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A transition-metal-free postmodification of the Groebke-Blackburn-Bienayme (GBB) reaction for the synthesis of spiro[chromene-imidazo[1,2-a]pyridin]-3'-imine was discovered. The unusual transformation represents the first example of activation and the reaction of the imidazole carbon atom. In this postcondensational modification, KOt-Bu acts as a base, which, after the isomerization of an alkyne moiety to allene, causes the next unique nucleophilic reaction of the imidazole carbon atom that results in spirocyclic structures. The proposed reaction mechanism was confirmed based on the DFT calculations.

In this project, a moderately efficient approach to multisubstituted N-(isoquinolin-1-yl)sulfonamide derivatives was illustrated, utilizing ortho-alkynylbenzaldoximes and zwitterionic ketenimine salts in a tandem reaction catalyzed by silver oxide. The oxophilicity of Ag2O, along with its nature as Lewis acid, pave the way for a smooth [3 + 2] cycloaddition between isoquinoline N-oxides and ketenimine species, which is a key step in this reaction. DFT calculation suggests that 1,3-dipolar cycloaddition of nitrone and ketenimine proceeds through a selective stepwise mechanism.

This paper describes a diversity-oriented approach to the formation of 3-oxoisoindoline-1-carboxamide derivatives utilizing the potential of the nitro group as a directing group. The reaction proceeds through a novel class of post-transformation reactions through a sequential four-component Ugi reaction/oxidative nucleophilic substitution of hydrogen. The 3-oxoisoindoline-1-carboxamide derivatives were synthesized in the presence of a base under mild reaction conditions with high regio- and chemoselectivity. The aerobic oxidation, high bond-forming efficiency, high atom economy, and good to excellent yields are the main advantages of this approach.

β-secretase 1 (BACE1) plays a pivotal role in the pathology of Alzheimer׳s disease via accumulation beta amyloid in the brain. In this context, identifying new scaffolds that block BACE1 is of great importance despite all pharmacokinetic drawbacks that peptide-like structures have. Here, we report a new core structure based on novel unusual amino acids by substituting phenyl amide group in the P1 position and small alkyl groups in the P1′ site that results in the formation of new biological active peptides in micromolar level. Three different scaffolds were designed based on docking studies to efficiently interact with critical Asp32 residue in the active site of BACE1 and incorporated in peptides synthesis by Fmoc solid-phase peptide synthesis (SPPS) methodology to achieve desired compounds in good yield. The inhibitory activity of all synthesized peptides was examined by FRET-based enzymatic assay. The peptide 7 showed the best inhibitory activity with IC50 = 98.14 µM. Results of this investigation revealed that utilizing unusual amino acids as building blocks for the synthesis of peptidomimetics would be an option for the development and optimization of pharmaceutical structures. The inhibition of β-secretase 1 (BACE1) is potentially important approach to treatment of Alzheimer disease (AD). Novel series of peptides coupled to the new unusual amino acids scaffold were investigated as BACE1 inhibitors in this study. The design of these peptides was mostly affected by OM00-3. Based on observations, in good agreement between BACE-1 inhibition assessment and docking methodology, peptide 7 was the most potent compound between all and could be the basis of future studies.

Timely detection of amyloid aggregations has a critical role in the treatment of degenerative nervous system disorders such as Alzheimer’s, Parkinson’s disease and systemic amyloidosis. Thioflavin T (ThT) is a dye considered for the detection of amyloids. However, ThT cannot cross the blood–barrier barrier due to positive charge and low lipophilicity. In the present study, a variety of 2-benzylidene-1,3-indandione derivatives 5a–5j were synthesized as neutral fluorescence probe candidates for identification of amyloid. Among these compounds, only compound 2-(2-hydroxybenzylidene)-1,3-indandione 5a was selected for further examination, because its fluorescence intensity showed the significant increasing upon interaction with amyloid aggregates. The compound 5a was compared to standard and conventional probe such as ThT. The compound 5a was excited at its specified wavelength, and the fluorescence emission signal was recorded in the presence of different concentrations of the protein/peptide (amyloid aggregated and native protein). According to the obtained results, it can be seen that 2-(2-hydroxybenzylidene)-1,3-indandione 5a selectively and specifically bind to amyloid fibrils, such as ThT. Due to the neutrality of electrical charge and high lipophilicity coefficient of the synthesized compound 5a, it is possible for it to cross from the blood–brain barrier. Our results show that this synthetic derivative can be considered as a suitable probe to detect in vitro amyloid aggregations.

An efficient approach for the synthesis of pyrazolopyridines containing the aminochromane motif through a base-catalyzed cyclization reaction is reported. The synthesis was carried out through a three-component reaction of (arylhydrazono)methyl-4H-chromen-4-one, malononitrile, primary amines in the presence of Et3N at room temperature. However, carrying out the reaction under the same conditions without base led to a fused chromanyl-cyanopyridine. High selectivity, high atom economy, and good to high yields in addition to mild reaction conditions are the advantages of this approach.

Arg-Gly-Asp (RGD) peptides represent the most outstanding recognition motif involved in cell adhesion that binds to the αv β3 integrin, which has been targeted for cancer therapy. Various RGD-containing peptides and peptidomimetics have been designed and synthesized to selectively inhibit this integrin. In this study, the synthesis of RGD-based peptides through the incorporation of the short bioactive peptide Phe-Ala-Lys-Leu-Phe (FAKLF) at the C and N termini of RGD has been achieved by using a solid-phase peptide synthesis approach. The peptides were purified by means of preparative RP-HPLC and their structures were confirmed through HRMS (ESI). The MTT assay revealed that the RGD and FAKLF peptides inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, with IC50 values of 3000 and 500 ng mL-1 , respectively. Interestingly, a drastic improvement was observed in the antiproliferative activity of the combined structures of the FAKLFRGD and RGDFAKLF peptides, leading to IC50 values of 200 and 136.7 ng mL-1 , respectively. Meanwhile, based on apoptosis results, the potential of peptides to induce apoptosis, in accordance with their antiproliferative activity, indicated that the RGD and FAKLF peptides, and the peptides synthesized based on their combinations induced cell apoptosis in a dose-dependent manner followed by inhibition of the proliferation of endothelial cells. Moreover, the incorporation of d-leucine increased the induction of apoptosis by these peptides.

Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. In present study, the influence of curcumin and its degradation products (DPs) on the amyloid aggregation of Tau protein and the related PHF6 peptide were investigated. We provided experimental/theoretical evidence for suppressing effects of the compounds on the amyloid formation using far-UV CD as well as AFM, XRD and docking techniques and showed that the parent curcumin displayed stronger inhibition effect against Tau fibril aggregation. The obtained results suggest that the curcumin/DPs binding sites on the Tau molecule are likely to be the same, and provide a good structural basis to explain the efficient aggregation suppressing behavior of the curcumin, compared to the DPs. So, developing more stable curcumin nanoparticle formulations with improved curcumin bioavailability are of great importance. Curcumin's multi-functionality is also highly significant for the therapeutic application of this natural compound against various human diseases.

An efficient metal-free approach for the synthesis of N-coumaryl amino acids and the first one-step synthesis of 4-hydrazinocoumarin from 4-hydroxycoumarin was developed. The nucleophilic addition of amino acid methyl esters to 4-tosylcoumarins produced a series of 4-N-α-coumaryl amino acids in good to excellent yields without racemization. The antioxidant activities of the synthesized compounds were investigated using DPPH and FRAP methods. 4-Hydrazinocoumarin and N-coumaryl tyrosine had the best antioxidant activity. The antimicrobial activities of the compounds against Gram-positive was stronger than Gram-negative. 4-Hydrazinocoumarin showed the best antibacterial effect.

4,4′-bipyridinium sulfonic acid chloride {[SO3H-4,4′-bipyridine-SO3H]Cl2}, as a new solid acid, was synthesized and fully characterized by fourier transform infrared spectroscopy (FT-IR), X-ray diffraction analysis (XRD), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDX), thermal gravimetric analysis (TGA), 1H NMR and 13C NMR as well as mass spectra. [SO3H-4,4′-bipyridine-SO3H]Cl2 was successfully applied as a new and efficient catalyst for the preparation of amidoalkyl phenols and bis amidoalkyl phenols as a new category of compounds at 110 °C under solvent-free conditions.

Recent studies have reported the potential of pyrano-pyridine compounds in inhibiting cell growth and apoptosis induction in cancer cells. Here, we investigated the effect of new pyrano-pyridine derivatives on proliferation, oxidative damages, and apoptosis in K562 leukemia cells. Among different tested compounds, we found 8-(4-chlorobenzylidene)-2-amino-4-(4-chlorophenyl)-5, 6, 7, 8-tetrahydro-6-phenethyl-4H-pyrano-[3,2-c]pyridine-3-carbonitrile (4-CP.P) as the most effective compound with IC50 value of 20 μM. Gel electrophoresis, fluorescence microscopy, and flow cytometry analyses indicated the apoptosis induction ability of 4-CP.P in K562 cells. Further analyses revealed that 4-CP.P induces significant increase in cellular reactive oxygen species production, lipid peroxidation, protein oxidation, and total thiol depletion. Interestingly, while 4-CP.P significantly increased the activity of superoxide dismutase, it reduced the catalase activity in a time-dependent manner. These data propose that 4-CP.P treatment causes free radicals accumulation that ultimately leads to oxidative stress condition and apoptosis induction. Therefore, we report the 4-CP.P as a novel, potent compound as a chemotherapeutic agent in cancer treatment.

We were interested in the design and synthesis of novel bioisosteric analogues of leuprolide acetate containing the oxadiazole moiety at the C- or N-terminal of the peptide. An efficient approach for the synthesis of 2-amino-1,3,4-oxadiazoles through the reaction of hydrazide with ammonium thiocyanate and desulfurization reaction of the thiosemicarbazides using different coupling reagents was employed. These compounds are bioisosteres of the amide bond. Furthermore, the coupling of 2-amino-1,3,4-oxadiazoles at the C-terminal of leuprolide analogues was carried out, using a coupling reagent in the solution phase. On the other hand, the addition of a 2-amino-1,3,4-oxadiazole to the N-terminal of the peptide sequence was carried out through the reaction of the 2-amino-1,3,4-oxadiazole with succinic anhydride that led to the formation of a carboxylic acid moiety. Addition of the synthesized oxadiazole containing carboxylic acid to the peptide sequence was performed using a coupling reagent and on the surface of the resin. The synthesized peptides containing the oxadiazole moiety at the C- or N-terminal of the peptide sequence are peptidomimetics of leuprolide acetate. All of the synthesized peptides were purified using preparative HPLC and their structures were confirmed using HR-MS (ESI).

The tripeptide Tyr–Gly–Ser and a series of conjugations to coumarin, cinnamic and gallic acid were synthesized in salt form and their antioxidant and antimicrobial activities were investigated. The N-connecting hydroxycoumarin, cinnamic and gallic acid derivatives to peptides and the use of BBr3 as a demethylating agent for peptides was reported. Their activities were investigated based on the conjugated moiety structures. Studies of their activities showed that conjugated tripeptides 7,8-dihydroxycoumarin-peptide (17), caffeic acid-peptide (22) and gallic acid-peptide (28) were found to be superior to ascorbic acid with respect to their antioxidant activity, and 12, 14, 24, and 25 exhibited the most antimicrobial activity in the series compared to amoxicillin. Additionally, the incredible florescence intensity and brightness of 17 in water and DMSO, compared to other synthesized compounds, qualified this peptide as a suitable probe in the human body.

Scaffold-generating transformations of the Groebke-Blackburn-Bienayme (GBB) reaction products are reviewed. The literature cases were grouped according to the reactions employed as the post-condensational event as follows: lactamization, intramolecular arylation, intramolecular Michael addition, cyclizations involving an alkyne moiety and miscellaneous. Although synthetic strategic based on the post-GBB modifications have been exploited to a lesser extent compared to post-Ugi modifications, the interest of researchers to the GBB reaction as the platform for designing new polycyclic scaffolds has been on the rise in the past decade.

An efficient approach for the synthesis of pyranoquinolines through the indium-catalyzed activation of alkynes is reported. Intramolecular hydroamidation of alkynes can proceed through alkyne activation by indium(III) and then 6-exo-dig cyclization, leading to a fused pyran ring with high selectivity, high atom economy, and good to excellent yields. The cyclization was accomplished through the oxygen, not the nitrogen, of the amide functional group.

An efficient synthesis of quinazolinone sulfonamide derivatives through four-component reaction is reported. The four-component reaction is based on the reaction of isatoic anhydride, hydrazine hydrate, saccharin, and aromatic aldehydes in the presence of nano-catalyst SBA-Pr-SO3H. Saccharin was used as a novel source of sulfonamide moiety in this reaction.

Context: Curcumin, a naturally occurring polyphenol, has been extensively studied for its broad-spectrum anticancer effects. The potential benefits are, however, limited due to its poor water solubility and rapid degradation which result in low bioavailability on administration. Objectives: This study encapsulates curcumin in nanoliposomes including an integrin-homing peptide combined with a C end R neuropilin-1 targeting motif for targeted delivery and receptor-mediated internalization, respectively. Materials and methods: The linear GHHNGR (Glycine–Histidine–Histidine–Asparagine–Glycine–Arginine) was synthesized through F-moc chemistry on 2-chlorotrityl chloride resin and conjugated to oleic acid. The lipoyl-peptide units were then co-assembled with lecithin and 0–75 mole % Tween-80 into liposomes. Curcumin was passively entrapped using a film hydration technique and its degradation profile was examined within seven consecutive days. The cytotoxic effects of the curcumin-loaded liposomes were studied on MCF-7 and MDA-MB-468, during 24 h exposure in MTT assay. Results: The maximum curcumin entrapment (15.5% W/W) and minimum degradation (

Despite the attention given to the treatment of multiple sclerosis (MS), still no certain cure is available. The main purpose of MS drugs is acting against neuroinflammation which underlies the pathology of MS. Neuroinflammation is associated with endoplasmic reticulum (ER) stress that mediates neural apoptosis. In the present study, we hypothesized that the tetrapeptide N-acetyl-ser-asp-lys-pro (Ac-SDKP) with the previously described anti-fibrotic effects might have anti-inflammatory, anti-oxidative and anti-ER stress roles in the hippocampus. We used myelin oligodendrocyte glycoprotein (MOG) to induce experimental autoimmune encephalomyelitis (EAE), a widely-accepted animal model of MS, in C57BL/6 mice. The protein levels of ER stress-related molecules including caspase-12, C/EBP homologous protein (CHOP), and protein disulfide isomerase (PDI) in the hippocampus were examined by immunoblotting. Hence, reactive oxygen species (ROS) production, lipid peroxidation and antioxidant capacity of the hippocampus were studied. Moreover, hippocampal morphology changes, leukocytes infiltration, and the levels of IL-6 and IL-1β pro-inflammatory cytokines were evaluated. Our results displayed that Ac-SDKP down regulates caspase-12 and CHOP expression in the hippocampus-resident oligodendrocytes of EAE mice. Further, treatment with Ac-SDKP decreased oxidative stress markers and caspase-3 activation in the hippocampus of EAE mice. According to our findings, Ac-SDKP showed beneficial effects against ER stress and oxidative stress in addition to inflammation in the hippocampus of EAE mice. The present study provides the basis for further research on the therapeutic applications of Ac-SDKP to reduce ER stress and oxidative stress-induced apoptosis in neurodegenerative disorders.

The synthesis of modified RGD peptides and their conjugation to the pyrazine skeleton at their N-terminus are described. To modify and alter the RGD sequence, short bioactive peptides such as FALKF and NGRG were added to the RGD N-terminus. Moreover, the in vitro investigation of these modified peptides, by a cell adhesion assay using the melanoma cell lines M21 expressing alpha(v)beta(3) and M21L lacking alpha(v) expression, was made and interestingly peptide 4 containing the pyrazine moiety with the linear RGDFAKLF sequence gave the best IC50 value with M21 and all the peptides were unable to bind to M21L, demonstrating the selective recognition to alpha(v)beta(3). The results showed pyrazine plays an essential role in the activity of the peptides. From these results, we can suggest that these peptides can affect cancer cells by abrogation of cell adhesion (cell migration).

SBA-Pr-SO3H was found as a nanocatalyst for the cyclocondensation of isatoic anhydride, aromatic aldehydes and γ-amino acids (gabapentin and baclofen) to access novel 2-aryl-4-quinazolinone γ-amino acid derivatives in solvent-free reaction conditions in good to high yields. Compared to the classical approaches, this process is a simple, highly yielding, time saving, and environmentally friendly method.

Many patients worldwide suffer from cardiovascular diseases for which an underlying factor is thrombosis. Devising a molecular imaging technique for early detection of thrombosis in a clinical setting is highly recommended. Because fibrin is a major constituent of clots and is present in all types of thrombi but absent in circulation, it is a highly specific and sensitive target for molecular imaging of thrombi. It is assumed that cyclization of peptides will improve the receptor binding affinity and stability of the peptide. In the present study, we have developed linear and cyclic fibrin-binding peptides for thrombus imaging and compared their biological properties. Linear HYNIC-GPRPP and cyclic HYNIC-CGPRPPC peptides were synthesized using a standard Fmoc strategy and radiolabeled with Tc-99m. The stability of the radiolabeled peptides in human plasma and their affinity for fibrin and blood clots were determined. Blood clearance and biodistribution were evaluated in rats and mice, respectively. The peptide with the highest affinity was injected to a live rabbit femoral thrombosis model, and scintigraphic images were obtained. In vitro studies show that peptides are stable in human plasma and have a high affinity for human fibrin. They also demonstrated fast blood clearance in rats and high thrombus uptake in the Balb/c mice femoral thrombosis model. Femoral thrombosis was visualized 30 min postinjection of cyclic peptide in a live rabbit model using single photon emission computed tomography (SPECT)/X-ray computed tomography. The results indicate that the cyclic peptide is a promising agent for molecular imaging of fibrin using SPECT.

Mesoporous silica SBA-15 functionalized with 8-hydroxyquinoline-5-sulfonic acid (HQS-SBA-15) was used as a new recyclable nanocatalyst for the one-pot synthesis of 2-thiohydantoin derivatives under solvent-free conditions. The catalyst exhibited excellent recyclability at least for 3 times with a high catalytic activity.

Ghullam Reza Barbari,1 Farid Dorkoosh,1 Mohsen Amini,2 Nika Bahari Javan,1 Mohammad Sharifzadeh,3 Fateme Atyabi,1 Saeed Balalaie,4 Niyousha Rafiee Tehrani,5 Morteza Rafiee Tehrani1 1Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Chemistry, Khajeh Nasir Toosi University, Tehran, Iran; 5School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Background: Despite years of experience and rigorous research, injectable insulin is the sole trusted treatment method to control the blood glucose level in diabetes type 1 patients, but injection of insulin is painful and poses a lot of stress to the patients, especially children, therefore, development of a non-injectable formulation of insulin is a major breakthrough in the history of medicine and pharmaceutical sciences. Methods: In this study, a novel peptide grafted derivative of chitosan (CPP-g- chitosan) is synthesized and its potential for oral delivery of proteins and peptides is evaluated. Drug-loaded nanoparticles were developed from this derivative using ionic gelation method with application of sodium tripolyphosphate (TPP) as a cross-linking agent. Human insulin was used as the model protein drug and release kinetic was studied at gastrointestinal pH. Finally the developed nanoparticles were filled into very tiny enteric protective capsules and its effects on blood glucose level are evaluated in laboratory animals. Results: Presence of the positively charged cell-penetrating peptide moiety in the structure of chitosan polymer had slight inhibitory effects on the release of insulin from the nanoparticles in simulated gastric fluid (pH 1.2) comparing to native chitosan. The nanoparticles were positively charged in gastrointestinal pH with size ranging from 180 nm to 326 nm. The polypeptide grafted to chitosan is a novel analog of Penetratin, presenting both the hydrophilic and hydrophobic characteristics altering the release behavior of the nanoparticles and significantly increase the absorption of insulin into the rat epithelium comparing to nanoparticles from simple chitosan. In-vivo results in diabetic rat proved that this nanoparticulate system can significantly lower the blood glucose levels in diabetic rats and remain effective for a duration of 9–11 hours. Conclusion: The results indicate that nanoparticles developed from this new peptide conjugated derivative of chitosan are very promising for oral delivery of proteins and peptides. Keywords: peptide grafted, oral delivery, cell-penetrating peptide, penetratin

This chapter summarizes multicomponent reactions based on amino acids and their derivatives in the heterocycles chemistry. It provides the classification of multicomponent reactions of amino acids and derivatives according to the ring size of heterocyclic compounds in five categories: Four-membered heterocycles, Five-membered heterocycles, Six-membered heterocycles, Seven-membered heterocycles and fused heterocycles. Chiral β-amino acids constitute interesting building blocks for the synthesis of chiral β-lactams. One of the recent reports on this concept is the synthesis of conformationally constrained tricyclic β-lactam enantiomers through Ugi four-center, three-component reactions of a monoterpene-based β-amino acid. The chapter discusses the synthesis of β-lactam peptidomimetics through Ugi MCR. It describes the stereoselective synthesis of fully substituted tetrahydrofurans through 1, 3-dipolar cycloaddition with cinnamaldehydes. The chapter focuses on the occurrence of an oxidative pathway mediated by highly reactive 2(1H)pyrazinoium salts leads to the first direct preparative method for the straightforward assembly of diversely decorated pyrazin-2,3-(1H,4H)-diones.

Ghullam Reza Barbari,1 Farid Abedin Dorkoosh,1 Mohsen Amini,2 Mohammad Sharifzadeh,3 Fateme Atyabi,1 Saeed Balalaie,4 Niyousha Rafiee Tehrani,5 Morteza Rafiee Tehrani1 1Department of Pharmaceutics, 2Department of Medicinal Chemistry, 3Department of Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, 4Department of Chemistry, Khaje Nasiroddin University, 5Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Abstract: A simple and reproducible water-in-oil (W/O) nanoemulsion technique for making ultrasmall (

A series of novel pseudopeptides contained coumarin skeleton were synthesized through the Ugi-four-component reaction. The 3-substituted coumarin-3-carboxamides were formed through reaction of benzaldehyde derivatives, anilines, coumarin-3- carboxylic acid and isocyanides with high yields and high bond-forming efficiency at room temperature. These novel amidated cou- marins exhibit brilliant fluorescence in range of 535�547 nm in chloroform.

A series of 3-cyano-2-pyridone derivatives were synthesized by one-pot four-component condensation reaction involving a benzaldehyde derivative, alkyl cyanoacetate, acyclic or cyclic ketones, and ammonium acetate in reflux condition. The X-ray structure of the products 5a and 5d confirm symmetric dimers via hydrogen bonding interactions between individual pyridine molecules showing, in addition, also π–π stacking interactions.

The one-pot three-component reaction of primary and secondary amines, carbon disulfide and β-nitrostyrene derivatives in neat condition at room temperature afforded functionalized dithiocarbamate derivatives in good to high yields. High bond-forming efficiency and easy work-up are advantages of this reaction. In vitro antimicrobial activities of synthesized compounds were studied against four Gram-positive bacteria, four Gram-negative bacteria and four fungi. The screening for the antimicrobial activity was performed by twofold serial dilution technique. Notably, some synthesized compounds displayed comparable or even better antibacterial and antifungal activities against some tested strains than the reference drugs ampicillin, streptomycin and amphotericin B, respectively. A series of novel dithiocarbamates 4a-j have been synthesized via three-component reaction and compared pharmacologically concerning their antimicrobial and antibacterial activities as well as antifungal activity .

Pro-apoptotic peptides induce intrinsic apoptosis pathway in cancer cells. However, poor cellular penetration of the peptides is often associated with limited therapeutic efficacy. In this report, a series of peptide-gold nanoparticle platforms were developed to evaluate the anticancer activity of a novel alpha-lipoic acid-peptide conjugate, LA-WKRAKLAK, with respect to size and shape of nanoparticles. Gold nanoparticles (AuNPs) were found to enhance cell internalization as well as anticancer activity of the peptide conjugates. The smaller nanospheres showed a higher cytotoxicity, morphological change and cellular uptake compared to larger nanospheres and nanorods, whereas nanorods showed more hemolytic activity compared to nanospheres. The findings suggested that the anticancer and biological effects of the peptides induced by intrinsic apoptotic pathway were tuned by peptide-functionalized gold nanoparticles (P-AuNPs) as a function of their size and shape.

An efficient strategy for the one-pot syntheses of indolo[1,2-a]quinoxalinones catalyzed by CuI have been developed. The procedures combine the Ugi four-component reaction of aldehydes, 2-iodoaniline, 2-indole carboxylic acid, and isocyanides followed by the copper-catalyzed intramolecular N-arylation of the Ugi product in one-pot procedure, which afford the desired products in good to very good yields.

The three-component reaction of primary amines, dialkyl acetylenedicarboxylates and β-nitrostyrene derivatives in the presence of Iron(III) chloride afforded 1,2,3,4-tetra-substituted pyrroles in high yields. These reactions could precede via domino Michael addition/cyclization process.

We wish to report a mild and efficient Crossed-Aldol reaction for the synthesis of α, ?-bis(substituted-ben- zylidene)cycloalkanones in the presence of catalytic amounts of covalently anchored sulfonic acid onto sil- ica gel under heterogeneous and solvent-free conditions. The present methodology offers several advantages such as excellent yields, simple procedure and work up steps, short reaction times and easy recovery of the catalyst. We have also demonstrated that the catalyst can be reused successfully.

The domino Knoevenagel hetero-Diels–Alder reaction of the O-propargylated salicylaldehydes and 4-hydroxycoumarin leads to pyrano[2,3-c]coumarins 3 and pyrano[2,3-c]chromones 4 in high yield in the presence of CuI as a Lewis acid. In all cases, the reaction was shown to exhibit high regioselectivity and form product 3 as main product.

A new method for the preparation of tetracyclic uracils (oxa-helicene) 4 was developed. The intramolecular hetero-Diels–Alder reaction of 1-oxa-1,3-butadiene 3 and an unactivated alkyne in the presence of CuI led to tetracyclic uracils 4 in aqueous media with good yields. The 1-oxa-1,3-butadiene 3 was prepared through Knoevenagel reaction of O-propargylated salicylaldehyde derivatives and barbituric acid or 1,3-dimethylbarbituric acid.

Esterification of carboxylic acids with alcohols and phenols by using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in the presence of triethylamine as a base proceeded smoothly under mild conditions to afford the corresponding esters in good to high yields in acetonitrile at room temperature.

The synthesis of amides and phenylhydrazides from the reaction of corresponding carboxylic acids with primary aliphatic, aromatic amines or phenylhydrazine in the presence of triethylamine or diisopropylethyl amine as a base using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) proceeds smoothly under mild conditions to afford the corresponding amides or phenylhydrazides in good to high yields in ethyl acetate at room temperature.

A novel and convenient method has been developed for the synthesis of thiol esters from the corresponding carboxylic acids and thiols at room temperature using 2-(1H-benzotriazole-1-yl)1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as the coupling reagent.

Knoevenagel condensation of various aromatic and heteroaromatic aldehydes with active methylene compounds like methyl and ethyl cyanoacetate, malononitrile, and cyanoacetamide proceeds smoothly with stirring in water in the presence of 4 mol% of diammonium hydrogen phosphate. The reactions were carried out at room temperature in short periods with very simple workup procedure and good to high yields.

Three-component condensation of benzaldehyde derivatives, alkyl cyanoacetates and thiourea in the presence of piperidine in reflux condition provides a direct route to piperidinium 6-aryl-5-cyano 2-thiopyrimidonate salts in good yields. These reactions were also carried out under microwave irradiation. The yields of products under the microwave condition were better as compared to the reflux media. The acidification of these ionic forms resulted in the formation of 6-aryl-5-cyano-2-thiopyrimidone derivatives. The X-ray structures of the ionic forms (4, 5, and 7) show that there are anionic thiopyrimidinone skeletons hydrogen bridged with piperidinium cations.

Three-component condensation of phenylglyoxal, alkyl acetoacetates or acetylacetone and urea proceeds smoothly, catalyzed by ZnCl2, to afford the corresponding new 3,4- dihydropyrimidinones. This reaction is also catalyzed by AlCl3:ZnCl2 (3:1) under microwave irradiation in solvent-free conditions. One-pot three-component condensation of dimethyl urea, acetylacetone or alkyl acetoacetate and phenylglyoxal catalyzed by ZnCl2 or AlCl3:ZnCl2 (3:1) yields new multisubstituted imidazoline-2-ones derivatives. Structures of products were studied by X-ray crystallographic data. The reaction of phenylglyoxal, urea and β-ketoesters in the presence of hydrochloric acid produces only 5-phenylhydantoins.

A series of 3-cyano-2-pyridone derivatives were synthesized by one-pot four-component condensation reaction involving a benzaldehyde derivative, alkyl cyanoacetate, acyclic or cyclic ketones, and ammonium acetate in reflux condition. The X-ray structure of the products 5a and 5d confirm symmetric dimers via hydrogen bonding interactions between individual pyridine molecules showing, in addition, also π–π stacking interactions.

The three-component condensation of benzaldehyde derivatives, alkyl propiolates, and primary amines catalyzed by silica gel, zeolite HY, montmorillonite K-10, and acidic alumina under microwave irradiation gave N-substituted 4-aryl-1,4-dihydropyridines in short reaction times and high yields. The best results were obtained with silica gel.

Polyfunctional 1,4-disubstituted piperazines were successfully synthesized stereoselectively via a one-pot, five-component Ugi/nucleophilic addition reaction sequence. Regio- and stereo-selective addition of piperazine to an activated alkyne under catalyst-free conditions and high yields of products are advantages of this method.

A novel and efficient protocol is developed for the synthesis of various spiro-2-amino pyrimidinones via the three-component condensation of alkyl cyanoacetates, guanidinium carbonate and N-substituted 4-piperidinones in ethanol at reflux. High yields, neutral conditions, and short reaction times are advantages of this method.

The four-component reaction of dimethyl acetylenedicarboxylate (=dimethyl but-2-ynedioate; DMAD), aromatic aldehydes, and malononitrile (=propanedinitrile) leads to polyfunctionalized 1,4-dihydropyridine derivatives. The reaction proceeds at room temperature and in the presence of a catalytic amount (20%) of (NH4)2HPO4 as a base in aqueous media.

Water as a medium accelerates many organic reactions such as Claisen rearrangement, Aldol and Michael condensations, addition of nucleophi les to carbonyl compounds I . Recently, microwave dielectric heating is rapidly becoming an established procedure in organic synthesis in organic solvents2 or dry media3. 1 ,3,5-Tri-N-substituted-hexahydro-2-oxol ,3, 5-triazines (triazones) group have been known for many years in l iteratures4-6. Triazones are used for protection of amino groupS7.8, as wel l as for the synthesis of polyamines9, polyfunctional amino acids and amino a\Cohols7. Many water soluble triazones are used as ferti l izers 1 0 .

The three-component condensation of benzaldehyde derivatives, alkyl propiolates, and primary amines catalyzed by silica gel, zeolite HY, montmorillonite K-10, and acidic alumina under microwave irradiation gave N-substituted 4-aryl-1,4-dihydropyridines in short reaction times and high yields. The best results were obtained with silica gel.

A new method for the preparation of tetracyclic uracils (oxa-helicene) 4 was developed. The intramolecular hetero-Diels–Alder reaction of 1-oxa-1,3-butadiene 3 and an unactivated alkyne in the presence of CuI led to tetracyclic uracils 4 in aqueous media with good yields. The 1-oxa-1,3-butadiene 3 was prepared through Knoevenagel reaction of O-propargylated salicylaldehyde derivatives and barbituric acid or 1,3-dimethylbarbituric acid.

Diammonium hydrogen phosphate, (NH 4 ) 2 HPO 4 (DAHP), efficiently catalyzes the one-pot, three-component reaction of an aromatic aldehyde, malononitrile and 4-hydroxycoumarin in aqueous media under mild conditions at room temperature, to afford the corresponding dihydropyrano[ c ]chromenes in high yields. ( S )-Proline has also been used as another neutral catalyst for this reaction at reflux.