preparation of chiral 1-acyl-2-acylamido-2-deoxyglycerophosphorycholines from serine

A facile and efficient stereospecific route to the enzyme-inhibitory 2-amide analogs of phosphatidycholine is reported.     

Nucleoside und Nucleotide. Teil 16. Verhalten von 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyrimidinon-5′-triphosphat, 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)pyridinon-5′-triphosphat und 4-Amino-1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyridinon-5′-triphosphat gegenüber DNA-Polymerase

Nucleosides and Nucleotides. Part 16. The Behaviour of 1-(2′-Deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidinone-5′-triphosphate, 1-(2′-Deoxy-β-D -ribofuranosyl-2(1H))-pyridinone-5′-triphosphate and 4-Amino-1-(2′-desoxy-β-D -ribofuranosyl)-2(1H)-pyridinone-5′-triphosphate towards DNA Polymerase The behaviour of nucleotide base analogs in the DNA synthesis in vitro was studied. The investigated nucleoside-5′-triphosphates 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone-5′-triphosphate (pppM_d), 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppII_d) and 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppZ_d) can be considered to be analogs of 2′-deoxy-cytidine-5′-triphosphate. However, their ability to undergo base pairing to the complementary guanine is decreased. When pppM_d, pppII_d or pppZ_d are substituted for pppC_d in the enzymatic synthesis of DNA by DNA polymerase no incorporation of these analogs is observed. They exhibit only a weak inhibition of the DNA synthesis. The mode of the inhibition is uncompetitive which shows that these nucleotide analogs cannot serve as substrates for the DNA polymerase.     

Synthesis and biological evaluation of SGLT2 inhibitors: gem-difluoromethylenated Dapagliflozin analogs

Dapagliflozin is currently the most advanced SGLT2 inhibitor, which has been used in Phase III clinical trials for treatment of diabetes. Here we describe the design and synthesis of Dapagliflozin analogs modified with gem-difluoromethylene group. Their biological evaluation of in vitro inhibitory activity against human SGLT2 showed that some of the analogs with CF₂ at C-4 are better SGLT2 inhibitors compared with Dapagliflozin.     

Routes for synthesis of [2′-D3]-2-methyl-2-hepten-6-one

Conclusions Routes were developed for the stereoselective synthesis of the deuterium analog of 2-methyl-2-hepten-6-one, and from it the deuterium analogs of geranium ester.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No.2, pp.384–389, February, 1973.     

Synthesis of oxirnes. IV. 2-pyridinealdoxime methiodides from 2-picoline methiodides

The Ortoleva-King-Krohnke sequence was used to prepare substituted 2-pyridinealdoxime methiodides. The methodology was extended to prepare three analogs in which two molecules of 5-hydroxy-2-pyridinealdoxime methiodide were coupled through the 5-position with dihalides.     

5-Hydroxy-2,3-dihydrobenzofuran-derived polyfunctional antioxidants 2. Synthesis of 2-dodecylselenomethyl-5-hydroxy-2,3-dihydrobenzofurans and their antioxidant profile <Emphasis Type="Italic">versus</Emphasis> 2-dodecylthiomethyl-substituted analogs

A number of 2-dodecylselenomethyl-5-hydroxy-2,3-dihydrobenzofurans were synthesized from the corresponding 5-alkoxy-2-iodomethyl-substituted derivatives. The rate constants of the reaction with peroxide radicals and stoichiometric coefficients of inhibition were measured for the synthesized compounds and their 2-dodecylthiomethyl substituted analogs in the model reaction of initiated styrene oxidation. The dissociation energies of O–H bond were also calculated. 2-Dodecylselenomethyl-5-hydroxy-2,3-dihydrobenzofurans exceed their sulfurcontaining analogs and tocopherols by antioxidant activity in the thermal autooxidation of methyl oleate by a factor of 9–14 and 19–20, respectively.     

Reactions of 1,3-dioxacycloalkanes and their 2-arsena, 2-bora, 2-germa, 2-sila,and 2-thia analogs with nitriles

New reactions of five-, six-, and seven-membered 1,3-dioxacycloalkanes and their 2-arsena, 2-bora, 2-germa, 2-sila, and 2-thia analogs with nitriles giving rise to 1,3-oxazacycloalkanes and then to amino alcohols are surveyed. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1499–1507, July, 2005.     

Synthesis of fluorine-containing analogs of ellipticine and other heterocycles from 2-Nitro-and 2-amino-4,5-difluoroanilines

2-Nitro- and 2-amino-4,5-difluoroanilines were used as starting materials to synthesize fluorine-containing imidazole, oxazole, and indoloquinoxaline derivatives. The latter may be regarded as ellipticine analogs.     

A novel synthetic route to 2-alkylpropane-1,3-sultones and its application to the synthesis of 2-alkyl derivatives of tramiprosate

A practical synthetic route to various 2-alkylpropane-1,3-sultones, the key intermediates for the preparation of 2-substituted homotaurines as analogs of tramiprosate, was developed.     

Studying the signaling role of 2-oxoglutaric acid using analogs that mimic the ketone and ketal forms of 2-oxoglutaric acid

2-Oxoglutaric acid (2-OG), a Krebs cycle intermediate, is a signaling molecule in many organisms. To determine which form of 2-OG, the ketone or the ketal form, is responsible for its signaling function, we have synthesized and characterized various 2-OG analogs. Only 2-methylenepentanedioic acid (2-MPA), which resembles closely the ketone form of 2-OG, is able to elicit cell responses in the cyanobacterium Anabaena by inducing nitrogen-fixing cells called heterocysts. None of the analogs mimicking the ketal form of 2-OG are able to induce heterocysts because none of them are able to interact with NtcA, a 2-OG sensor. NtcA interacts with 2-MPA and 2-OG in a similar manner, and it is necessary for heterocyst differentiation induced by 2-MPA. Therefore, it is primarily the ketone form that is responsible for the signaling role of 2-OG in Anabaena.     

Rearrangement ions—II: Mass spectra of the C-13 labeled 2-methyl-2-hydroxy-propanes and 2-methyl-2-aminopropanes

The mass spectra of 2-methyl-2-hydroxypropane (I) and 2-methyl-2-aminopropane (II) exhibit fragment ions which suggest skeletal rearrangement processes. The C-13 analogs of I and II, labeled in the 1- and 2-positions, were prepared in order to determine the most probable mechanistic pathways for fragmentation. Label retentions in major fragment ions indicate that I and II decompose into common fragments through structurally similar intermediates.     

Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits

NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS), which function in normal physiology and, when overproduced, in pathophysiology. Recent studies using mice deficient in Nox2 identify this isoform as a novel target against Nox2-implicated inflammatory diseases. Nox2 activation depends on the binding of the proline-rich domain of its heterodimeric partner p22phox to p47phox. A high-throughput screen that monitored this interaction via fluorescence polarization identified ebselen and several of its analogs as inhibitors. Medicinal chemistry was performed to explore structure-activity relationships and to optimize potency. Ebselen and analogs potently inhibited Nox1 and Nox2 activity but were less effective against other isoforms. Ebselen also blocked translocation of p47phox to neutrophil membranes. Thus, ebselen and its analogs represent a class of compounds that inhibit ROS generation by interrupting the assembly of Nox2-activating regulatory subunits.     

Synthesis and antimicrobial activity of some benzoxazinoids derivatives of 2-nitrophenol and 3-hydroxy-2-nitropyridine

Benzoxazinoids (BXs), alkaloids frequently found in Gramineae species, are natural defensives that can potentially be exploited to the development of novel antimicrobial agents. Here, BXs analogs were synthesized from 2-nitrophenol (benzoxazinone series) and 3-hydroxy-2-nitropyridine (pyridoxazinone series) and tested against fungal and bacteria of medical interest. The starting materials were submitted to adequate nucleophilic substitution in order to functionalize of analogs, followed by a reductive cyclization catalyzed by palladium on carbon. Next, the biological assays showed that pyridoxazinone serie has a good antibacterial activity, especially against Enterococcus faecalis (Minimum inhibitory concentration—MIC: 7.8-15.6?μg.mL^?1) and Acinetobacter baumannii (MIC 31.25-125?μg.mL^?1). Antifungal activity, in turn, was related to compound 2e which showed a MIC of 62.5?μg.mL^?1 against Candida albicans, Candida glabrata, and Candida tropicalis. All analogs complied with Lipinski's rules and were predicted to have a low toxicity.     

Aziridine-2-phosphonic acid,the valuable synthon for synthesis of 1-amino-2-functionalized ethanephosphonic acids

The ring-opening of aziridine-2-phosphonic acid with a series of nucleophiles was studied. This reaction was found to proceed regioselectively and to provide a good preparative method for the synthesis of phosphonic analogs of various 2-substituted 1-aminoethanecarboxylic acids.