Synthesis of pyrrolomorphinan derivatives as κ opioid agonists

We synthesized pyrrolomorphinan derivatives 6, 7, and 9 to examine whether the pyrrole ring would be an accessory site in the κ opioid receptor selective antagonist, nor-binaltorphimine. Derivative 6 had an α,β-unsaturated ketone substituent that strongly bound to the κ receptor. The compound with the highest κ receptor selectivity, 6e, produced a dose-dependent antinociceptive effect in the mouse acetic acid writhing test. However, derivatives 7 and 9, which did not have α,β-unsaturated ketone substituents, showed less κ receptor selectivity than compound 6. Based on structure–activity relationships, we proposed that these compounds adopted active structures for κ selective agonist activity. The pyrrole ring would not function as an accessory site, but the ability of the side chain on the pyrrole ring to localize above the C-ring appeared to confer κ selective agonist activity. These results will promote the design of novel κ agonists.     

Synthesis and SAR of tetrahydroisoquinolines as Rev-erbα agonists

The design and synthesis of a novel series of Rev-erbα agonists is described. The development and optimization of the tetrahydroisoquinoline series was carried out from an earlier acyclic series of Rev-erbα agonists. Through the optimization of the scaffold 1, several potent compounds with good in vivo profiles were discovered.     

Synthesis of indole analogs as potent β-glucuronidase inhibitors

Natural products are the main source of motivation to design and synthesize new molecules for drug development. Designing new molecules against β-glucuronidase inhibitory is utmost essential. In this study indole analogs (1–35) were synthesized, characterized using various spectroscopic techniques including ¹H NMR and EI-MS and evaluated for their β-glucuronidase inhibitory activity. Most compounds were identified as potent inhibitors for the enzyme with IC₅₀ values ranging between 0.50 and 53.40 μM, with reference to standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Structure-activity relationship had been also established. The results obtained from docking studies for the most active compound 10 showed that hydrogen bond donor features as well as hydrogen bonding with (Oε1) of nucleophilic residue Glu540 is believed to be the most importance interaction in the inhibition activity. It was also observed that hydroxyl at fourth position of benzylidene ring acts as a hydrogen bond donor and interacts with hydroxyl (OH) on the side chain of catalysis residue Tyr508. The enzyme-ligand complexed were being stabilized through electrostatic π-anion interaction with acid-base catalyst Glu451 (3.96 Å) and thus preventing Glu451 from functioning as proton donor residue.     

Biomass as source of chemicals VII — Synthesis of new oxiranes

Application of a solid-liquid phase transfer technique in low hydrated organic medium makes the synthesis of the corresponding oxiranes possible for the first time. These new molecules, obtained from biomass, can be applied in many different ways in macromolecular chemistry.     

Synthesis of 1′-Deoxypsicofuranosyl-deoxynucleosides as Potential Anti-HIV Agents

Abstract

Various routes to the targets 1, 2, 3, 1-deoxy-psicofuranosyl nucleoside analogues related to anti-HIV agents, are reported. Two routes afforded their 6′-benzylated derivatives 9, 10 and 15. Only the epoxide 12 and deoxynucleosides 19 and 22 were able to be deprotected leading in the first case to 16 and its ring opening derivative 17 and in the second case to 20 and to the target 3.     

Synthesis of (±)-cis-3-Aminomethyl-1-indanylmethanol as a Precursor of Carbocyclic Analogues of Nucleosides

Abstract

Aminoalcohol precursor of carbocyclic analogues of nucleosides (±)-cis-3-aminomethyl-1-indanylmethanol was efficiently synthesized starting from benzonorbornadiene (5) previously prepared by addition of cyclopentadiene to 1-bromo-2-fluorobenzene.     

Synthesis of new series of α-cyclodextrin esters as dopamine carrier molecule

A new series of amphiphilic α-cyclodextrins were synthesized by grafting N-acylated amino acids [valine, leucine, phenylalanine, methionine, and tryptophan (3a-e)] to the primary hydroxyl groups via ester bond formation. The synthetic pathway involves selective hexa-bromination of the primary hydroxyls followed by per-substitution with the carboxylate moiety of the N-acetyl residues in the presence of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene). The ability of the synthetic compounds for the extraction of dopamine was studied. The results showed a considerable ability of some of the amphiphilic compounds for the extraction of dopamine into octanol phase from water. To complete the study, the binding affinity of dopamine toward the synthetic host molecules was calculated by using of the molecular docking technique.     

Synthesis of 3′-O-Propargylthymidine as a Candidate Antiretroviral Agent

Abstract

3′-O-Propargylthymidinc, which may be viewed as a stnictural analogue of the potent antiretroviral agent 3′-azido-3′-deoxythymidine (AZT), was synthesized from 5′-O-(4,4′-dimethoxytritylthymidine by reaction with propargyl bromide followed by gentle acidolysis. The 3′-O-propargyl derivative was tested for antiretroviral activity in SC-1 mouse fibroblasts infected with Rauscher murine leukemia virus (MuLV). No inhibition of MuLV proliferation was observed at concentrations of 3′-O-propargylthymidine from 0.001 to 100 μM. whereas the IC₅₀ against the host cells was 30 μM. By comparison, AZT had an IC₅₀ for MuLV growth of 0.01 μM and an IC₅₀ for cell growth of >100 μM. Thus, replacement of the 3′-N-N≡N group in AZT by a 3′-OCH₂C≡CH group increased cytotoxicity but decreased antiretroviral activity relative to AZT.     

Synthesis of 3′-Trifluoromethyl Nucleosides as Potential Antiviral Agents

Abstract

1,2-Di-O-acetyl-3-deoxy-3-trifluoromethyl-5-O-benzoyl-β-D-riboruranose was synthesized from the precursor keto sugar by the use of Ruppert's reagent (CF₃SiMe₃) as the source of a nucleophilic trifluoromethyl group. Coupling of this trifluoromethyl sugar with nucleobases and elaboration gave novel deoxy and dideoxynucleosides. A single crystal X-ray analysis confirmed the structure and stereochemistry. The deoxynucleosides were converted through an elimination reaction to their dideoxydidehydro derivatives.     

Synthesis of β-ionone derived chalcones as potent antimicrobial agents

A series of chalcones (3a–v) have been synthesized by condensation of β-ionone (1) with a variety of aldehydes (2a–v). The synthesized compounds have been screened for their in vitro antimicrobial activity against five bacterial and five fungal strains, using disc diffusion assay. The evaluated compounds display a wide range of activities, from completely inactive to the highly active compounds. Some of the compounds are also active against methicillin resistant staphylococcus aureus (MRSA).     

Synthesis of guanidino sugar conjugates as GlcβArg analogs

The β-glucosyl linkage to the guanidine group of arginine (Arg) is found in amylogenin, a glycoprotein from sweet corn. Such a linkage is formed by a rare N-glycosylation of proteins. Synthesis of analogs of the unusual N-glycosidic linkage (GlcβArg) with an acetamido or triazole spacer between the glycosyl residue and the guanidine moiety was accomplished by the reaction of fully acetylated sugar unit containing a free amino group with bis-Boc-thiourea. Synthesis of N-glucosylarginine with an amido linker was also achieved during the present study. This methodology was also extended to the synthesis of cationic glucolipid.     

Synthesis of benzothiazole derivatives as a potent α-glucosidase inhibitor

Diabetes is one of the pre-dominant metabolic disorders all over the world. It is the prime reason of mortality and morbidity due to hyperglycemia which is link with numerus obstacles. Delaying absorption and digestion of carbohydrate has great therapeutic impact for governing postprandial hyperglycemia. Consequently, alpha glucosidase is one of the potential therapeutic approaches that reduce absorption of glucose and delay carbohydrate digestion hence maintaining blood glucose level. In this regard we have synthesized benzothiazole based oxadiazole in search of potent anti-diabetic agent as α-glucosidase Inhibitors. Benzothiazole based oxadiazole derivatives 1–23 have been synthesized, characterized by ¹HNMR, ¹³CNMR, and MS and evaluated for α-glucosidase Inhibition. All analogs exhibited a varying degree of α-glucosidase inhibitory activity with IC₅₀ values ranging in between 0.5 ± 0.01–30.90 ± 0.70 μM when compared with the standard acarbose (IC₅₀ = 866.30 ± 3.20 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.     

Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents

A series of new 4β-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide.     

Synthesis of (±)-licarin-B

The synthesis of (±)-licarin-B, a neolignan of Licaria aritu Ducke (Lauraceae), was achieved by pyrolysis of 3-hydroxy-3-piperonyl-1-propyl-2-methoxy-4-(E)-propenylphenyl ethers.     

Synthesis of (–)-Muricatacin

The synthesis of (–)-muricatacin starting from 1-bromododecane and 2-pentyn-l-ol is described. 2-Pentadecyn-1-ol (4), which was prepared from 1-bromododecane (2) and 2-pentyn-1-ol (3), was converted to epoxy alcohol 6 through a two-step reaction sequence, 6 being successively submitted to tosylation, iodination, chain extension with tert-butyl lithioacetate, and acid-catalyzed cyclization to give (–)-muricatacin (1a). Recrystallization afforded optically pure 1a.     

Synthesis of (±)-Xanthoxins

The enzymatic properties of P2-2 enzyme were determined by using cells of M. radiodurans. The enzyme was: most active at 60°C incubation temperature, stable at 40°C in neutral buffer, and inactivated by heating at 80°C for 15min. Maximal lytic activity occurred at pH 8.5 in Tris-HCl buffer. The range of enzyme stability was between pH 5.5 and 8. Bivalent metal ions, p-chloromercuribenzoate and monoiodo acetate inhibited lytic activity. The molecular weight was estimated to be 16,000 daltons by gel filtration on Sephadex G-75. The enzymatic digestion of peptidoglycans from the cell walls of M. radiodurans and M. lysodeikticus liberated free amino groups, but neither reducing groups nor N-acetylhexosamine, indicating that the enzyme was an endopeptidase. From analysis of the N-terminal amino acids of the digests, it is suggested that the P2-2 enzyme cleaves the peptide bond at the carboxyl group of D-alanine in peptidoglycan.     

Synthesis of (±)-Hydroxytremetone

(±)Hydroxytremetone (III) has been synthesized from 2-(α-hydoxyisopropyl)-6-hydroxycoumaran (V b) via its O-acetate V c by dehydration with phosphorus tribromide in pyridine solution, followed by acylation with a mixture of trifluoroacetic anhydride and acetic acid. Isohydroxytremetone (IX b) was also synthesized.     

Synthesis and evaluation of β-carboline derivatives as inhibitors of human immunodeficiency virus

A series of β-carboline derivatives were synthesized by utilizing aromatization and chemoselective alkylation method recently reported from our laboratory. Synthesized derivatives were evaluated for anti-HIV activity in human CD4+ T cell line (CEM-GFP) infected with HIV-1 NL_4.3 virus. 1-Formyl-β-carboline-3-carbxylic acid methyl ester (15) showed inhibition of human immunodeficiency virus at IC₅₀ = 2.9 μM.     

Synthesis and identification of α-cyano bis(indolyl)chalcones as novel anticancer agents

Microwave-assisted synthesis of 23 α-cyano bis(indolyl)chalcones (6a–w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC₅₀ = 0.8 μM). In a preliminary mechanism of action studies some α-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.     

Synthesis of new thiazolo-pyrrolidine–(spirooxindole) tethered to 3-acylindole as anticancer agents

Anticancer therapeutics with profiles of high potency, low toxicity, and low resistance is of considerable interest. A new series of functionalized spirooxindole linked with 3-acylindole scaffold is reported, starting from chalcones derived from 3-acetyl indole with isatin, and l-4-thiazolidinecarboxylic acid. The reactions proceeded regioselectivity, stereoselectivity, without side products in high yield (71–89%). The new spirooxindole hybrids have been evaluated in vitro for their antiproliferative effects against colon cancer (HCT-116), hepatocellular carcinoma (HepG2) and prostate cancer (PC-3). The selectivity of their activity was evaluated. Some of the synthesized compounds showed considerable anticancer activities. Compound 4k proved to retain a high cytotoxic activity and selectivity against colon cancer cells HCT-116 (IC₅₀ = 7 ± 0.27 µM, SI: 3.7), and HepG2 (IC₅₀ = 5.5 ± 0.2 µM, SI: 4.7) in comparison to (IC₅₀ = 12.6 ± 0.5, SI: 0.4 and 5.5 ± 0.3 µM, SI: 0.9, respectively). Compound 4k was less active (IC₅₀ = 6 ± 0.3 µM, SI: 4.3) than cisplatin (IC₅₀ = 5 ± 0.56 µM, SI: 1.0) but showed greater selectivity towards prostate cancer cells PC-3 in comparison to cisplatin. The details of the binding mode of the active compounds were clarified by molecular docking. Ligand Efficiency (LE) and Ligand Lipophilic Efficiency (LLE) were evaluated and revealed that compound 4k had acceptable value.