Stereochemical control of skeletal diversity

[reaction: see text]. Substrates having appendages that pre-encode skeletal information (sigma-elements) can be converted into products having distinct skeletons using a common set of reaction conditions. The sequential use of the Ugi 4CC-IMDA reaction, followed by allylation, hydrolysis, and acylation of a chiral amino alcohol appendage (sigma-element), leads to substrates for a ROM/RCM or RCM reaction. The stereochemistry of the sigma-element and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to the challenging problem of skeletal diversity.     

A planning strategy for diversity-oriented synthesis

In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) populates chemical space broadly with small-molecules having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in chemical space. Ideally, these pathways also yield compounds having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the molecules. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic analysis. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic analysis. This analysis facilitates synthetic planning, communication, and teaching in this evolving discipline.     

Diversity-oriented synthesis of bicyclic ring systems via a conjugate addition/aldol/RCM process

Diversity-oriented synthesis(DOS) has been widely applied in the generation of a large collection of highly functionalized molecules with diverse chemical skeletons.Herein,we report the diversity-oriented synthesis of a series of structurally diverse bicyclic substrates via an efficient tandem conjugate addition/aldol process followed by ring-closing metathesis(RCM).This approach allows us to efficiently prepare a number of structurally complex molecules for the further chemical biology studies.     

Simultaneous accumulation of both skeletal and appendage-based diversities on tandem Ugi/Diels-Alder products

Diversity-oriented organic synthesis (DOS) is a key concept for construction of skeletally diverse small molecule libraries to discover drug-like small molecules. Here, we describe a DOS class to transform a complex 7-oxanorbornene skeleton, which is readily accessible by a tandem Ugi/Diels-Alder reaction, into two heterotricycle skeletons selectively by using tandem ROM/CM/RCM reaction. In the present study, the mode of cyclization is pre-encoded by building blocks used in the complexity-generating tandem Ugi/Diels-Alder reaction. Since variable alkenes can be used in the CM reaction, our approach can be extended to construct both skeleton- and appendage-diverse small molecule libraries.     

A cyclic enamine derived from 1,2-O-isopropylidene-alpha-D-xylofuranose as a novel carbohydrate intermediate to achieve skeletal diversity

The commercially available carbohydrate 1,2-O-isopropylidene-alpha-D-xylofuranose was efficiently transformed into the high-added-value synthetic scaffold 8. The transformation requires the synthesis of the 5-O-tosyl derivative 7 and its subsequent intramolecular cyclization under basic conditions to give the cyclic enamine 8. Reaction of 8 with O-, N-, S-, and C-nucleophiles and amino acids allowed its efficient transformation (one-step, high yields, and easy purifications) into fused cyclic sugar derivatives with rather unusual molecular skeletons in a completely regio- and stereoselective manner. The characteristics of the sugar derivative 8 established here, high reactivity, synthetic accessibility, and the potential for conversion into a vast collection of products by the action of different nucleophiles, indicate that it will prove to be a useful chiral intermediate for achieving skeletal diversity. The constrained structures and dense functionalization of the polycyclic sugar derivatives generated from 8 make these compounds promising candidates for use as starting agents for the production of new analogues and as drugs.     

Skeletal diversity via a branched pathway: efficient synthesis of 29 400 discrete,polycyclic compounds and their arraying into stock solutions

We report the synthesis and arraying of 29 400 structurally diverse and complex polycyclic carbocycles using diversity-oriented synthesis (DOS) and the "one bead-one stock solution" technology platform. Skeletal diversity, a difficult challenge in DOS, was achieved with a branching reaction pathway using one or two Diels-Alder reactions. This pathway yields small molecules having 10 different skeletons.     

Skeletal diversity via a folding pathway: synthesis of indole alkaloid-like skeletons

Inspired by the skeletal diversity of naturally occurring indole alkaloids and the rich potential of chemistry developed by Padwa and co-workers, we conceived a pathway entailing six modes of intramolecular reactions leading to indole alkaloid-like skeletons. In this context, an efficient folding pathway via a rhodium-catalyzed tandem cyclization-cycloaddition involving three of the modes has been developed (two of which are shown above) that affords densely functionalized compounds with three distinct skeletons in a stereocontrolled manner.     

A statistical model for predicting protein folding rates from amino acid sequence with structural class information

Prediction of protein folding rates from amino acid sequences is one of the most important challenges in molecular biology. In this work, I have related the protein folding rates with physical-chemical, energetic and conformational properties of amino acid residues. I found that the classification of proteins into different structural classes shows an excellent correlation between amino acid properties and folding rates of two- and three-state proteins, indicating the importance of native state topology in determining the protein folding rates. I have formulated a simple linear regression model for predicting the protein folding rates from amino acid sequences along with structural class information and obtained an excellent agreement between predicted and experimentally observed folding rates of proteins; the correlation coefficients are 0.99, 0.96 and 0.95, respectively, for all-alpha, all-beta and mixed class proteins. This is the first available method, which is capable of predicting the protein folding rates just from the amino acid sequence with the aid of generic amino acid properties and structural class information.     

Concise and diversity-oriented synthesis of novel scaffolds embedded with privileged benzopyran motif

A branching DOS strategy for an unbiased natural product-like library with embedded privileged benzopyran motif was established to provide complexity and diversity of resulting heterocycles with desired drug-likeness. The importance of skeletal diversity conducted on a privileged substructure was demonstrated through the biological evaluation of a small molecule library representing 22 unique core skeletons via in vitro cytotoxicity assay.     

A substrate-based folding process incorporating chemodifferentiating ABB' three-component reactions of terminal alkynoates and 1,2-dicarbonyl compounds: a skeletal-diversity-oriented synthetic manifold

A novel three-component reaction (3CR)-based folding process that is able to generate complexity and skeletal diversity is described. The process utilizes chemodifferentiating organocatalyzed ABB' 3CRs of a terminal conjugated alkynoate (building block) with alpha-dicarbonyl compounds (diversity-generating blocks) to generate an array of different molecular topologies (gamma-lactones, linear propargylic enol ethers, or 1,3-dioxolane rings). Amides and esters behave as efficient reactivity-encoding elements (sigma) of the attached keto functionality. Three chemical properties govern the chemical outcome of this folding process: acidity, nucleophilicity (of the catalyst), and carbonyl electrophilicity. Overall, this substrate-based folding process generates three different molecular architectures from the same modular functionalities (ketones) and under the same reaction conditions (methyl propiolate and tertiary amine). In addition, and very importantly for combinatorial applications, all of the products share a common reactive functionality that allows them to be collective substrates for a subsequent diversity-generating process.     

Diversity-oriented synthesis and solid-phase organic synthesis under controlled microwave heating

Diversity-oriented organic synthesis (DOS) and solid-phase organic synthesis (SPOS) are proven technologies for generating small molecule libraries for chemical genetics studies. Integration of controlled microwave heating with DOS and SPOS not only speeds up the library preparation process but also offers unique opportunities in tackling issues which are hardly addressed by thermal heating. Microwave-assisted synthesis is illustrated for (a) highly regioselective Wittig olefination of cycloalkanones by accurate regulation of temperature; (b) tandem Wittig-IMDA sequence toward stereochemical diversity of gamma-butyrolactones; (c) one-pot alkylation-amidation approach toward appendage diversity through use of building blocks; and (d) one-pot U-4CR-annulation strategy toward skeletal diversity via careful reaction design. Microwave-assisted solid-phase organic synthesis (MASPOS) is highlighted by incorporating with split-pool combinatorial synthesis (SPCS) of indole sulfonamides via a key on-resin Cu(II)- or Pd(II)-catalyzed heteroannulation under microwave heating. Design and fabrication of a novel diglycine-derived catlinker are described and its role in facilitating on-resin reaction is evaluated. A traceless synthesis of indole sulfonamides via microwave-assisted Cu(II)-catalyzed heteroannulation of the catlinker-tethered substrates is also given.     

Fluorous mixture synthesis of two libraries with hydantoin-, and benzodiazepinedione-fused heterocyclic scaffolds

Diversity-oriented synthesis (DOS) and fluorous mixture synthesis (FMS) are two aspects of combinatorial chemistry. DOS generates library scaffolds with skeletal, substitution, and stereochemistry variations, whereas FMS is a highly efficient tool for library production. The combination of these two aspects in solution-phase synthesis of two novel heterocyclic compound libraries is presented in this paper. Mixtures of different fluorous amino acids undergo [3 + 2] cycloadditions followed by postcondensation reactions. The mixtures are then demixed by fluorous HPLC. Fluorous tags are removed by cyclization to afford hydantoin- and benzodiazepinedione-fused heterocyclic compounds as individual, pure, and structurally defined molecules. The application of MS-directed HPLC purification and parallel four-channel LC/MS analysis further increases the efficiency of FMS.     

The Construction of New Proteins and Enzymes-a Prospect for the Future?

Only a vanishingly small proportion of the almost infinite number of possible proteins occur in nature. Can this remaining potential of structural and functional diversity be used in the construction of new proteins? Is a “second evolution” of proteins and enzymes about to occur? These questions have suddenly become of interest because the recombinant DNA technique allows the synthesis of any given amino acid sequence. Examples of enzyme models demonstrate clearly that the unusual catalytic properties of enzymes are associated with the presence of a specifically folded polypeptide chain which has a complex three-dimensional form. The critical hurdle in the path of artificial proteins is thus the design of amino acid sequences which are able to fold into tertiary structures. — Recent studies on the topology and the mechanism of folding have provided considerable insight into the occurrence of, and the rules governing the three-dimensional architecture of proteins. Secondary structures apparently play a key role in the folding process; helices and “β-structures” act as nucleation centers directing folding and account for the surprisingly small number of different folding topologies. The problem of secondary structure formation can be investigated directly by means of conformational studies on model peptides. Oligopeptides with tailormade physicochemical, structural and conformational properties can already be designed. The theoretical and experimental basis for the construction of polypeptides with stable tertiary structures is therefore established. The path to macromolecules with an immense variety of novel properties lays before us.     

Predicting protein folding rates using the concept of Chou's pseudo amino acid composition

One of the most important challenges in computational and molecular biology is to understand the relationship between amino acid sequences and the folding rates of proteins. Recent works suggest that topological parameters, amino acid properties, chain length and the composition index relate well with protein folding rates, however, sequence order information has seldom been considered as a property for predicting protein folding rates. In this study, amino acid sequence order was used to derive an effective method, based on an extended version of the pseudo-amino acid composition, for predicting protein folding rates without any explicit structural information. Using the jackknife cross validation test, the method was demonstrated on the largest dataset (99 proteins) reported. The method was found to provide a good correlation between the predicted and experimental folding rates. The correlation coefficient is 0.81 (with a highly significant level) and the standard error is 2.46. The reported algorithm was found to perform better than several representative sequence-based approaches using the same dataset. The results indicate that sequence order information is an important determinant of protein folding rates.     

Expanding the chemical space in practice: diversity-oriented synthesis

Diversity-Oriented Synthesis (DOS) aims to broaden the frontier of accessible collections of complex and diverse small molecules. This review endeavours to dissect the DOS concept through three elements of diversity: building block, stereochemistry, and skeleton. Recent examples in the literature that emphasize the efficient combinations of these elements to generate diversity are reported.     

Diversity-oriented synthesis: producing chemical tools for dissecting biology

Small molecule modulators of biological function can be discovered by the screening of compound libraries. However, it became apparent that some human disease related targets could not be addressed by the libraries commonly used which typically are comprised of large numbers of structurally similar compounds. The last decade has seen a paradigm shift in library construction, with particular emphasis now being placed on increasing a library's structural, and thus functional diversity, rather than only its size. Diversity-oriented synthesis (DOS) aims to generate such structural diversity efficiently. This tutorial review has been written to introduce the subject to a broad audience and recent achievements in both the preparation and the screening of structurally diverse compound collections against so-called 'undruggable' targets are highlighted.     

Diversity‐Oriented Synthesis of Drug‐Like Macrocyclic Scaffolds Using an Orthogonal Organo‐ and Metal Catalysis Strategy

Small‐molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity‐oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three‐dimensionality, to target a broad area of biological space. In this study, an organocatalysis‐derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity‐generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one‐pot protocol facilitated the synthesis of drug‐like macrocycles with natural‐product‐like levels of shape diversity in a single step.     

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.

Fragment-based screening of a shape-diverse collection yielded four hits against three proteins. Up to 14 analogues of each hit were rapidly generated, enabling four fragment growth vectors to be explored using inexpensive materials and reliable synthetic transformations.     

Improving protein structural class prediction using novel combined sequence information and predicted secondary structural features

Protein structural class prediction solely from protein sequences is a challenging problem in bioinformatics. Numerous efficient methods have been proposed for protein structural class prediction, but challenges remain. Using novel combined sequence information coupled with predicted secondary structural features (PSSF), we proposed a novel scheme to improve prediction of protein structural classes. Given an amino acid sequence, we first transformed it into a reduced amino acid sequence and calculated its word frequencies and word position features to combine novel sequence information. Then we added the PSSF to the combine sequence information to predict protein structural classes. The proposed method was tested on four benchmark datasets in low homology and achieved the overall prediction accuracies of 83.1%, 87.0%, 94.5%, and 85.2%, respectively. The comparison with existing methods demonstrates that the overall improvements range from 2.3% to 27.5%, which indicates that the proposed method is more efficient, especially for low-homology amino acid sequences.     

Diversity-oriented synthesis of 13- to 18-membered macrolactams via ring-closing metathesis

An efficient build/couple/pair approach to diversity-oriented synthesis was employed to access several structurally complex macrolactams. In this paper, we describe the successful evaluation of ring-closing metathesis toward the systematic generation of skeletal diversity. By appropriately varying the nature and chain length of the alkenol fragment, a diverse collection of 13- to 18-membered macrolactams were obtained.