Heterocyclic Libraries Research Articles

Structural Simplification of Bioactive Natural Products with Multicomponent Synthesis. 2. Antiproliferative and Antitubulin Activities of Pyrano[3,2-c]pyridones and Pyrano[3,2-c]quinolones

Pyrano[3,2- c]pyridone and pyrano[3,2- c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.

Diversity-Oriented Synthesis of Privileged Benzopyranyl Heterocycles from s-cis-Enones

A novel strategy for the construction of benzopyranyl heterocyclic series with maximized diversity in the polar surface area on rigid scaffolds has been developed through a divergent synthetic pathway with high efficiency. s-cis-Enones embedded in a benzopyran skeleton were identified as versatile key intermediates for the synthesis of four different heterocycle libraries fused with a benzopyran substructure. These four novel core skeletons were designed by a creative recombination of the privileged skeletons: benzopyran, pyridine, pyrazole, pyrazolopyrimidine, and pyrimidine. The regioselective synthesis of each core skeleton was achieved by the introduction of three s-cis enone intermediates. This paper also explores the regioselective formation of arylpyrazole through the condensation of beta-keto aldehyde with arylhydrazine under three different conditions and presents the mechanistic information that was obtained from the regioisomeric ratio of arylpyrazole based on the substituent's electronic effect and reaction temperature. It appears that the regioselective synthesis of arylpyrazole was achieved through the intriguing interplay of the nucleophilicity on arylhydrazine and the electrophilicity on dielectrophiles.

Synthesis of novel 3-[5-ethyl-2-(2-phenoxy-ethyl)-pyridin]-5-substituted isoxazoline libraries via 1,3-dipolar cycloaddition and evaluation of antimicrobial activities

A series of novel 3-[5-ethyl-2-(2-phenoxy-ethyl)-pyridin]-5-substituted isoxazolines were synthesized via 1,3-dipolar cycloaddition of in situ generated nitrile oxide from 4-[2-(5-ethylpyridyl)-ethoxy]-benzaldoxime with alkenes to obtain new heterocyclic libraries containing a pyridine moiety in addition to the isoxazoline ring. The newly synthesized compounds were screened for their antimicrobial activity and were compared with standard drugs. The compounds demonstrated potent to weak antimicrobial activity. Of the compounds studied, compounds 3c and 3f showed significant antibacterial as well as antifungal activity. Compounds 3e and 3g showed moderate activity. The title compounds represent a novel class of potent antimicrobial agents.

Solid-Phase Synthesis of Linked Heterocycles from a Selenopolystyrene Resin

A linked heterocycle library of isoxazoles, 1,2,3-triazoles, bicyclo[2.2.1]hepta-2,5-diene or 4-methylcyclohexa-1,3-diene and 1,2,4-oxadiazoles was prepared by solid-phase organic synthesis. Key steps on resin-bound selenium were electrophilic additions; 1,3-dipolar cycloaddition; Porco's two-step, one-pot condensation of amidoxime and carboxylate; and Diels-Alder reaction.

Microreactor Array Assembly, Designed for Diversity Oriented Synthesis Using a Multiple Core Structure Library on Solid Support

AbstractThe application of spatially encoded principles in solid phase combinatorial synthesis requires no chemical or physical coding strategies. The resulting products are encoded by their position inside the array and their synthesis history. The advantages of microreactor arrays for solid phase synthesis as one of the embodiments in the field of microreaction technology are discussed. Here, we review the reactor design, necessary process steps, and a strategy for the diversity oriented array synthesis. In particular, the glass‐made microreactor and its assembly for 1563 parallel solid phase reactions, which can be performed at temperatures up to 120 °C, are described. Bead loading and liquid handling steps were adapted to this array. The production of large libraries demands suitable synthesis protocols and building blocks. The optimization of appropriate synthesis conditions is a time‐consuming process. A multiple core structure library approach for the efficient synthesis of diverse heterocyclic libraries is described. The aim of this work was to prove the feasibility of the glass‐microreaction array for massive parallel library synthesis.

Hypervalent Iodine Mediated Intramolecular Cyclization of Thioformanilides: Expeditious Approach to 2-Substituted Benzothiazoles

A new, mild, and efficient method has been developed for the synthesis of 2-substituted benzothiazoles via the intramolecular cyclization of thioformanilides by using hypervalent iodine reagents in CH2Cl2 at ambient temperature. The reaction proceeds via a thiyl radical in high yields to give the novel compound oxybis benzothiazole and is also amenable to generating combinatorial libraries of heterocyclic compounds by solid-phase synthesis.

In vitro and direct in vivo testing of mixture-based combinatorial libraries for the identification of highly active and specific opiate ligands

The use of combinatorial libraries for the identification of novel opiate and related ligands in opioid receptor assays is reviewed. Case studies involving opioid assays used to demonstrate the viability of combinatorial libraries are described. The identification of new opioid peptides composed of L-amino acids, D-amino acids, or L-, D-, and unnatural amino acids is reviewed. New opioid compounds have also been identified from peptidomimetic libraries, such as peptoids and alkylated dipeptides, and those identified from acyclic (eg, polyamine, urea) and heterocyclic (eg, bicyclic guanidine) libraries are reviewed.

Design and Synthesis of a Tetracyclic Pyrimidine-Fused Benzodiazepine Library

Method development for a heterocyclic library which entails novel scaffolds of benzodiazepines fused with various heterocycles, such as pyrimidines, indolines, and tetrahydroquinolines, was accomplished. The new synthetic strategy is based on an electrophilic cyclization reaction involving an iminium intermediate formed by the corresponding aminopyrimidine with a carbonyl compound to give the desired heterocycles in high yields. Subsequent replacement of the chloro group in the resulted structures with a nucleophile, such as boronic acids, amines, alcohols and thiols, led to a library of privileged compounds with up to eight accessible diversity points.

Discovery of EGFR Selective 4,6-Disubstituted Pyrimidines from a Combinatorial Kinase-Directed Heterocycle Library

The epidermal growth factor receptor (EGFR) tyrosine kinase was one of the first receptor tyrosine kinases to be targeted for drug development by the pharmaceutical industry due to its ubiquitous overexpression in a variety of tumors. Despite the validation of several quinazoline-based scaffolds in the clinic, there is a dearth of alternative chemical structure classes that are capable of inhibiting EGFR kinase activity selectively. Here we describe the discovery of potent and highly selective 4,6-disubstituted pyrimidine inhibitors of enzymatic and cellular EGFR activity and provide an explanation for their exceptional degree of kinase selectivity.

Allosteric inhibitors of Bcr-abl–dependent cell proliferation

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.

In Vitro and Direct In Vivo Testing of Mixture-Based Combinatorial Libraries for the Identification of Highly Active and Specific Opiate Ligands

The use of combinatorial libraries for the identification of novel opiate and related ligands in opioid receptor assays is reviewed. Case studies involving opioid assays used to demonstrate the viability of combinatorial libraries are described. The identification of new opioid peptides composed of L-amino acids, D-amino acids, or L-, D-, and unnatural amino acids is reviewed. New opioid compounds have also been identified from peptidomimetic libraries, such as peptoids and alkylated dipeptides, and those identified from acyclic (eg, polyamine, urea) and heterocyclic (eg, bicyclic guanidine) libraries are reviewed.

Simultaneously electrogenerated diene and dienophile: A unique access to novel polyfunctionalized 1,4-benzoxazine derivatives as neuroprotective agents

New insights into the scope of a multistep one-pot electrochemical synthesis of polyfunctionalized 2-alkylamino-1,4-benzoxazine derivatives are delineated. This cascade sequence, wherein both cycloaddition partners are generated in situ, at room temperature, under metal-free conditions, should be useful to generate libraries of heterocycles which constitute the molecular framework of medicinally relevant compounds. In this respect, 2-alkylamino-1,4-benzoxazine derivatives proved to be potent neuroprotective agents in vitro, on immortalized HT22 hippocampal cell cultures, and in vivo, in an animal model mimicking the cerebral palsy in human newborns.

Solid-phase synthesis of oxazolones and other heterocycles via Wang resin-bound diazocarbonyls

The preparation of Wang resin bound α-diazo-β-ketoesters is described. These highly useful intermediates were used for the synthesis of a series of heterocycle libraries, which were obtained from the resin using TFA cleavage. In addition, a novel route for the synthesis of oxazolones using an N–H insertion strategy is disclosed.

A structurally diverse heterocyclic library: A benzothiazepine-fused ? -lactam library derived from reaction of 2,3-dihydro-1,5-benzothiazepines and acyl chlorides: Synthesis and stereochemistry

A 1H-azeto[2,1-d][1,5]benzothiazepin-1-one, beta-lactam derivatives of dihydrobenzothiazepines library derived from reactions of 2,4-disubstituted 2,3-dihydro-1,5-benzothiazepines and acyl chlorides, including phthalimidoacetyl chloride, chloroacetyl chloride, dichloroacetyl chloride and phenoxyacetyl chloride, was built up through parallel solution-phase synthesis. Stereochemistry of 1H-azeto[2,1-d][1,5]benzothiazepin-1-ones in the reaction process is discussed.

The Virtue of the Multifunctional Triazene Linkers in the Efficient Solid‐Phase Synthesis of Heterocycle Libraries.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Virtue of the Multifunctional Triazene Linkers in the Efficient Solid-Phase Synthesis of Heterocycle Libraries

With the implementation of combinatorial chemistry into the modern drug discovery process, the approach to novel diverse heterocycle libraries is an indispensable requirement. Triazenes, which are concealed diazonium salts, can be used to link functionalized arenes and amines to generate various heterocyclic structures, namely, benzoannelated nitrogen heterocycles, upon cleavage from the resin. Since triazene anchors are stable toward various reagents and perform well under a range of reaction conditions, these multifunctional linkers are well suited for automated solid-phase syntheses and the syntheses of complex organic molecules, such as natural products, on solid supports.

Simultaneously Electrogenerated Cycloaddition Partners for Regiospecific Inverse‐Electron‐Demand Diels—Alder Reactions: A Route for Polyfunctionalized 1,4‐Benzoxazine Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Natural Product‐Like and Other Biologically Active Heterocyclic Libraries Using Solid‐Phase Techniques in the Postgenomic Era

AbstractFor Abstract see ChemInform Abstract in Full Text.

Safety-catch approach to orthogonal synthesis of a triazine library.

A novel safety-catch method for orthogonal synthesis of highly pure trisubstituted triazines was developed. Since the polymer-support used in this method is not acid-labile, this strategy can be uniquely applied to the synthesis of acid-sensitive triazine library compounds. This method will dramatically increase the diversity of triazine and other related heterocyclic library compounds.

Translation of DNA into synthetic N-acyloxazolidines.

The translation of DNA into synthetic molecules enables their manipulation by powerful evolution-based methods previously available only to proteins and nucleic acids. The development of increasingly sophisticated DNA-templated small-molecule syntheses is crucial to broadening the scope of this approach. Here, we report the translation of DNA templates into monocyclic and bicyclic N-acyloxazolidines using multistep DNA-templated organic synthesis. Second-generation template architectures, used for the first time in a multistep DNA-templated synthesis, together with reactions and linker cleavage strategies not previously described in a DNA-templated format, were crucial to the successful translation. The products generated in this work represent the most complex small molecules to date synthesized in a DNA sequence-programmed manner and provide the basis for DNA-templated synthetic heterocycle libraries.