Inhibition of FBPase is considered a promising way to reduce hepatic gluconeogenesis and therefore could be a potential approach to treat type 2 diabetes. Herein we report the discovery of a series of purine phosphonic acids as AMP mimics targeting the AMP site of FBPase, which was achieved using a structure-guided drug design approach. These non-nucleotide purine analogues inhibit FBPase in a similar manner and with similar potency as AMP. More importantly, several purine analogues exhibited potent cellular and in vivo glucose-lowering activities, thus achieving proof-of-concept for inhibiting FBPase as a drug discovery target. For example, compounds 4.11 and 4.13 are as equipotent as AMP with regard to FBPase inhibition. Furthermore, compound 4.11 inhibited glucose production in primary rat hepatocytes and significantly lowered blood glucose levels in fasted rats.

A series of substituted bis[(para-methoxy)benzyl] (bisPMB) esters of 1-naphthalenemethylphosphonate (NMPA) were synthesized and evaluated as phosphonate prodrugs. BisPMB NMPA esters (4b and 4c) with significantly improved aqueous stability were identified that also resulted in increased intracellular levels of NMPA following prodrug incubation with primary rat hepatocytes.

A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.

Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.

Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.

Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified. Their efficacy in cellular models of cell death and inflammation are also discussed.

A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.

Fastigilin C (2), a complex helenanolide, has been reported to exhibit cytotoxic and antineoplastic activity, thus making it an attractive target for total synthesis. We wish to report the first total syntheses of (+/-) and (-)-fastigilin C ((+/-)- and (-)-2). As a result of our interest in the utilization of furan-terminated cyclizations as the key step in the construction of diverse ring systems, we envisioned (eq 1) furan 3 as the precursor to bicyclo[5.3.0]decane furan 4, which should afford 2. In the forward direction, a Mukaiyama Michael-aldol protocol affords 3 with complete control of relative stereochemistry. A mercury(II)-mediated-furan-terminated cyclization gives 4, which is ultimately converted (17 steps, 24.6% overall yield) to (+/-)-fastigilin C ((+/-)-2). A porcine pancreatic lipase mediated resolution of 4-hydroxy-2-methyl-2-cyclopentenone leads to (S)-(+)-4-methoxy-2-methyl-2-cyclopentenone, which is converted (17 steps) to (-)-fastigilin C ((-)-2) in 14% overall yield.

Intramolecular opening of an enantiomerically pure epoxide by an amide enolate (1 --> 2) is shown to be an effective method for cyclopentane construction with control of both ring and side chain absolute configuration. This opening serves as the key step in a synthesis of the Golgi apparatus-blocking macrolide (+)-brefeldin A (3). Other features of the synthesis include improved procedures for the enantioselective hydrogenation of a beta-keto ester to the corresponding beta-hydroxy ester, and for the Julia-Lythgoe reduction of a beta-acetoxy sulfone to the trans alkene.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA mild method for the synthesis of furans. Application to 2,5-bridged furano macrocyclic compoundsJames A. Marshall and Edward D. RobinsonCite this: J. Org. Chem. 1990, 55, 11, 3450–3451Publication Date (Print):May 1, 1990Publication History Published online1 May 2002Published inissue 1 May 1990https://pubs.acs.org/doi/10.1021/jo00298a012https://doi.org/10.1021/jo00298a012research-articleACS PublicationsRequest reuse permissionsArticle Views1334Altmetric-Citations201LEARN 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 (1)»Supporting Information Supporting Information Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of the tumor-inhibitory tobacco constituents .alpha.- and .beta.-2,7,11-cembratriene-4,6-diol by diastereoselective [2,3] Wittig ring contractionJames A. Marshall, Edward D. Robinson, and Jacques LebretonCite this: J. Org. Chem. 1990, 55, 1, 227–239Publication Date (Print):January 1, 1990Publication History Published online1 May 2002Published inissue 1 January 1990https://pubs.acs.org/doi/10.1021/jo00288a038https://doi.org/10.1021/jo00288a038research-articleACS PublicationsRequest reuse permissionsArticle Views856Altmetric-Citations45LEARN 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

AbstractCoupling of the acetylenes (I) with acetaldehyde (II) and subsequent oxidation yield the acetylenic ketones (III).

The total synthesis of (+)-α-CBT (16) was effected from the achiral 17-membered ketone 3 by a sequence featuring asymmetric reduction, diastereoselective [2,3] Wittig ring contraction and hydroxyl directed epoxidation as stereochemically important steps.

The alkoxy substituted 17-membered ethers 8 and 10 afford the syn/trans propargylic alcohols 11 and 12 as the major products upon [2,3] Wittig ring contraction.