The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Paul A. Wender - One of the best experts on this subject based on the ideXlab platform.
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improved protein kinase c affinity through final step Diversification of a simplified salicylate derived bryostatin analog scaffold
Organic Letters, 2014Co-Authors: Paul A. Wender, Daryl StavenessAbstract:Bryostatin 1, in clinical trials or preclinical development for cancer, Alzheimer’s disease, and a first-of-its-kind Strategy for HIV/AIDS eradication, is neither readily available nor optimally suited for clinical use. In preceding work, we disclosed a new class of simplified bryostatin analogs designed for ease of access and tunable activity. Here we describe a final step Diversification Strategy that provides, in only 25 synthetic steps, simplified and tunable analogs with bryostatin-like PKC modulatory activities.
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Function-oriented synthesis: biological evaluation of laulimalide analogues derived from a last step cross metathesis Diversification Strategy.
Molecular Pharmaceutics, 2008Co-Authors: Susan L. Mooberry, Michael K. Hilinski, Erin A. Clark, Paul A. WenderAbstract:Laulimalide is a potent microtubule stabilizing agent and a promising anticancer therapeutic lead. The identification of stable, efficacious and accessible analogues is critical to clinically exploiting this novel lead. To determine which structural features of laulimalide are required for beneficial function and thus for accessing superior clinical candidates, a series of side chain analogues were prepared through a last step cross metathesis Diversification Strategy and their biological activities were evaluated. Five analogues, differing in potency from 233 nM to 7.9 μM, effectively inhibit cancer cell proliferation. Like laulimalide, they retain activity against multidrug resistant cells, stabilize microtubules and cause the formation of aberrant mitotic spindles, mitotic accumulation, Bcl-2 phosphorylation and initiation of apoptosis. Structural modifications in the C23−C27 dihydropyran side chain can be made without changing the overall mechanism of action, but it is clear that this subunit has more...
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Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis Diversification Strategy.
Organic Letters, 2006Co-Authors: Paul A. Wender, Michael K. Hilinski, Nicolas G. Soldermann, Philip R. Skaanderup, Susan L. MooberryAbstract:An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis Diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical Strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available Diversification feedstock.
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identification of a tunable site in bryostatin analogs c20 bryologs through late stage Diversification
Organic Letters, 2005Co-Authors: Paul A. Wender, Jeremy L BaryzaAbstract:The C20 region of our bryostatin analogs was identified as a nonpharmacophoric site that could be varied to tune analogs for function and physical properties without significantly affecting their binding affinity for PKC. The use of this site in a late-stage Diversification Strategy has enabled the facile synthesis of a variety of new C20 analogs, all of which retain nanomolar affinity for PKC, in agreement with our pharmacophore hypothesis.
Susan L. Mooberry - One of the best experts on this subject based on the ideXlab platform.
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Function-oriented synthesis: biological evaluation of laulimalide analogues derived from a last step cross metathesis Diversification Strategy.
Molecular Pharmaceutics, 2008Co-Authors: Susan L. Mooberry, Michael K. Hilinski, Erin A. Clark, Paul A. WenderAbstract:Laulimalide is a potent microtubule stabilizing agent and a promising anticancer therapeutic lead. The identification of stable, efficacious and accessible analogues is critical to clinically exploiting this novel lead. To determine which structural features of laulimalide are required for beneficial function and thus for accessing superior clinical candidates, a series of side chain analogues were prepared through a last step cross metathesis Diversification Strategy and their biological activities were evaluated. Five analogues, differing in potency from 233 nM to 7.9 μM, effectively inhibit cancer cell proliferation. Like laulimalide, they retain activity against multidrug resistant cells, stabilize microtubules and cause the formation of aberrant mitotic spindles, mitotic accumulation, Bcl-2 phosphorylation and initiation of apoptosis. Structural modifications in the C23−C27 dihydropyran side chain can be made without changing the overall mechanism of action, but it is clear that this subunit has more...
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Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis Diversification Strategy.
Organic Letters, 2006Co-Authors: Paul A. Wender, Michael K. Hilinski, Nicolas G. Soldermann, Philip R. Skaanderup, Susan L. MooberryAbstract:An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis Diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical Strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available Diversification feedstock.
Roussos Dimitrakopoulos - One of the best experts on this subject based on the ideXlab platform.
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a diversified tabu search approach for the open pit mine production scheduling problem with metal uncertainty
European Journal of Operational Research, 2012Co-Authors: Amina Lamghari, Roussos DimitrakopoulosAbstract:This paper presents a metaheuristic solution approach based on Tabu search for the open-pit mine production scheduling problem with metal uncertainty. To search the feasible domain more extensively, two different Diversification strategies are used to generate several initial solutions to be optimized by the Tabu search procedure. The first Diversification Strategy exploits a long-term memory of the search history. The second one relies on the variable neighborhood search method. Numerical results on realistic large-scale instances are provided to indicate the efficiency of the solution approach to produce very good solutions in relatively short computational times.
Dirk Menche - One of the best experts on this subject based on the ideXlab platform.
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total synthesis of ajudazol a by a modular oxazole Diversification Strategy
Organic Letters, 2020Co-Authors: Philipp Wollnitzke, Sebastian Essig, Jan Philipp Golz, Karin Von Schwarzenberg, Dirk MencheAbstract:The total synthesis of the potent respiratory chain inhibitor ajudazol A was accomplished by a concise Strategy in 17 steps (longest linear sequence). The modular approach was based on a direct oxa...
Dimitris Georgiadis - One of the best experts on this subject based on the ideXlab platform.
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late stage Diversification of phosphinic dehydroalanine pseudopeptides based on a giese type radical c alkylation Strategy
Organic Letters, 2019Co-Authors: Kostas Voreakos, L Devel, Dimitris GeorgiadisAbstract:A straightforward, late-stage Diversification Strategy for the installation of side chains on readily accessible unsaturated phosphinopeptidic scaffolds based on a Giese-type addition of alkyl radicals has been investigated. Among different alternatives, the preferred methodology is operationally simple as it can be carried out in an open flask with no need for protection of acidic moieties. Direct application to the synthesis of SPPS-compatible building blocks or to longer peptides is also reported.
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Late-Stage Diversification of Phosphinic Dehydroalanine Pseudopeptides Based on a Giese-Type Radical C‑Alkylation Strategy
2019Co-Authors: Kostas Voreakos, L Devel, Dimitris GeorgiadisAbstract:A straightforward, late-stage Diversification Strategy for the installation of side chains on readily accessible unsaturated phosphinopeptidic scaffolds based on a Giese-type addition of alkyl radicals has been investigated. Among different alternatives, the preferred methodology is operationally simple as it can be carried out in an open flask with no need for protection of acidic moieties. Direct application to the synthesis of SPPS-compatible building blocks or to longer peptides is also reported