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Special Issue "Diversity Oriented Synthesis"

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (28 February 2011)

Special Issue Editor

Guest Editor
Prof. Dr. Peter Wipf

757 Chevron Science Center, Department of Chemistry, University of Pittsburgh, PA 15260, USA
Website | E-Mail
Fax: +1 412 624 0787
Interests: natural product total synthesis; organometallic chemistry; heterocyclic chemistry; combinatorial chemistry; medicinal chemistry

Special Issue Information

Dear Colleagues,

In many ways, Diversity-Oriented Synthesis (DOS) represents the conceptualization and expansion of some long-established research principles in medicinal chemistry and drug discovery. The physicochemical metrics that allow us to evaluate the structural similarity within a set of organic molecules often fall short in capturing the essence of the 3-dimensional array of functional groups that the chemist’s eye looks recognizes. In particular, there is a major discrepancy between theory and utility if these metrics are mainly based on generic descriptors such as molecular weight and logP, which tend to cluster in a narrow range. Research in applying the tools of organic synthesis to the construction of scaffold and stereochemical diversity in small organic molecules has never been so active, benefiting from decades of natural products chemistry and advances in multicomponent and pericyclic reactions, as well as asymmetric catalysis. Many of the resulting new organic products are finding their way into public and industrial high throughput screening programs, and therefore serve to link chemical and biological space.
This Special Issue on Diversity-Oriented Synthesis will offer an attractive forum to present the synthesis, structural and cheminformatics analysis, pharmacology and therapeutic potential offered by new and innovative molecular architectures. I strongly encourage authors to submit papers for this Special Issue on DOS, within the scope of Molecules. I hope that the topics covered will reflect the potential and the excitement of DOS in the chemical community.

Dr. Peter Wipf
Guest Editor

Keywords

  • natural product-like agents
  • molecular scaffolds
  • stereodivergence and stereoselectivity
  • multicomponent reactions
  • pericyclic processes
  • chemical library synthesis
  • cheminformatics
  • diversity analysis
  • probe molecules
  • biological screening

Published Papers (8 papers)

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Research

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Open AccessArticle Coupling Two Different Nucleic Acid Circuits in an Enzyme-Free Amplifier
Molecules 2012, 17(11), 13211-13220; doi:10.3390/molecules171113211
Received: 21 September 2012 / Revised: 31 October 2012 / Accepted: 1 November 2012 / Published: 6 November 2012
Cited by 12 | PDF Full-text (763 KB) | Supplementary Files
Abstract
DNA circuits have proven to be useful amplifiers for diagnostic applications, in part because of their modularity and programmability. In order to determine whether different circuits could be modularly stacked, we used a catalytic hairpin assembly (CHA) circuit to initiate a hybridization chain
[...] Read more.
DNA circuits have proven to be useful amplifiers for diagnostic applications, in part because of their modularity and programmability. In order to determine whether different circuits could be modularly stacked, we used a catalytic hairpin assembly (CHA) circuit to initiate a hybridization chain reaction (HCR) circuit. In response to an input nucleic acid sequence, the CHA reaction accumulates immobilized duplexes and HCR elongates these duplexes. With fluorescein as a reporter each of these processes yielded 10-fold signal amplification in a convenient 96-well format. The modular circuit connections also allowed the output reporter to be readily modified to a G-quadruplex-DNAzyme that yielded a fluorescent signal. Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)
Open AccessArticle Diversity-Oriented Synthesis Based on the DPPP-Catalyzed Mixed Double-Michael Reactions of Electron-Deficient Acetylenes and β-Amino Alcohols
Molecules 2011, 16(5), 3802-3825; doi:10.3390/molecules16053802
Received: 6 April 2011 / Revised: 29 April 2011 / Accepted: 5 May 2011 / Published: 5 May 2011
Cited by 11 | PDF Full-text (311 KB)
Abstract
In this study, we prepared oxizolidines through 1,3-bis(diphenylphosphino)-propane (DPPP)–catalyzed mixed double-Michael reactions of b-amino alcohols with electron-deficient acetylenes. These reactions are very suitable for the diversity-oriented parallel syntheses of oxizolidines because: (i) they are performed under mild metal-free conditions and (ii) the products
[...] Read more.
In this study, we prepared oxizolidines through 1,3-bis(diphenylphosphino)-propane (DPPP)–catalyzed mixed double-Michael reactions of b-amino alcohols with electron-deficient acetylenes. These reactions are very suitable for the diversity-oriented parallel syntheses of oxizolidines because: (i) they are performed under mild metal-free conditions and (ii) the products are isolated without complicated work-up. To demonstrate the applicability of mixed double-Michael reactions for the preparation of five-membered-ring heterocycles, we prepared 60 distinct oxazolidines from five β-amino alcohols and 12 electron-deficient acetylenes. We synthesized 36 of these 60 oxazolidines in enantiomerically pure form from proteinogenic amino acid–derived β-amino alcohols. Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)
Figures

Open AccessArticle Diversity-Oriented Synthesis of a Library of Substituted Tetrahydropyrones Using Oxidative Carbon-Hydrogen Bond Activation and Click Chemistry
Molecules 2011, 16(5), 3648-3662; doi:10.3390/molecules16053648
Received: 9 March 2011 / Accepted: 12 April 2011 / Published: 2 May 2011
Cited by 2 | PDF Full-text (315 KB)
Abstract
Eighteen (2RS,6RS)-2-(4-methoxyphenyl)-6-(substituted ethyl)dihydro-2H-pyran-4(3H)ones were synthesized via a DDQ-mediated oxidative carbon-hydrogen bond activation reaction. Fourteen of these tetrahydropyrans were substituted with triazoles readily assembled via azide-alkyne click-chemistry reactions. Examples of a linked benzotriazole and pyrazole motif
[...] Read more.
Eighteen (2RS,6RS)-2-(4-methoxyphenyl)-6-(substituted ethyl)dihydro-2H-pyran-4(3H)ones were synthesized via a DDQ-mediated oxidative carbon-hydrogen bond activation reaction. Fourteen of these tetrahydropyrans were substituted with triazoles readily assembled via azide-alkyne click-chemistry reactions. Examples of a linked benzotriazole and pyrazole motif were also prepared. To complement the structural diversity, the alcohol substrates were obtained from stereoselective reductions of the tetrahydropyrone. This library provides rapid access to structurally diverse non-natural compounds to be screened against a variety of biological targets. Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)
Open AccessArticle Synthesis of Lasofoxifene, Nafoxidine and Their Positional Isomers via the Novel Three-Component Coupling Reaction
Molecules 2010, 15(10), 6773-6794; doi:10.3390/molecules15106773
Received: 21 August 2010 / Revised: 13 September 2010 / Accepted: 20 September 2010 / Published: 28 September 2010
Cited by 4 | PDF Full-text (440 KB) | Supplementary Files
Abstract
A Lewis acid-mediated three-component coupling reaction was successfully applied for the synthesis of lasofoxifene (1), nafoxidine (2), and their positional isomers, inv-lasofoxifene (3) and inv-nafoxidine (4). In the presence of HfCl4,
[...] Read more.
A Lewis acid-mediated three-component coupling reaction was successfully applied for the synthesis of lasofoxifene (1), nafoxidine (2), and their positional isomers, inv-lasofoxifene (3) and inv-nafoxidine (4). In the presence of HfCl4, the desired one-pot coupling reaction among 4-pivaloyloxybenzaldehyde (5), cinnamyltrimethylsilane (6), and anisole proceeded to afford the corresponding 3,4,4-triaryl-1-butene 7 in high yield. The iodocarbocyclization of the coupling product and the successive elimination of hydrogen iodide forming the olefin part, followed by the migration of the double-bond afforded the common synthetic intermediate of lasofoxifene (1) and nafoxidine (2) via a very concise procedure. Additionally, the syntheses of their positional isomers inv-lasofoxifene (3) and inv-nafoxidine (4) were also achieved through very convenient protocols. Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)
Figures

Open AccessArticle Modular Synthesis of Polyphenolic Benzofurans, and Application in the Total Synthesis of Malibatol A and Shoreaphenol
Molecules 2010, 15(9), 5909-5927; doi:10.3390/molecules15095909
Received: 29 July 2010 / Revised: 26 August 2010 / Accepted: 27 August 2010 / Published: 27 August 2010
Cited by 6 | PDF Full-text (298 KB)
Abstract A modular strategy for the synthesis of hexacyclic dimeric resveratrol polyphenolic benzofurans is reported. The developed synthetic technology was applied to the total synthesis of malibatol A, shoreaphenol, and other biologically relevant poly-phenols. Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)

Review

Jump to: Research

Open AccessReview Targeting Oncogenic Protein-Protein Interactions by Diversity Oriented Synthesis and Combinatorial Chemistry Approaches
Molecules 2011, 16(6), 4408-4427; doi:10.3390/molecules16064408
Received: 10 March 2011 / Revised: 4 May 2011 / Accepted: 25 May 2011 / Published: 27 May 2011
Cited by 13 | PDF Full-text (501 KB)
Abstract
We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder
[...] Read more.
We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder drug development success. Protein-protein interactions (PPIs) are key players in numerous cellular processes and aberrant interruption of this complex network provides a basis for various disease states, including cancer. Thus, it is now believed that cancer drug discovery, in addition to the design of single-targeted bioactive compounds, should also incorporate diversity-oriented synthesis (DOS) and other combinatorial strategies in order to exploit the ability of multi-functional scaffolds to modulate multiple protein-protein interactions (biological hubs). Throughout the review, we highlight the chemistry driven approaches to access diversity space for the discovery of small molecules that disrupt oncogenic PPIs, namely the p53-Mdm2, Bcl-2/Bcl-xL-BH3, Myc-Max, and p53-Mdmx/Mdm2 interactions. Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)
Figures

Open AccessReview From Polymer to Small Organic Molecules: A Tight Relationship between Radical Chemistry and Solid-Phase Organic Synthesis
Molecules 2011, 16(4), 3252-3314; doi:10.3390/molecules16043252
Received: 8 March 2011 / Revised: 28 March 2011 / Accepted: 11 April 2011 / Published: 18 April 2011
Cited by 7 | PDF Full-text (688 KB)
Abstract
Since Gomberg’s discovery of radicals as chemical entities, the interest around them has increased through the years. Nowadays, radical chemistry is used in the synthesis of 75% of all polymers, inevitably establishing a close relationship with Solid-Phase Organic Synthesis. More recently, the interest
[...] Read more.
Since Gomberg’s discovery of radicals as chemical entities, the interest around them has increased through the years. Nowadays, radical chemistry is used in the synthesis of 75% of all polymers, inevitably establishing a close relationship with Solid-Phase Organic Synthesis. More recently, the interest of organic chemists has shifted towards the application of usual “in-solution” radical chemistry to the solid-phase, ranging from the use of supported reagents for radical reactions, to the development of methodologies for the synthesis of small molecules or potential libraries. The aim of this review is to put in perspective radical chemistry, moving it away from its origin as a synthetic means for solid supports, to becoming a useful tool for the synthesis of small molecules. Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)
Open AccessReview Challenges and Perspectives of Chemical Biology, a Successful Multidisciplinary Field of Natural Sciences
Molecules 2011, 16(3), 2672-2687; doi:10.3390/molecules16032672
Received: 9 February 2011 / Revised: 9 March 2011 / Accepted: 15 March 2011 / Published: 23 March 2011
Cited by 2 | PDF Full-text (701 KB)
Abstract Objects, goals, and main methods as well as perspectives of chemical biology are discussed. This review is focused on the fundamental aspects of this emerging field of life sciences: chemical space, the small molecule library and chemical sensibilization (small molecule microassays). Full article
(This article belongs to the Special Issue Diversity Oriented Synthesis)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.


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