Rational peptide design for targeting cancer cell invasion.

Cell invasion is an important process in cancer progression and recurrence. Invasion and implantation of cancer cells from their original place to other tissues, by disabling vital organs, challenges the treatment of cancer patients. Given the importance of the matter, many molecular treatments have been developed to inhibit cancer cell invasion. Because of their low production cost and ease of production, peptides are valuable therapeutic molecules for inhibiting cancer cell invasion. In recent years, advances in the field of computational biology have facilitated the design of anti-cancer peptides. In our investigation, using computational biology approaches such as evolutionary analysis, residue scanning, protein-peptide interaction analysis, molecular dynamics, and free energy analysis, our team designed a peptide library with about 100 000 candidates based on A6 (acetyl-KPSSPPEE-amino) sequence which is an anti-invasion peptide. During computational studies, two of the designed peptides that give the highest scores and showed the greatest sequence similarity to A6 were entered into the experimental analysis workflow for further analysis. In experimental analysis steps, the anti-metastatic potency and other therapeutic effects of designed peptides were evaluated using MTT assay, RT-qPCR, zymography analysis, and invasion assay. Our study disclosed that the IK1 (acetyl-RPSFPPEE-amino) peptide, like A6, has great potency to inhibit the invasion of cancer cells.

Chemoselective Reduction of α,ß-Unsaturated Carbonyl Compounds via a CS2/t-BuOK System: Dimethyl Sulfoxide as a Hydrogen Source.

A novel and practical approach to access saturated ketones from unsaturated ketone derivatives via a CS2/t-BuOK system in dimethyl sulfoxide (DMSO) is reported. The in situ generation of xanthate salt through the reaction of carbon disulfide and potassium tert-butoxide is essential to this transformation. Deuterium-labeling experiments demonstrated that DMSO can act as a hydrogen donor.

Mn-Mediated Direct Regioselective C-H Trifluoromethylation of Imidazopyridines and Quinoxalines.

A simple and highly efficient strategy has been developed for direct C-H trifluoromethylation at C-3 of imidazopyridines and C-8 of quinoxalines with readily available Langlois reagent through KMnO4/AcOH system. This protocol showed broad substrate scope and afforded moderate-to-excellent yields of both products. It is the first report that the functionalization of quinoxalines occurred regioselectively at the C-8 position of quinoxalines. Mechanistic studies revealed that reaction proceeded via radical pathway.

Synthesis of Polysubstituted Pyrimidines through Palladium-Catalyzed Isocyanide Insertion to 2H-Azirines.

The domino process of the palladium-catalyzed coupling reaction of isocyanides with 2H-azirine provides various tetrasubstituted pyrimidines via one C-C bond and two C-N bond formations with satisfactory yields. The title compounds are obtained with good functional group tolerance, high atom economy, and broad substrate scopes.

Development of a Novel Histatin-5 Mucoadhesive Gel for the Treatment of Oral Mucositis: In Vitro Characterization and In Vivo Evaluation.

Antimicrobial peptides have appeared to be promising candidates for therapeutic purposes due to their broad antimicrobial activity and non-toxicity. Histatin-5 (Hst-5) is a notable salivary antimicrobial peptide that exhibited therapeutic properties in the oral cavity. Oral mucositis is an acute inflammation of the oral cavity, following cancer therapy. The current treatment methods of oral mucositis have low effectiveness. The aim of this study was to design, formulate and characterize a mucoadhesive gel delivery system for Hst-5 usage in the treatment of oral mucositis. Carbopol 934 and hydroxypropyl methylcellulose (HPMC) have been used in the development of a Hst-5 mucoadhesive gel that was optimized by using Box-Behnken design. The optimized formulation was evaluated in-vitro, based on mucoadhesive strength, viscoelasticity, spreadability, release rate, peptide secondary structure analysis, antimicrobial activity, and storage stability. The efficacy of Hst-5 gel was assessed in vivo in a chemotherapy-induced mucositis model. The results showed a sustained release of Hst-5 from the new formulation. Hst-5 gel exerted antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. The histopathological, immunohistochemical and statistical analysis showed that the Hst-5 gel had wound healing activity in vivo. The findings of this study indicate that the mentioned compound possesses promising potential as a novel and efficient therapeutic agent in managing oral mucositis. Moreover, the results suggest that the compound is commercially feasible for further development and utilization.

Decarboxylative Cyclization of Proline with o-Alkynylbenzaldehyde through an Unexploited 8π-Electrocyclization: A DFT Study.

We employed density functional theory (DFT) methods to investigate the most plausible mechanism of cyclization/ring expansion of proline with o-alkynylbenzaldehyde. This one-pot reaction starts with the in situ formation of azomethine ylide, which can undergo three different reaction pathways to form the final product. Two mechanisms are based on nucleophilic addition and 4π-electrocyclization of the azomethine ylide, and our results indicate that the rate-determining step (RDS) of these two cyclizations are 40.1 and 40.2 kcal/mol, respectively. The third novel pathway relies upon 8π-electrocyclization as the key step of this reaction; interestingly, the RDS of this cyclization is ∼20.6 kcal/mol, which shows this route to be most feasible. Thus, we introduce a novel mechanism for the electrocyclization reaction of conjugated azomethine ylides that can help chemists to design and access a new series of compounds.

Synthesis of Pyrrolidin-5-one-2-carboxamides through Cyclization of N-Substituted-2-alleneamides.

The synthesis of pyrrolidin-5-one-2-carboxamides 6a-p has been developed via a one-pot Ugi reaction of allenic acids, primary amines, isocyanides, and aldehydes followed by regioselective cyclization of the resultant N-substituted-2-allenamides with KOt-Bu at room temperature. The cyclization reaction was carried out through a 5-exo-dig approach, which resulted in good yields and high atom-economy under transition-metal-free and mild reaction conditions.

Multicomponent Assembly of Trisubstituted Imidazoles and Their Photochemical Cyclization into Fused Polyheterocyclic Scaffolds.

A straightforward route to a large and diverse library of trisubstituted imidazoles was established via a three-component reaction of 2-oxoaldehydes, 1,3-dicarbonyl compounds, and acyclic nitrogen bis-nucleophiles. The obtained products were subsequently explored in a photochemical cyclization yielding a variety of imidazole-fused polycyclic compounds.

DABSO as a SO2 gas surrogate in the synthesis of organic structures.

1,4-Diazabicyclo[2.2.2]octane bis(sulfur dioxide), DABCO·SO2, or DABSO, a bench-stable colorless solid, is industrially produced by the reaction of DABCO with condensed and bubbled sulfur dioxide gas at a low temperature. However, in some cases, it could catalyze organic reactions. DABSO is mostly used as a surrogate of gaseous sulfur dioxide to react with organic substrates, including Grignard reagents, aryl or alkyl halides, boronic acids, various amines, diazonium salts, carboxylic acids, heterocycles, acrylamides, alkenes, alkynes, and ß-alkynyl ketones, through one-pot protocols, annulation, or coupling reactions. Most of these synthetic reactions proceed via the formation of a sulfinate radical or anion. Using DABSO as a reagent, various simple to complex structures can be constructed, such as metal sulfinates, sulfonyl fluorides, sulfonamides, sulfonohydrazides, sulfonic esters, sulfonic thioesters, and sulfones. In this review, we want to investigate mechanistically the role of DABSO in organic synthesis.

Synthesis of functionalized 1-aminoisoquinolines through cascade three-component reaction of ortho-alkynylbenzaldoximes, 2H-azirines, and electrophiles.

We have developed a new three-component approach using ortho-alkynylbenzaldoximes involving the formation of a cyclic nitrone in the presence of Br2 or ICl for the synthesis of 1-aminoisoquinolines via cascade 6-endo-cyclization, 1,3-dipolar cycloaddition reaction with 2H-azirines, and ring-opening reaction sequences. The broad range of structurally diverse products, good to high yields, high atom-economy and high bond-formation efficiency make this method an attractive alternative for the synthesis of 1-aminoisoquinolines.

Regio- and diastereoselective transition metal-free hydroalkylation of N-allenyl sulfonamides by push-pull 2-alkynylquinolines.

We describe a novel and efficient synthetic strategy to construct the linear homoallylic quinolone structures through the intermolecular addition of 2-alkynylquinoline to N-allenyl sulfonamides. We developed the regio- and diastereoselective transition metal-free hydroalkylation of 1,2-dienes by a structure containing a push-pull system. Moreover, the present work was carried out with a high atom economy, mild reaction conditions, and moderate to high yields.

A metal-free tandem dehydrogenative α-arylation reaction of propargylic alcohols with 2-alkynylbenzaldoximes toward the synthesis of α-(4-bromo-isoquinolin-1-yl)-propenone skeletons.

A tandem reaction of 2-alkynylbenzaldoximes with propargylic alcohols has been developed for the synthesis of α-(4-bromo-isoquinolin-1-yl)-propenones. Employing 2-alkynylbenzaldoximes as a precursor in the presence of Br2 generates 4-bromo-isoquinoline-N-oxides. Subsequently, dehydroxylation of propargylic alcohols gives carbocation intermediates, which are trapped using the N-oxides, affording aryl-substituted α-enones.

Domino Decarboxylative Arylation and C-O Selective Bond Formation toward Chromeno[2,3-b]pyridine-2-one Skeletons.

Practical Pd-catalyzed 2-pyridones were designed to achieve chromeno[2,3-b]pyridine-2-ones. The reaction proceeds through domino nucleophilic addition and decarboxylative arylation, respectively. This methodology offers a moderately efficient approach to construct the bioactive, fused-heterocyclic skeletons via selective C-O bond formation and decarboxylative arylation in a single step with high selectivity and good yields.

Synthesis of Spiro[chromene-imidazo[1,2-a]pyridin]-3'-imines via 6-exo-dig Cyclization Reaction.

A transition-metal-free postmodification of the Groebke-Blackburn-Bienaymé (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.

Transition-metal-free oxidative cyclization reaction of enynals to access pyrane-2-one derivatives.

A novel and efficient metal-free C-H functionalization of enynals is developed to synthesize α-pyrone derivatives via the formation of two C-O bonds. In this project, K2S2O8 has been introduced as an efficient oxygen source and C-H functionalization agent in regioselective oxidative cyclization reaction with a relatively broad substrate scope.

The effect of different exogenous kisspeptins on sex hormones and reproductive indices of the goldfish (Carassius auratus) broodstock.

Despite several studies on fish hormone therapy, finding new candidates may provide more reproductive efficiency in artificial propagation. Kisspeptins, being upstream of the hypothalamic-pituitary-gonadal axis, appear to play a key role in the reproduction process. In the present study, the effect of different variants of kisspeptide, including goldfish (Carassius auratus) kiss1 kisspeptin (Kiss1), human kisspeptin (Hkiss), and their combination (Kiss1 + H), on the reproductive indices of goldfish broodstock in comparison to Ovaprim (a typical synthetic Gnrh hormone) was investigated. Peptides (Kiss1 and Hkiss) were synthesized using a solid-phase synthesis approach. Kiss1 and Hkiss were injected at a dose of 100 µg kg-1 body weight, blood samples were taken 6 h after injection and sex hormones (E2, Dhp, and 11-Kt), gonadotropins (Lh and Fsh), cortisol and reproductive indices (fecundity, fertilization and hatching percentage) were measured. The results showed a significant increase of plasma sex hormones and gonadotropins in fish treated with kisspeptins. In addition, the cortisol and lipoprotein lipase in Kiss1, Hkiss and Kiss1 + H were remarkably increased compared to Ovaprim. In conclusion, kisspeptins could be a more suitable candidate than Ovaprim for accelerating and synchronizing oocyte maturation in the fisheries industry.

Regio- and Diastereoselective Indium-Catalyzed Conia-Ene Reaction of ortho-Alkynyl Diketopiperazines to Access Fused Diketopiperazinoindolines.

An efficient synthesis of diketopiperazinoindolines through an indium-catalyzed intramolecular 5-exo-dig cyclization of ortho-alkynyl diketopiperazines has been reported. The formation of diketopiperazinoindolines proceeds via a regio- and diastereoselective Conia-ene reaction. This synthetic method opens a new door for easy access to functionalized fused diketopiperazinoindolines in high to excellent yields with exclusive Z diastereoselectivity.

Synthesis of Spiro-ß-lactam-pyrroloquinolines as Fused Heterocyclic Scaffolds through Post-transformation Reactions.

A sequential post-transformation of Ugi four-component reaction/nucleophilic substitution was developed for the synthesis of spiro-ß-lactam-pyrroloquinolines. This method involves the Ugi-4CR of 2-chloro-3-formyl quinolines 1a-h, amines 2a-d, 2-chloroacetic acid 3, and isocyanides 4a, 4b for the synthesis of versatile precursors 5a-v. The Ugi adducts were intramolecularly cyclized under basic conditions through the sequential nucleophilic aromatic substitution (SNAr)/second-order nucleophilic substitution (SN2) reaction to give spiro-ß-lactam-pyrroloquinoline scaffolds 6a-t. This approach is an efficient method for the synthesis of fused bioactive heterocyclic backbones containing quinoline, pyrrolidone, and ß-lactam with high bond-forming efficiency.

Synthesis, Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4-Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate.

A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2-(2-hydroxyphenyl)-4H-benzo[e][1,3]oxazin-4-one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC50 values of 1.268 and 3.254 µm, respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors.

Trastuzumab-monomethyl auristatin E conjugate exhibits potent cytotoxic activity in vitro against HER2-positive human breast cancer.

Targeted therapy using specific monoclonal antibodies (mAbs) conjugated to chemotherapeutic agents or toxins has become one of the top priorities in cancer therapy. Antibody-drug conjugates (ADCs) are emerging as a promising strategy for cancer-targeted therapy. In this study, trastuzumab, a humanized monoclonal anti-HER2 antibody, was reduced by dithiothreitol and conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) through a valine-citrulline peptide linker (trastuzumab-MC-Val-Cit-PABC-MMAE [trastuzumab-vcMMAE]). After conjugation, ADCs were characterized by using UV-vis, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and flow cytometry. The antitumor activity of the ADC was evaluated in breast cancer cells in vitro. In addition, ADCs were further characterized using purification by the protein A chromatography, followed by assessment using apoptosis and MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assays. Hydrophobic interaction chromatography was used to determine drug-to-antibody ratio species of ADCs produced. Our finding showed that approximately 5.12 drug molecules were conjugated to each mAb. H2L2, H2L, HL, H2, H, and L forms of ADCs were detected in nonreducing SDS-PAGE. The binding of trastuzumab-vcMMAE to HER2-positive cells was comparable with that of the parental mAb. The MTT assay showed that our ADCs induced significant cell death in HER2-positive cells, but not in HER2-negative cells. The ADCs produced was a mixture of species, unconjugated trastuzumab (14.147%), as well as trastuzumab conjugated with two (44.868%), four (16.886%), six (13.238%), and eight (10.861%) molecules of MMAE. These results indicated that MMAE-conjugated trastuzumab significantly increases the cytotoxic activity of trastuzumab, demonstrating high affinity, specificity, and antitumor activity in vitro. Trastuzumab-vcMMAE is an effective and selective agent for the treatment of HER2-positive breast tumors.