Room Temperature Diels-Alder Reactions of 4-Vinylimidazoles.

In the course of studying Diels-Alder reactions of 4-vinylimidazoles with N-phenylmaleimide, it was discovered that they engage in cycloaddition at room temperature to give high yields of the initial cycloadduct as a single stereoisomer. In certain cases, the product precipitated out of the reaction mixture and could be isolated by simple filtration, thereby avoiding issues with aromatization observed during chromatographic purification. Given these results, intramolecular variants using doubly activated dienophiles were also investigated at room temperature. Amides underwent cycloaddition at room temperature in modest yields, but the initial adducts were not isolable with Nimid-benzyl-protected systems. Attempts to extend these results to the corresponding esters and hydroxamate were less successful with these substrates only undergoing cycloaddition at elevated temperatures in lower yields. Density functional theory calculations were performed to evaluate the putative transition states for both the inter- and intramolecular variants to rationalize experimental observations.

Total synthesis of haploscleridamine, villagorgin A and an approach towards lissoclin C.

An investigation of asymmetric total syntheses of three indole-imidazole alkaloids from histidine are described. A common advanced piperidinone was contructed via a ring-closing metathesis which was then subjected to a modified Fischer indole synthesis. Deprotection of an N-tosyl group via a dissolving metal reduction affords haploscleridamine which upon reaction with aqueous formaldehyde in trifluoroethanol provided villagorgin A. On closer examination, it was found that villagorgin A was produced as a byproduct during the reductive detosylation in the presence of magnesium and methanol. Attempts to obtain the brominated haploscleridamine congener, lissoclin C through use of bromophenyl hydrazone were thwarted by reductive debromination during deprotection efforts. Investigation of the enantiopurity of the synthetic natural products revealed production of almost racemic materials in some batches as the result of partial racemization of an early stage intermediate. A revised approach routinely provided scalemic haploscleridamine and villagorgin in 30% ee. Analysis of the enantiomer composition of all intermediates by HPLC using columns with chiral stationary phases; this analysis revealed several steps where erosion of enantiomer composition occurred.

Novel thiazolidines of potential anti-proliferation properties against esophageal squamous cell carcinoma via ERK pathway.

The discovery of a new class of extracellular-signal-regulated kinase (ERK) inhibitors has been achieved via developing novel 2-imino-5-arylidene-thiazolidine analogues. A novel synthetic method employing a solid support-mediated reaction was used to construct the targeted thiazolidines through a cascade reaction with good yields. The chemical and physical stability of the new thiazolidine library has successfully been achieved by blocking the labile C5-position to aerobic oxidation. A cell viability study was performed using esophageal squamous cell carcinoma cell lines (KYSE-30 and KYSE-150) and non-tumorous esophageal epithelial cell lines (HET-1A and NES-G4T) through utilization of an MTT assay, revealing that (Z)-5-((Z)-4-bromobenzylidene)-N-(4-methoxy-2-nitrophenyl)-4,4-dimethylthiazolidin-2-imine (6g) was the best compound among the synthesized library in terms of selectivity. DAPI staining experiments were performed to visualize the morphological changes and to investigate the apoptotic activity. Moreover, western blots were used to probe the mechanism/pathway behind the observed activity/selectivity of thiazolidine 6g which established selective inhibition of phosphorylation in the ERK pathway. Molecular modeling techniques have been utilized to confirm the observed activity. A molecular docking study revealed similar binding interactions between the synthesized thiazolidines and reported co-crystalized inhibitors with ERK proteins. Thus, the present study provides a starting point for the development of interesting bioactive 2-imino-5-arylidene-thiazolidines.

Self-assembling Peptides with Internal Ionizable Unnatural Amino Acids: A General Approach to pH-responsive Peptide Materials.

Self-assembled peptides are an emerging family of biomaterials that show great promise for a range of biomedical and biotechnological applications. Introducing and tuning the pH-responsiveness of the assembly is highly desirable for improving their biological activities. Inspired by proteins with internal ionizable residues, we report a simple but effective approach to constructing pH-responsive peptide assembly containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. Through a combined experimental and computational investigation, we demonstrate that these residues can be accommodated and stabilized within the internal hydrophobic compartment of the peptide assembly. The hydrophobic microenvironment shifts their pKa significantly from a basic pH typically found for free amines to a more biologically relevant pH in the weakly acidic range. The pH-induced ionization and ionization-dependent self-assembly and disassembly are thoroughly investigated and correlated with the biological activity of the assembly. This new approach has unique advantages in tuning the pH-responsiveness of self-assembled peptides across a large pH range in a complex biological environment. We anticipate the ionizable amino acids developed here can be widely applicable to the synthesis and self-assembly of many amphiphilic peptides with endowed pH-responsive properties to enhance their biological activities toward applications ranging from targeted therapeutic delivery to proton transport.

One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line.

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2-15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC50 values using an MTT assay.

Liquid chromatography enantiomeric separation of chiral ethanolamine substituted compounds.

Eleven racemic ethanolamine derivatives were prepared, and their enantiomers were separated using liquid chromatography with various chiral columns. These derivatives included chiral vicinal amino alcohols, ß-hydroxy ureas, ß-hydroxy thioureas, and ß-hydroxy guanidines, all of which are present in many active pharmaceutical ingredients. The screening study was performed with six chiral stationary phase containing columns, including four recently introduced superficially porous particles bonded with two macrocyclic glycopeptides, a cyclodextrin derivative and a cyclofructan derivative. The two remaining columns contained chiral stationary phases, based on either a cellulose derivative or derivatized amylose, both bonded to fully porous particles. The cyclodextrin and cellulose-based chiral stationary phases proved to be the most broadly effective selectors and were able to separate 8 and 7 of the 11 tested compounds, respectively. With respect to analyte structural features, marked differences in enantiorecognition were observed between compounds containing phenyl and cyclohexyl groups adjacent to the stereogenic center. Additionally, replacing a small electronegative oxygen atom by a larger and less electronegative sulfur atom induced a significant difference in chiral recognition by the cellulose derivative as well as by the vancomycin-based chiral selectors.

Pyrrole carboxamide introduction in the total synthesis of pyrrole-imidazole alkaloids.

In this review various strategies for the incorporation of the signature pyrrole carboxamide moiety in the total syntheses of pyrrole-imidazole alkaloids (PIA) are discussed. These so-called oroidin alkaloids have a broad range of biological activities and display interesting skeletal diversity and complexity. These alkaloids are sponge-derived secondary metabolites and thus far more than 200 members of the PIA family have been isolated over the past few decades. Methods range from classical amide bond forming processes to non-traditional bond formation including the de novo synthesis of the pyrrole itself.

Enantiomeric Separation of New Chiral Azole Compounds.

Twelve new azole compounds were synthesized through an ene reaction involving methylidene heterocycles and phenylmaleimide, producing four oxazoles, five thiazoles, and one pyridine derivative, and ethyl glyoxal for an oxazole and a thiazole compound. The twelve azoles have a stereogenic center in their structure. Hence, a method to separate the enantiomeric pairs, must be provided if any further study of chemical and pharmacological importance of these compounds is to be accomplished. Six chiral stationary phases were assayed: four were based on macrocyclic glycopeptide selectors and two on linear carbohydrates, i.e., derivatized maltodextrin and amylose. The enantiomers of the entire set of new chiral azole compounds were separated using the three different mobile phase elution modes: normal phase, polar organic, and reversed phase. The most effective chiral stationary phase was the MaltoShell column, which was able to separate ten of the twelve compounds in one elution mode or another. Structural similarities in the newly synthesized oxazoles provided some insights into possible chiral recognition mechanisms.

Total Synthesis of the Nagelamides - Synthetic Studies toward the Reported Structure of Nagelamide D and Nagelamide E Framework.

The nagelamides are a small subset of the oroidin family of marine sponge-derived alkaloids and are, for the most part, dimeric in nature. As part of our efforts to develop synthetic access to this family, a Stille cross-coupling strategy is used to construct the bis-imidazolyl core skeleton. Reduction of the bis-vinylimidazole delivered the core framework of nagelamide D. Introduction of the 2-amino groups via the corresponding azides and introduction of the pyrrolecarboxamides through a double Mitsunobu reaction using a pyrrole hydantoin provided the putative structure of nagelamide D. The spectroscopic data for the synthetic and sponge-derived materials did not match well, whereas the spectroscopic data were a good match for closely related oroidin alkaloids, supporting the structure of the synthetic material. The structure of the synthetic material was further corroborated by obtaining an X-ray crystal structure of a derivative. Electrocyclization of an advanced precursor affords a dihydrobenzimidazole, which is expected to serve as a key intermediate en route to nagelamide E and ageliferin.

Total Synthesis of (±)-2-Debromohymenin via Gold-Catalyzed Intramolecular Alkyne Hydroarylation.

An intramolecular, gold-catalyzed alkyne hydroarylation results in the formation of the core pyrroloazepinone framework of the hymenin group of oroidin alkaloids. Elaboration of the cyclic adduct via C2-azidation, bromination of the pyrrole, and deprotection set the stage for global reduction with Mo(CO)6 resulting in the formation 2-debromohymenin.

[4-(4-Meth-oxy-phen-yl)-8-oxo-3-(phenyl-selan-yl)spiro-[4.5]deca-3,6,9-trien-2-yl]methyl-cyanamide.

The title compound, C25H22N2O2Se, crystallizes in the space group P21/c with one mol-ecule in the asymmetric unit. The compound was synthesized by the addition of phenyl-selenyl bromide to a cyanamide. The phenyl-selenyl portion and the cyano group, as well as the ketone functional group in the cyclo-hexa-2,5-dien-1-one portion of the structure, are disordered, with occupancy factors of 0.555 (14) and 0.445 (14).

Novel thiazolidines: Synthesis, antiproliferative properties and 2D-QSAR studies.

A series of N-substituted (Z)-2-imino-(5Z)-ylidene thiazolidines/thiazolidin-4-ones were synthesized and their antiproliferative activities against colon (HCT-116) and breast (MCF7) cancer cell lines were evaluated utilizing an MTT growth assay. A 2D-QSAR investigation was conducted to probe and validate the obtained antiproliferative properties for the thiazolidine derivatives. The majority of the thiazolidines exhibit higher potency against a colon cancer cell line relative to the standard reference. The p-halophenylimino p-anisylidene derivatives exhibited the highest anti-proliferative activity against HCT116 relative to control (IC50 = 8.9-10.0 µM compared to 20.4 µM observed for 5-fluorouracil as positive control). An X-ray study confirmed the Z, Z'-configurations for two examples of the synthesized compounds.

Crystal structures of 4-{(E)-3-[(imino-λ5-aza-nyl-idene)amino]-prop-1-en-yl}-N,N-di-methyl-imidazole-1-sulfonamide and 2-[(imino-λ5-aza-nyl-idene)amino]-4-{(E)-3-[(imino-λ5-aza-nyl-idene)amino]-prop-1-en-yl}-N,N-di-methyl-imidazole-1-sulfonamide.

The structures of two azide containing imidazole derivatives are reported. Allylic azides are fairly reactive making them attractive starting compounds to convert into amides. The first, C8H12N6O2S, contains one azide group with an Nα-Nß distance of 1.229 (2) Šand an Nß-Nγ distance of 1.128 (2) Å. The second, C8H11N9O2S, contains two azide groups with an average Nα-Nß distance of 1.249 (2) Šand an average Nß-Nγ distance of 1.132 (2) Å. Each compound contains a bulky protecting group (di-methyl-amino-sulfon-yl) which can be easily removed under mildly acidic conditions.

Intramolecular Diels-Alder Reaction of a Silyl-Substituted Vinylimidazole en Route to the Fully Substituted Cyclopentane Core of Oroidin Dimers.

An intramolecular Diels-Alder reaction of a silyl-substituted vinylimidazole delivers a diastereomeric mixture of C4-silyl functionalized dihydrobenzimidazoles. Subsequent diastereoselective reduction and elaboration of the lactone gives rise to a polysubstituted tetrahydrobenzimidazole, which, upon oxidative rearrangement, affords a single spirofused imidazolone containing all of the relevant functionality for an approach to the oroidin dimers axinellamine, massadine, and palau'amine.

Tandem Oxidative Dearomatizing Spirocyclizations of Propargyl Guanidines and Ureas.

Treatment of propargyl ureas or guanidines with iodosobenzene diacetate results in an oxidative tandem amination/etherification dearomatizing spirocyclization. This transformation leads directly to the complete framework of the Leucetta alkaloids, spirocalcaridine A and B.

Total synthesis and cytotoxicity of Leucetta alkaloids.

The total synthesis of a number of representative natural products isolated from Leucetta and Clathrina sponges containing a polysubstituted 2-aminoimidazole are described. These syntheses take advantage of the site specific metallation reactions of 4,5-diiodoimidazoles resulting in the syntheses of three different classes of Leucetta derived natural products. The cytotoxicities of these natural products, along with several precursors in MCF7 cells were determined through an MTT growth assay. For comparative purposes a series of naphthimidazole-containing family members are included.

Thio acid-mediated conversion of azides to amides - exploratory studies en route to oroidin alkaloids.

The utility of the thio acid-azide coupling reaction to afford amides is explored in imidazole-containing substrates for application in the total synthesis of examples of oroidin alkaloids. Good yields of the expected amides are obtained in both monomeric and dimeric substrates. Bis azides react preferentially at the 2-azido position but hydrosulfenylation and reduction interfere. 2-Thiophenyl and 2-oxo groups were evaluated as 2-amino surrogates, the thioether delivered the expected amide, whereas 2-imidazolone gave a mixture of the expected amide and the hydrosulfenylation product.

Studies Towards the Leucetta-derived Alkaloids Spirocalcaridine A and B - Possible Biosynthetic Implications.

An exploration of an abiotic approach to spirocalcaridines A and B is described centered on electrophile-induced dearomatizing spirocyclization of aryl enyne derivatives. Elaboration of the α-iodoenone via an Ullmann-like, copper-catalyzed amidation provided a formamide which upon treatment with methylamine undergoes a dienol-arene rearrangement, providing the corresponding kealiinine-like framework. This observation suggests a possible biosynthetic links between the spirocalcaridines and the naphthimidazole group of Leucetta alkaloids.