Diastereoselective Spirocyclization: Entry to Spirocyclic Diketopiperazines.

We report a novel approach to access spirocyclic compounds containing a diketopiperazine (DKP) motif fused on a pyrrolidine ring. The shared spirocyclic carbon is at the ketone oxidation state, bearing two carbon-nitrogen bonds, one of which is introduced stereoselectively during the cyclization event. The reaction proceeds through an acid-catalyzed cyclization of a pendent chiral aminoamide unit onto a 2,3-dehydroproline amide moiety with up to >98:2 diastereoselectivity. We have demonstrated the generality of this methodology and its applicability to access chemically diverse DKP-containing structures. The extent of stereoinduction and how it varies according to the bulkiness of the substituent on the pendent aminoamide is demonstrated through a diverse substrate set. This methodology gives access to an underexplored spirocyclic diketopiperazine motif that may be useful in identifying new bioactive molecules.

Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).

Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation. Herein we describe the discovery and optimization of small molecule PPI (protein-protein interaction) inhibitors of NKG2D/NKG2DL. Rapid SAR was guided by structure-based drug design and accomplished by iterative singleton and parallel medicinal chemistry synthesis. These efforts resulted in the identification of several potent analogs (14, 21, 30, 45) with functional activity and improved LLE.

Identification of small-molecule protein-protein interaction inhibitors for NKG2D.

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

An Esthetic Evaluation of Different Abutment Materials in the Anterior Maxilla: A Randomized Controlled Clinical Trial Using a Crossover Design.

PURPOSE: To assess the effect of implant abutment material and soft tissue thickness on the peri-implant soft tissue color using spectrophotometry and to evaluate gingival esthetics and patient satisfaction with three different abutments. MATERIALS AND METHODS: Twenty-five patients with a missing maxillary tooth in the esthetic area received an endosseous implant using a two-stage protocol. Gray titanium, pink anodized titanium, and hybrid zirconia custom abutments were fabricated for each participant and inserted for one week with a cross-over design in a randomized manner. Color measurements were made using a spectrophotometer comparing midfacial peri-implant soft tissue and marginal gingiva of the contralateral tooth. CIE Lab color scale was used following the formula: ΔE = [(∆L)2 + (∆a)2 + (∆b)2 ]½ . PES scores were recorded, and patient satisfaction questionnaires were completed at each abutment change visit and at 1-year follow-up. Statistical analysis was performed using Friedman's test and the Wilcoxon signed-rank test with Bonferroni correction as well as the Mann-Whitney U test (α = 0.05). RESULTS: Abutment material type significantly affected the ΔΕ values of the peri-implant mucosa when compared to the contralateral teeth. At baseline, the highest ΔΕ means ± standard deviation (SD) values were obtained with gray titanium (11.25 ± 2.98), followed by pink anodized titanium (9.90 ± 2.51), and zirconia abutments (6.46 ± 1.43). Differences were statistically significant irrespective of soft tissue thickness. The highest PES values were obtained with zirconia abutments (10.88 ± 0.88), followed by pink anodized titanium (10.12 ± 1.13) and the lowest with gray titanium (9.68 ± 1.41). PES differences were significant only for the thin soft tissue group. Regarding patient satisfaction, VAS scores for the pink anodized and zirconia hybrid abutment groups were higher than the gray titanium group for each question. CONCLUSION: The color difference between soft tissues around teeth and implants was significant in all groups regardless of tissue thickness. The hybrid zirconia abutments resulted in the least color difference, followed by pink anodized and gray titanium. Significantly different PES values were recorded only for the thin tissue group. There was no significant difference in patient satisfaction between zirconia and pink anodized abutments at the 1-year follow up. Pink anodized abutments represent a good esthetic alternative to zirconia hybrid abutments especially in mechanically challenging situations.

A Mechanistically Inspired Halenium Ion Initiated Spiroketalization: Entry to Mono- and Dibromospiroketals.

Employing halenium affinity (HalA) as a guiding tool, the weak nucleophilic character of alkyl ketones was modulated by the templating effect of a tethered 2-tetrahydropyranyl(THP)-protected alcohol towards realizing a bromenium ion initiated spiroketalization cascade. Addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals. Alternatively, exclusion of ethanol from the reaction mixture biased the transient oxocarbenium towards α-deprotonation that precedes a second bromofunctionalization event thus, furnishing dibrominated spiroketals. The regio- and stereoselectivity exploited in the current methodology provides a novel and rapid access to the dibrominated spiroketal motifs exhibited by several natural products.

Design of Large Stokes Shift Fluorescent Proteins Based on Excited State Proton Transfer of an Engineered Photobase.

The incredible potential for fluorescent proteins to revolutionize biology has inspired the development of a variety of design strategies to address an equally broad range of photophysical characteristics, depending on potential applications. Of these, fluorescent proteins that simultaneously exhibit high quantum yield, red-shifted emission, and wide separation between excitation and emission wavelengths (Large Stokes Shift, LSS) are rare. The pursuit of LSS systems has led to the formation of a complex, obtained from the marriage of a rationally engineered protein (human cellular retinol binding protein II, hCRBPII) and different fluorogenic molecules, capable of supporting photobase activity. The large increase in basicity upon photoexcitation leads to protonation of the fluorophore in the excited state, dramatically red-shifting its emission, leading to an LSS protein/fluorophore complex. Essential for selective photobase activity is the intimate involvement of the target protein structure and sequence that enables Excited State Proton Transfer (ESPT). The potential power and usefulness of the strategy was demonstrated in live cell imaging of human cell lines.

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles.

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pK a limitation of "hard" nucleophiles in enantioselective transformations.

Total Synthesis of Kadcoccinic Acid A Trimethyl Ester.

The first total synthesis of the trimethyl ester of kadcoccinic acid A is described. The central structural element of our synthesis is a cyclopentenone motif that allows the assembly of the natural product skeleton. A gold(I)-catalyzed cyclization of an enynyl acetate led to efficient construction of the cyclopentenone scaffold. In this step, optimization studies revealed that the stereochemistry of the enynyl acetate dictates regioisomeric cyclopentenone formation. The synthesis further highlights an efficient copper-mediated conjugate addition, merged with a gold(I)-catalyzed Conia-ene reaction to connect the two fragments, thereby forging the D-ring of the natural product. The synthetic strategy reported herein can provide a general platform to access the skeleton of other members of this family of natural products.

Absolute Stereochemical Determination of Organic Molecules through Induction of Helicity in Host-Guest Complexes.

Stereochemistry is a fundamental molecular property with important ramifications for structure, function, and activity of organic molecules. The basic building blocks of living organisms (amino acids and sugars) exhibit a precisely selected set of molecular handedness that has evolved over millions of years. The absolute stereochemistry of these building blocks is manifested in the structure and function of the cell machinery (e.g., enzymes, proteins, etc.), which are essential components of life. In the many chemical subdisciplines, molecular stereochemistry is exceedingly important and is often a strong determinant of structure and function. Besides its biological implications, the centrally important role of stereochemistry in many disciplines of chemistry and related fields has led to tremendous effort and activity, highlighted by the success in stereoselective syntheses of a host of functionalities. In the present climate, it is often the difficulty of assigning absolute stereochemistry as opposed to synthesis, which has become a nontrivial challenge, requiring the attention of the community. There will not be a general solution to this problem, as each system will have its own unique requirements and challenges; however, the need for rapid, routine, and microscale analysis is apparent. This is especially true with parallel and high-throughput arrays for screening conditions and catalysts, generating a large number of samples that require analysis.In this Account, we summarize our contribution to this field through the development of molecular receptors for sensing molecular asymmetry. These methodologies strive to unambiguously assign the absolute configuration of asymmetric center(s). To accomplish this task, our laboratory has designed a variety of host molecules, bearing various binding elements, to form stable complexes with chiral molecules (guests). During this complexation event, the stereochemistry of a target molecule induces a supramolecular chirality (i.e., helicity) within the host system. The design of the host system is such that the helicity of the host/guest complex can be observed and assigned via Exciton Coupled Circular Dichroism (ECCD), a nonempirical technique for identifying handedness, which is correlated back to the absolute stereochemistry of the bound chiral molecule. Taking advantage of the high sensitivity of chiroptical techniques (in terms of the required amount of sample for analysis) and fast response time, these methodologies offer a microscale, rapid, and nonempirical solution for assignment of absolute stereochemistry.The first part of this Account describes application of porphyrin tweezers as reporters of chirality for the absolute stereochemical determination of various classes of organic molecules. This methodology is suitable to report the absolute configuration of organic molecules that contain two binding elements (nitrogen or oxygen based functionalities). In the second part, host systems that do not require two sites of attachment to form ECCD active complexes will be described. This enables the absolute stereochemical assignment of challenging chiral molecules with functional groups lacking routine techniques for analysis.

A study on the protease activity and structure of pepsin in the presence of atenolol and diltiazem.

Pepsin, as the main protease of the stomach, plays an important role in the digestion of food proteins into smaller peptides and performs about 20% of the digestive function. The role of pepsin in the development of gastrointestinal ulcers has also been studied for many years. Edible drugs that enter the body through the gastrointestinal tract will interact with this enzyme as one of the first targets. Continuous and long-term usage of some drugs will cause chronic contact of the drug with this protein, and as a result, the structure and function of pepsin may be affected. Therefore, the possible effect of atenolol and diltiazem on the structure and activity of pepsin was studied. The interaction of drugs with pepsin was evaluated using various experimental methods including UV-Visible spectroscopy, fluorescence spectroscopy, FTIR and enzymatic activity along with computational approaches. It was showed that after binding of atenolol and diltiazem to pepsin, the inherent fluorescence of the protein is quenched. Determination of the thermodynamic parameters of interactions between atenolol and diltiazem with pepsin indicates that the major forces in the formation of the protein-drug complexes are hydrophobic forces and also atenolol has a stronger protein bonding than diltiazem. Additional tests also show that the protease activity of pepsin, decreases and increases in the presence of atenolol and diltiazem, respectively. Investigation of the FTIR spectrum of the protein in the presence and absence of atenolol and diltiazem show that in the presence of atenolol the structure of protein has slightly changed. Molecular modeling studies, in agreement with the experimental results, confirm the binding of atenolol and diltiazem to the enzyme pepsin and show that the drugs are bind close to the active site of the enzyme. Finally, from experimental and computational results, it can be concluded that atenolol and diltiazem interact with the pepsin and change its structure and protease activity.

A chiroptical approach for the absolute stereochemical determination of P-stereogenic centers.

A simple chiroptical solution for the absolute stereochemical determination for asymmetric phosphorus V stereocenters is presented. Strong coordination of the phosphorus oxide with the Zn-metallo center of the racemic host Zn-MAPOL 2 leads to an induced axial chirality of the host, yielding a strong ECCD signal. A mnemonic is proposed to correlate the asymmetry of the guest molecule with the observed ECCD signal.

Effect of time in function on the predictability of short dental implants (≤6 mm): A meta-analysis.

PURPOSE: To analyse randomised controlled clinical trials (RCTs) and prospective cohort studies reporting on the survival and failure rates of functionally loaded short implants (SI) based on the actual length of time in function. MATERIALS AND METHODS: This meta-analysis was conducted according to PRISMA guidelines for systematic reviews. Electronic and manual searches were conducted to identify RCTs and prospective cohort studies reporting survival and complication rates of short dental implants (≤6 mm) based on the time in function. Secondary outcomes included the location (maxilla or mandible), type of restoration (single crown [SC] versus fixed dental prosthesis [FDP]) and marginal bone loss (MBL). RESULTS: A total of 20 studies (11 RCTs and 9 prospective) fulfilled the inclusion criteria and featured a total of 1238 SI placed in 747 patients. The overall (early and late) mean percentage of short implant failure was 4%. SI with up to 1-year follow-up presented failure rate of 2%, while SI followed up for >3 years showed a failure rate of 10%. SI restored with SC presented a late failure rate of 4% while SI restored with FPD 2%. The late failure rate did not differ in terms of location (maxilla or mandible) both with 3%. CONCLUSION: Short implants in function for more than 3 years presented higher failure rates compared to SI in function for <3 years. Splinting crowns supported by SIs in the posterior area should be considered. However, SI is a valid option for selected cases given their relatively high long-term survival rates.

Palladium-Catalyzed Asymmetric Allylic Fluoroalkylation/Trifluoromethylation.

The first palladium-catalyzed asymmetric allylic trifluoromethylation is disclosed. The methodology evokes a fundamental principle by which the synergistic interplay of a leaving group and its subsequent activation of the nucleophilic trifluoromethyl group enabled the reaction. Allyl fluorides have been shown to be superior precursors for generation of π-allyl complexes, which lead to trifluoromethylated products with high selectivities and functional group tolerance. This study highlights the unique role of a bidentate diamidophosphite ligand class in palladium-catalyzed reactions that allow a challenging transformation to proceed.

Total Synthesis of (-)-Salinosporamide†A via a Late Stage C-H Insertion.

The synthesis of (-)-salinosporamide A, a proteasome inhibitor, is described. The synthesis highlights the assembly of a densely decorated pyrrolidinone core via an aza-Payne/hydroamination sequence. Central to the success of the synthesis is a late-stage C-H insertion reaction to functionalize a sterically encumbered secondary carbon. The latter functionalization leads to an enabling transformation where most of the prototypical strategies failed.

Group 1 ITI Consensus Report: The influence of implant length and design and medications on clinical and patient-reported outcomes.

OBJECTIVES: The aim of Working Group 1 was to address the influence of different local (implant length, diameter, and design) and systemic (medications) factors on clinical, radiographic, and patient-reported outcomes in implant dentistry. Focused questions on (a) short posterior dental implants (≤6 mm), (b) narrow diameter implants, (c) implant design (tapered compared to a non-tapered implant design), and (d) medication-related dental implant failures were addressed. MATERIALS AND METHODS: Four systematic reviews were prepared in advance of the Consensus Conference and were discussed among the participants of Group 1. Consensus statements, clinical recommendations, and recommendations for future research were based on structured group discussions until consensus was reached among the entire expert Group 1. The statements were then presented and accepted following further discussion and modifications as required by the plenary. RESULTS: Short implants (≤6 mm) revealed a survival rate ranging from 86.7% to 100%, whereas standard implant survival rate ranged from 95% to 100% with a follow-up from 1 to 5 years. Short implants demonstrated a higher variability and a higher Risk Ratio [RR: 1.24 (95% CI: 0.63, 2.44, p = 0.54)] for failure compared to standard implants. Narrow diameter implants (NDI) have been classified into three categories: Category 1: Implants with a diameter of <2.5 mm ("Mini-implants"); Category 2: Implants with a diameter of 2.5 mm to <3.3 mm; Category 3: Implants with a diameter of 3.3 mm to 3.5 mm. Mean survival rates were 94.7 ± 5%, 97.3 ± 5% and 97.7 ± 2.3% for category 1, 2 and 3. Tapered versus non-tapered implants demonstrated only insignificant differences regarding clinical, radiographic, and patient-reported outcomes. The intake of certain selective serotonin reuptake inhibitors and proton pump inhibitors is associated with a statistically significant increased implant failure rate. The intake of bisphosphonates related to the treatment of osteoporosis was not associated with an increased implant failure rate. CONCLUSIONS: It is concluded that short implants (≤6 mm) are a valid option in situations of reduced bone height to avoid possible morbidity associated with augmentation procedures; however, they reveal a higher variability and lower predictability in survival rates. Narrow diameter implants with diameters of 2.5 mm and more demonstrated no difference in implant survival rates compared to standard diameter implants. In contrast, it is concluded that narrow diameter implants with diameters of less than 2.5 mm exhibited lower survival rates compared to standard diameter implants. It is further concluded that there are no differences between tapered versus non-tapered dental implants. Certain medications such as selective serotonin reuptake inhibitors and proton pump inhibitors showed an association with a higher implant failure rate.

Group 5 ITI Consensus Report: Digital technologies.

OBJECTIVES: Working Group 5 was assigned the task to review the current knowledge in the area of digital technologies. Focused questions on accuracy of linear measurements when using CBCT, digital vs. conventional implant planning, using digital vs. conventional impressions and assessing the accuracy of static computer-aided implant surgery (s-CAIS) and patient-related outcome measurements when using s-CAIS were addressed. MATERIALS AND METHODS: The literature was systematically searched, and in total, 232 articles were selected and critically reviewed following PRISMA guidelines. Four systematic reviews were produced in the four subject areas and amply discussed in the group. After emendation, they were presented to the plenary where after further modification, they were accepted. RESULTS: Static computer-aided surgery (s-CAIS), in terms of pain & discomfort, economics and intraoperative complications, is beneficial compared with conventional implant surgery. When using s-CAIS in partially edentulous cases, a higher level of accuracy can be achieved when compared to fully edentulous cases. When using an intraoral scanner in edentulous cases, the results are dependent on the protocol that has been followed. The accuracy of measurements on CBCT scans is software dependent. CONCLUSIONS: Because the precision intraoral scans and of measurements on CBCT scans and is not high enough to allow for the required accuracy, s-CAIS should be considered as an additional tool for comprehensive diagnosis, treatment planning, and surgical procedures. Flapless s-CAIS can lead to implant placement outside of the zone of keratinized mucosa and thus must be executed with utmost care.

Survival rates of short dental implants (≤6 mm) compared with implants longer than 6 mm in posterior jaw areas: A meta-analysis.

PURPOSE: To systematically review randomized controlled clinical trials (RCTs) reporting on the long-term survival and failure rates, as well as the complications of short implants (≤6 mm) versus longer implants (>6 mm) in posterior jaw areas. MATERIALS AND METHODS: Electronic and manual searches were conducted to identify studies, specifically RCTs, reporting on short dental implants (≤6 mm) and their survival and complication rates compared with implants longer than 6 mm. Secondary outcomes analyzed were marginal bone loss and prosthesis survival rates. RESULTS: Ten RCTs fulfilled the inclusion criteria and featured a total of 637 short (≤6 mm) implants placed in 392 patients, while 653 standard implants (>6 mm) were inserted in 383 patients. The short implant survival rate ranged from 86.7% to 100%, whereas standard implant survival rate ranged from 95% to 100% with a follow-up from 1 to 5 years. The risk ratio (RR) for short implant failure compared to standard implants was 1.29 (95% CI: 0.67, 2.50, p = 0.45), demonstrating that overall, short implants presented higher risk of failure compared to longer implants. The heterogeneity test did not reach statistical significance (p = 0.67), suggesting low between-study heterogeneity. The prosthesis survival rates from the short implant groups ranged from 90% to 100% and from 95% to 100% for longer implant groups, respectively. CONCLUSION: Short implants (≤6 mm) were found to have higher variability and lower predictability in survival rates compared to longer implants (>6 mm) after periods of 1-5 years in function. The mean survival rate was 96% (range: 86.7%-100%) for short implants, and 98% (range 95%-100%) for longer implants. Based on the quantity and quality of the evidence provided by 10 RCTs, short implants with ≤6 mm length should be carefully selected because they may present a greater risk for failure compared to implants longer than 6 mm.

Propene as an Atom-Economical Linchpin for Concise Total Synthesis of Polyenes: Piericidin A.

A concise and convergent total synthesis of piericidin A is disclosed. The synthesis hinges on the utilization of propene as a synthetic linchpin to merge the properly elaborated alkyne fragments, leading to the 1,3,6-triene motif of piericidin A. Utilization of propene as a unique alkene, capable of sequential coupling with two alkynes, is further illustrated in the context of various 1,3,6-triene products. The latter process proceeds with high atom economy and efficiently gives rise to complex frameworks from readily accessible alkyne substrates. This strategic C-C bond formation offers an orthogonal paradigm in the design of synthetic routes, leading to higher step economy and more efficient syntheses of polyunsaturated natural products.

Di(1-naphthyl) methanol ester of carboxylic acids for absolute stereochemical determination.

The absolute stereochemistry of chiral carboxylic acids is determined as a di(1-naphthyl)methanol ester derivative. Computational scoring of conformations favoring either P or M helicity of the naphthyl groups, capable of exciton-coupled circular dichroic coupling, leads to a predicted stereochemistry for the derivatized carboxylic acids.

Absolute Stereochemical Determination of Asymmetric Sulfoxides via Central to Axial Induction of Chirality.

The absolute configuration of chiral sulfoxides is determined by means of host-guest complexation that leads to the induction of axial chirality in an achiral host. The central to axial induction of helicity is rationalized by a simple recognition of the relative length and size of the substituents attached to the S-center. This technique is used to determine the absolute configuration of chiral sulfoxides, requiring micrograms of sample, without the need for prefunctionalization.