Combinatorial Chemistry Approach Research Articles

Natural Product Hybrids as New Leads for Drug Discovery

AbstractFor Abstract see ChemInform Abstract in Full Text.

Acid Strength of Low-Valence Dopant Ions in Microporous Zeolites and AlPOs

Using periodic ab initio quantum mechanical calculations, we have investigated 16 low-valence dopant ions isomorphously substituted in the framework of the zeolite chabasite and of its isostructural aluminophosphate, AlPO-34. The low-valence ions are charge balanced by one acid proton. We have determined the stretching frequency of the acid OH group in each material, and examined its correlation with the structural and electronic parameters of the dopant ions. Results show that the behavior of zeolites and AlPOs is complex; optimization of their properties is suitable to combinatorial chemistry approaches, to which computational studies can make a substantial contribution.

Selection of low-molecular-mass trypsin and chymotrypsin inhibitors based on the binding loop of CMTI-III using combinatorial chemistry methods

Using a combinatorial chemistry approach, a decapaptide library containing the N-terminal fragment of trypsin inhibitor CMTI-III was synthesized by the solid-phase method. The peptide library was screened for trypsin and chymotrypsin inhibitory activity applying the iterative method in solution. Two decapeptides were selected and resynthesized for each enzyme. The association equilibrium constants ((1.1 ± 0.2) × 10 8 and (7.3 ± 1.6) × 10 7) determined for peptides with trypsin inhibitory activity indicate that they are 3–4-fold less active than the CMTI inhibitors. On the other hand, they are significantly more effective as compared with the starting sequence. Two peptides selected as chymotrypsin inhibitors displayed about 10 times higher activity (1.7 ± 0.4) × 10 7 and (1.1 ± 0.2) × 10 7, respectively) than those monosubstituted in position P 1 of the CMTI-III analogue. Considering low molecular weight of peptides selected and the lack of conformational constraints in their structures, the results are promising. They are good templates as starting sequences for further selection of small, peptidomimetic proteinase inhibitors.

Yb3+‐Doped Oxide Crystals for Diode‐Pumped Solid State Lasers: Crystal Growth, Optical Spectroscopy, New Criteria of Evaluation and Combinatorial Approach

AbstractFor Abstract see ChemInform Abstract in Full Text.

Natural product hybrids as new leads for drug discovery.

Natural products play an important role in the development of drugs, especially for the treatment of infections and cancer, as well as immunosuppressive compounds. However, the number of natural products is limited, whereas millions of hybrids as combinations of parts of different natural products can be prepared. This new approach seems to be very promising in the development of leads for both medicinal and agrochemical applications, as the biological activity of several new hybrids exceeds that of the parent compounds. The advantage of this concept over a combinatorial chemistry approach is the high diversity and the inherent biological activity of the hybrids.

Total and Local Quadratic Indices of the “Molecular Pseudograph’s Atom Adjacency Matrix”. Application to Prediction of Caco-2 Permeability of Drugs

The high interest in the prediction of the intestinal absorption for New Chemical Entities (NCEs) is generated by the increasing rate in the synthesis of compounds by combinatorial chemistry and the extensive cost of the traditional evaluation methods. Quantitative Structure–Permeability Relationships (QSPerR) of the intestinal permeability across the Caco-2 cells monolayer (PCaco-2) could be obtained by the application of new molecular descriptors. In this sense, quadratic indices of the “molecular pseudograph’s atom adjacency matrix” and multiple linear regression analysis were used to obtain good quantitative models to determine the PCaco-2. QSPerR models found are significant from a statistical point of view. The total and local quadratic indices were calculated with the TOMO-COMD software. A leave-one-out cross-validation procedure (internal validation) and the evaluation of external test set of 20 drugs (external validation) revealed that regression models had a good predictive power. A comparison with results derived from other theoretical studies shown a quite satisfactory behavior of the present method. The descriptors included in the prediction models permitted the interpretation in structural terms of the permeability process, evidencing the main role of H-bonding and size properties. The models found were used in virtual screening of drug intestinal permeability and a relationship between PCaco-2 calculated and percentage of human intestinal absorption for the 72 compounds was established. These results suggest that the proposed method is able to predict PCaco-2, being a good tool for screening of PCaco-2 for large sets of NCEs synthesized via combinatorial chemistry approach.

Combinatorial computational chemistry approach to the design of metal catalysts for deNO x

Combinatorial chemistry is an efficient technique for the synthesis and screening of a large number of compounds. Recently, we introduced the combinatorial approach to computational chemistry for catalyst design and proposed a new method called “combinatorial computational chemistry”. In the present study, we have applied this combinatorial computational chemistry approach to the design of precious metal catalysts for deNO x . As the first step of the screening of the metal catalysts, we studied Rh, Pd, Ag, Ir, Pt, and Au clusters regarding the adsorption properties towards NO molecule. It was demonstrated that the energetically most stable adsorption state of NO on Ir model cluster, which was irrespective of both the shape and number of atoms including the model clusters.

Combinatorial Computational Chemistry Approach to the High-Throughput Screening of Metal Sulfide Catalysts for CO Hydrogenation Process

We have already proposed that a “Combinatorial Computational Chemistry” approach is very effective for performing the theoretical high-throughput screening of new catalysts, and its validity was strongly confirmed in various catalyst systems. In the present study, we applied our combinatorial computational chemistry approach to the design of new metal sulfide catalysts for the CO hydrogenation process and proposed new guidance for designing the highly selective catalysts for methanol synthesis. We investigated H2 and CO adsorption on a large number of metal and metal sulfide catalysts by first-principles calculations, and succeeded in clarifying the relationship between the metal species in the metal and metal sulfide catalysts and the products of the CO hydrogenation processes. Our results indicated that Co, Mo, Ru, Rh, Ir, and Pd sulfide catalysts selectively produce methanol, while Re and Os sulfide catalysts selectively produce hydrocarbons. The above results are in good agreement with the experimental results of Koizumi and co-workers. Moreover, we proposed that the Pd sulfide catalyst has the highest selectivity for methanol from the CO hydrogenation process. This result strongly supports the experimental results by Koizumi and co-workers. Moreover, we propose that the metal sulfide catalysts, which realize the bridge-site adsorption of the CO molecule on both the metal and sulfur atoms, have high selectivity for methanol. This proposed guidance for designing the highly selective metal sulfide catalysts for methanol may be useful for the experiments.

Design of selective peptidomimetic agonists for the human orphan receptor BRS-3.

New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay. Focusing on the N-terminus, the d-Phe-Gln moiety of 4 was modified in a combinatorial SAR-oriented medicinal chemistry approach. With the incorporation of N-arylated glycine and alanine building blocks azaglycine, piperazine, or piperidine and the synthesis of semicarbazides and semicarbazones, a number of highly potent and selective compounds with a reduced number of peptide bonds were obtained, which also should have enhanced metabolic stability.

Rational Optimization of a Short Human P-selectin-binding Peptide Leads to Nanomolar Affinity Antagonists

P-selectin plays an important role in the development of various diseases, including atherosclerosis and thrombosis. In our laboratory we recently identified a number of specific human P-selectin-binding peptides containing a Glu-Trp-Val-Asp-Val consensus motif, displaying a low micromolar affinity for P-selectin (IC(50) = 2 microm). In search of more potent antagonists for P-selectin, we have optimized the EWVDV pentapeptide core motif via a two-step combinatorial chemistry approach. A dedicated library of peptide derivatives was generated by introducing seven substituents at the N and C termini of the motif. In particular, pentapeptides with gallic acid or 1,3,5-benzenetricarboxylic acid substituents at the N terminus proved to be considerably more potent inhibitors of P-selectin binding than the parental peptide. After removal of the N-terminal glutamic acid from the core sequence, which appeared to be replaceable by a carboxamide function without loss of affinity, a second library was synthesized to map the chemical moieties within the gallic acid or 1,3,5-benzenetricarboxyl acid groups responsible for the enhanced P-selectin binding. Moreover, by varying the length and rigidity of the connective spacer, we have further optimized the spatial orientation of the N-terminal substituent. The combined use of phage display and subsequent combinatorial chemistry led to the design of a number of gallic acid- containing peptides with low nanomolar affinity for P-selectin both under static and dynamic conditions (IC(50) = 15.4 nm). These small synthetic antagonists, which are equally as potent as the natural ligand P-selectin glycoprotein ligand-1, are promising leads in anti-atherothrombotic therapy.

Radiative and non-radiative energy transfers in Yb3+-doped sesquioxide and garnet laser crystals from a combinatorial approach based on gradient concentration fibers

The laser heated pedestal growth (LHPG) method allows us to grow Yb3+-doped oxide single crystal fiber with no Yb segregation. We have choosen Y3Al5O12 (YAG) Yttrium aluminum garnet and Y2O3 yttria sesquioxide as Yb3+-doped host crystals, which are considered to be among the best laser crystals due to unusual combination of favorable properties. A combinatorial chemistry approach has been applied by growing concentration gradient crystal fibers allowing the study of the excited state dynamics by the measurement of two important features in laser crystals: the intrinsic radiative lifetime and the analysis of radiative and non-radiative energy transfers which occur in the Yb3+ concentration quenching processes.

Yb3+-doped oxide crystals for diode-pumped solid state lasers: crystal growth, optical spectroscopy, new criteria of evaluation and combinatorial approach

Abstract Our recent scientific program has involved the general evaluation of Yb3+-doped oxide crystals for diode-pumped solid state lasers. Among crystalline families which provide the best expected performances, some have been grown: sesquioxide, oxyapatite, niobate and garnet fibres pulled either from the Laser Heated Pedestal Growth (LHPG) or the Micro-Pulling Down (μ-PD) technique, tungstates by the top nucleated floating crystal (TNFC) and garnet and oxiapatite by the Czochralski (CZ) technique. Optical spectra of all crystals have been performed. In addition, a combinatorial chemistry approach has been pointed out to study the radiative lifetime and the concentration quenching processes in these laser crystals.

Combinatorial enzymatic assay for the screening of a new class of bacterial cell wall inhibitors

We have developed a screening assay by thin-layer chromatography (TLC) to identify inhibitors for the bacterial essential enzymes MurA, -B, and -C. Libraries of compounds were synthesized using the mix-and-split combinatorial chemistry approach. Screening of the pooled compounds using the developed assay revealed the presence of many pools active in vitro. Pools of interest were tested for antibacterial activity. Individual molecules in the active pools were synthesized and retested with the TLC assay and with bacteria. We focused on the best five compounds for further analysis. They were tested for inhibition on each of the three enzymes separately, and showed no inhibition of MurA or MurB activity but were all inhibitors of MurC enzyme. This approach yielded interesting lead compounds for the development of novel antibacterial agents.

From the combinatorial chemistry boom to polymer-supported parallel chemistry: established technologies for drug discovery

The application of combinatorial chemistry has been changing since it was first described almost two decades ago. This review highlights relevant innovative ideas using the combinatorial chemistry approach, focusing on the present and future scope of this technology and its general acceptance among the scientific community. Recent developments include solid-supported reagents, catalysts, scavengers and purification, resin technology (polymer-supported chemistry on monolithic disks); reporter resins for solid-phase organic chemistry; dynamic combinatorial libraries; natural product-based libraries and chemical genetics; and microreactors.

Synthetic Combinatorial Libraries as an Alternative Strategy for the Development of Novel Treatments for Infectious Diseases

Synthetic combinatorial chemistry approaches have created a vast new source of molecular diversity for the potential identification of lead compounds. This revolutionary field enables hundreds to thousands times more compounds to be synthesized and screened in shorter periods of time relative to traditional approaches. Synthetic combinatorial libraries (SCLs) have been used in laboratories to develop antimicrobial and antifungal compounds, as well as novel treatments for HIV infection. Deconvolution procedures are an essential element in the identification of active individual compounds from mixture-based libraries. The positional scanning approach uses a positional scanning SCL (PSSCL), in which the key functionalities at each position of the active compound can be determined directly from the library screening data. Thus, a PS-SCL is composed of sublibraries, each addressing a single position of the sequence while representing the same collection of individual compounds. When used in concert, the data derived from each sublibrary yields information about the key functionalities for each position. Mixture-based PS-SCLs therefore, have the advantage of greatly decreasing the economics and time constraints of single compound array systems.

Design and discovery of small molecules targeting raf-1 kinase.

Raf kinase, an enzyme which acts downstream in the Ras signaling pathway, is involved in cancerous cell proliferation. Thus, small molecule inhibitors of Raf kinase activity may be important agents for the treatment of cancer. A novel class of Raf-1 inhibitors was discovered, using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials. The present review summarizes the medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase.

A combinatorial chemistry approach to gene targeting agents

A combinatorial chemistry approach to gene targeting agents

Novel peptidomimics as angiotensin-Converting enzyme inhibitors: A combinatorial approach

One of the efficient mode of treatments of chronic hypertension and cardiovascular disorders has been to restrain the formation of angiotensin-II by inhibiting the action of angiotensin-converting enzyme (ACE) on angiotensin-I. A number of ACE inhibitors (ACEIs) have been put to therapeutic use during the last two decades. The efforts continue towards achieving superior molecules or drugs with improved affinities, better bioavailability and thus long duration of action with minimum side effects. The present work evolves around similar objectives. In order to understand the mode of interaction of inhibitors with the active site of the enzyme and subsequently to have lead compounds as possible inhibitors the novel dipeptidomimics and tripeptidomimics have been designed and synthesized using combinatorial chemistry approach. A Focussed library of 10 di- and tri-peptides, eight dipeptidomemics and forty tripeptidomemics was generated. The pharmacophoric heterocyclic moieties and the amino acids have been selected to have affinities with the S 1, S 1′, and S 2′ subsites of the active site of the enzyme. ACE inhibition studies clearly demonstrated the structural-activity relationships within these classes of peptidomimics. The dipeptidomimics interacted only with S 1′ and S 2′ subsites, whereas the tripeptidomemics had additional interaction with S 1 subsite, which accounted for their significant ACE inhibition potencies. The in-vitro screening of these peptidomimics have resulted in identification of four promising tripeptidomimics 34[2-benzimidazolepropionyl-Val-Trp], 35[5hydroxytryptophanyl-Val-Trp], 40[2-benzimidazolepropionyl-Ile-Trp] and 45[2-benzimidazolepropionyl-Lys-Trp] with IC 50 values in micromolar concentrations.

Design and synthesis of a combinatorial chemistry library of 7-acyl, 10-acyl, and 7,10-diacyl analogues of paclitaxel (taxol) using solid phase synthesis.

A series of 10-acyl and 7,10-diacyl paclitaxel analogues (7a-7e and 9a-9u) have been synthesized using a solid phase combinatorial chemistry approach, and a second series of 7-acyl-10-deacetylpaclitaxel analogues have been prepared by conventional chemistry. In the first series, 10-deacetylpaclitaxel (4) was linked through its 2'-hydroxyl group using 1% polystyrene-divinyl benzene resin functionalized with butyldiethylsilane linker (PS-DES) and then acylated at the C-10 hydroxyl group with various anhydrides and dialkyl dicarbonates in the presence of CeCl(3). The resin-bound C-10 acylated paclitaxel derivatives (6a-6e) were then treated with various carboxylic acids in the presence of 1,3-diisopropylcarbodiimide in toluene to provide polymer-supported 7,10-diacylpaclitaxels (8a-8u). These 7-acyl- and 7,10-diacylpaclitaxels (6a-6e and 8a-8u) were cleaved from the resin to give the 24 paclitaxel analogues 7a-7e and 9a-9u. Nine 7-acyl-10-deacetylpaclitaxel analogues were also prepared by conventional chemistry. Methodology to determine the tubulin-assembly activity of compounds prepared in small quantities by a combinatorial approach has been developed, and four analogues with improved tubulin-assembly activity as compared with paclitaxel were found, together with two analogues with improved cytotoxicity.

Ethyl 2-[[2-(3-nitrophenyl)-5-phenyl-1H-imidazol-4-yl]sulfanyl]acetate: synthesis via a microwave-mediated combinatorial chemistry approach.

The orange title compound, C(19)H(17)N(3)O(4)S, can be synthesized either via microwave-mediated combinatorial chemistry strategies or conventional synthetic procedures. The phenyl and meta-nitrophenyl C(6) rings are essentially coplanar with the central imidazolyl ring, with interplanar angles of 0.87 (5) and 0.97 (4), respectively, resulting in optimum conjugation (SCH(2) moiety included); lambda(max) = 281 nm in CH(3)CN. The principal intermolecular interactions are N(imid)-H...O(nitro) and N(imid)-H...O[double bond]C [N...O = 3.058 (2) and 3.432 (3) A, and N-H...O = 128 and 153, respectively]. The closest H.S distance is an intramolecular C-H...S contact, with H...S = 2.54 A and C-H...S = 136.