Thiol-containing diketopiperazines have been recently identified as novel heterocyclic inhibitors of matrix metalloproteinase (MMPs). The compounds described had similar activities against the MMPs collagenase-1 and gelatinase-B. An inhibitor that showed greater than 10-fold selectivity for collagenase-1 over gelatinase-B was desired. Previously published work with peptidyl hydroxamates and thiols indicated that while preparing gelatinase selective inhibitors was straightforward, there was not an obvious route to selective inhibitors of collagenase-1. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1 and gelatinase-B substrate hydrolysis. A method for estimating the IC50 values of compounds generated by high-throughput parallel synthesis aided in the identification of compounds with the desired properties. We have found that thiol diketopiperazines derived from nitrophenylalanine are both potent and selective inhibitors of collagenase-1. In addition, we have demonstrated that combinatorial chemistry can be utilized to identify molecules with a desired selectivity profile without access to the traditional tools of rational drug design.

A sensitive lawn-based format has been developed to screen bead-tethered combinatorial chemical libraries for antimicrobial activity. This method has been validated with beads linked to penicillin V via a photocleavable chemical linker in several analyses including a spike-and-recover experiment. The lawn-based screen sensitivity was modified to detect antibacterial compounds of modest potency, and a demonstration experiment with a naive combinatorial library of over 46,000 individual triazines was evaluated for antibacterial activity. Numerous hits were identified, and both active and inactive compounds were resynthesized and confirmed in traditional broth assays. This demonstration experiment suggests that novel antimicrobial compounds can be easily identified from very large combinatorial libraries of small, nonpeptidic compounds.

This review is a survey of published articles describing the application of combinatorial and parallel diversity libraries to the identification and optimization of anti-inflammatory agents.

A novel series of matrix metalloproteinase (MMP) inhibitors is described. Incorporation of a terminal α-mercaptoketone or α-mercaptoalcohol in the zinc binding domain of a series of inhibitors led to compounds exhibiting low nanomolar activity against collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).

The solid phase synthesis of 3-acyl-2,4-pyrrolidinediones (3-acyl tetramic acids) has been reported. Cyclative cleavage of the penultimate intermediate via a Dieckmann cyclization yields the 3-acyl-2,4-pyrrolidinediones. Remarkably mild conditions are required for the cyclative cleavage; treatment of the resin-bound acyclic precursor with one equivalent of potassium hydroxide in methanol at room temperature for 5-30 minutes affords the product. The synthetic route routinely provides high yields in greater than 95% purity and is compatible with acid-labile protecting groups. Virtually any hydroxy-functionalized resin can be utilized for this synthesis.

A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).

The discovery of a novel series of heterocyclic matrix metalloproteinase (MMPs) inhibitors is described. Published crystal structures of peptidyl hydroxamates bound to MMPs were the basis for the rational design of diketopiperazine (DKP) inhibitors. Combinatorial Libraries were prepared and evaluated for their ability to inhibit collagenase-1, stromelysin-1, and gelatinase-B substrate hydrolysis. Deconvolution of active pools resulted in the identification of potent inhibitors (IC50's < 100 nM) of collagenase-1 and gelatinase-B, with the most potent inhibitor exhibiting an IC50 of 30 nM against collagenase-1. A description of the combinatorial evaluation process, as well as initial SAR interpretation for this novel series, is provided.

A novel route for the synthesis of diketopiperazines and diketomorpholines on a solid support is described. Two different approaches are reported for diketopiperazines. The cyclization step involves cyclization with simultaneous cleavage from the resin.

ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTA Reductive Alkylation Procedure Applicable to Both Solution- and Solid-Phase Syntheses of Secondary AminesAnna K. Szardenings, Timothy S. Burkoth, Gary C. Look, and David A. CampbellView Author Information Affymax Research Institute, 4001 Miranda Avenue, Palo Alto, California 94304 Cite this: J. Org. Chem. 1996, 61, 19, 6720–6722Publication Date (Web):September 20, 1996Publication History Received19 January 1996Revised19 June 1996Published online20 September 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/jo960124nhttps://doi.org/10.1021/jo960124nbrief-reportACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views1230Altmetric-Citations99LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Aldehydes,Amines,Oligomers,Post-translational modification Get e-Alerts

Trimethylorthoformate has been found to be an effective dehydrating solvent for the formation of imines, both in the solid phase as well as solution phase.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA Transition State Analog Inhibitor Combinatorial LibraryDavid A. Campbell, Jason C. Bermak, Timothy S. Burkoth, and Dinesh V. PatelCite this: J. Am. Chem. Soc. 1995, 117, 19, 5381–5382Publication Date (Print):May 1, 1995Publication History Published online1 May 2002Published inissue 1 May 1995https://pubs.acs.org/doi/10.1021/ja00124a030https://doi.org/10.1021/ja00124a030research-articleACS PublicationsRequest reuse permissionsArticle Views97Altmetric-Citations64LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSolid-Phase Synthesis of PeptidylphosphonatesDavid A. Campbell and Jason C. BermakCite this: J. Am. Chem. Soc. 1994, 116, 13, 6039–6040Publication Date (Print):June 1, 1994Publication History Published online1 May 2002Published inissue 1 June 1994https://pubs.acs.org/doi/10.1021/ja00092a093https://doi.org/10.1021/ja00092a093research-articleACS PublicationsRequest reuse permissionsArticle Views230Altmetric-Citations43LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPhosphonate Ester Synthesis Using a Modified Mitsunobu CondensationDavid A. Campbell and Jason C. BermakCite this: J. Org. Chem. 1994, 59, 3, 658–660Publication Date (Print):February 1, 1994Publication History Published online1 May 2002Published inissue 1 February 1994https://pubs.acs.org/doi/10.1021/jo00082a027https://doi.org/10.1021/jo00082a027research-articleACS PublicationsRequest reuse permissionsArticle Views1613Altmetric-Citations62LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.