Abstracts E1-E7

Category E.  Chemical Biology and Drug Design


E1.  Synthesis of Vinyl Sultams via Pd-Catalyzed Intramolecular C-Vinylation of Triazoles

Andie Jo Cassity, Jung Ho Jun, Nicole Marie Windmon, Naeem Asad, Anna J. Diepenbrock, and Paul R. Hanson

Department of Chemistry, University of Kansas, Lawrence KS, USA

The use of a C-vinylation driven “Click-Click Cyclize” method for the generation of electrophilic bicyclic 1,2,3-triazole-fused vinyl sultams is herein reported. This highly efficient method utilizes simple Cu(I) catalyzed azide alkyne cycloaddition (Click), and Pd catalyzed intramolecular vinylation to rapidly generate the triazole-fused sultams in yields ranging between 80–90%.  For the optimization of intramolecular C-vinylation utilizing Pd catalysts, several conditions were screened.  Additionally, the exo-vinyl Michael acceptor was further attenuated by the synthesis of a small secondary library of masked Michael acceptors via addition of primary or secondary amines by DBU catalysis.



E2.  Synthesis and in vitro cytotoxic evaluation of analogues of the tubulin-binding agents soblidotin and cemadotin

Abugafar M. L. Hossion and Blake R. Peterson

Department of Medicinal Chemistry, The University  of Kansas, Lawrence, KS, USA

To effectively kill targeted cells, anticancer antibody-drug conjugates generally incorporate highly toxic small molecules. Small molecules with sufficient potency for these applications include synthetic analogues of the natural product dolastatin 10 and dolastatin 15 such as soblidotin, cemadotin and synthadotin. These compounds selectively disrupt tumor vasculature and potently inhibit the polymerization of tubulin. In an effort to create more effective antibody-drug conjugates, we synthesized new analogues of soblidotin, cemadotin and synthadotin. We are investigating the biological properties of these soblidotin, cemadotin and synthadotin derivatives. Many of these agents are highly cytotoxic against human breast cancer (SKBR3), prostate cancer (PC3) and leukemia (Jurkat) cell lines with IC50 values ranging 0.02 nM to 100 nM. The synthesis and properties of these compounds will be described.



E3.  Phosphate tether-mediated, one-pot, sequential protocols for the synthesis of Sch725674, 13-Desmethyl-lyngbouilloside and corresponding simplified analogs

Salim Javed, Mahipal Bodugam, Arghya Ganguly, Jessica Torres and Paul R. Hanson•

Department of Chemistry, University of Kansas, Lawrence, KS, USA

Phosphate tether-mediated, one-pot, sequential protocols for the syntheses of 14-membered macrolactones Sch-725674 and 13-desmethyl-lyngbouilloside are reported.  The key reactions involved in the synthesis of these molecules are one-pot, sequential RCM/CM/H2, Sharpless asymmetric epoxidation, Roskamp homologation, Boeckman acylketene cyclization and ring-closing metathesis.  This efficient, library amenable, step economical approach is also employed in the synthesis of simplified analogs, including sulfur- and phosphorus-based derivatives of both Sch-725674 and 13-Desmethyl-lyngbouilloside.  Overall, the 14-membered macrolactone analogs contain three stereogenic centers, are obtained over a series of four one-pot, sequential processes starting from a common, readily-prepared triene phosphate triester, and require only four purification steps.



E4.  Novel sultam analogs of tetramic acid via intramolecular Dieckmann condensation

Jung Ho Jun, MoonYoung Hur, Jay Shankar Jha, Taylor Rose Atkinson, and Paul R. Hanson

Department of Chemistry, University of Kansas, Lawrence, KS, USA;

Tetramic acids are well known for their presence in biologically relevant compounds, however, sultam (cyclic sulfonamide) analogs of tetramic acids are relatively limited in the literature. A synthetic strategy using an intramolecular Dieckmann-like condensation driven Click-Click Cyclize method for the generation of chiral monocyclic and bicyclic sultam analogs of tetramic acids is reported. A sequential mesylation, followed by benzylation of linear and cyclic amino esters, generates precursors for the Dieckmann condensation cyclization. Efforts to diversify the core β-keto-sultam scaffolds to generate analogs of naturally-occurring tetramic acids will also be discussed.



E5.  Electrophilic Sultams: Synthesis and Reactivity

Maria Khan, Qin Zang, Elise Gao, Joanna Loh, Naeem Asad and Paul R. Hanson*

Department of Chemistry, University of Kansas, Lawrence, KS, USA

Covalent cysteine modulators have been utilized in the study of a variety of biological processes, including the regulation of proteins via ubiquitination, sumoylation, prenylation, farnesylation, phosphorylation and glycosylation, etc. In this regard, we report the synthesis of structurally diverse electrophilic sultam scaffolds as modulators of cysteine functionality within proteins. Several reaction pathways are utilized for the facile synthesis of an array of monocyclic and bicyclic electrophilic sultams. Corresponding reactivity profile studies will also be discussed.



E6.  Applications of ROMP-derived Oligomeric Silica and Co/C-Reagents for small molecule Synthesis

Pradip K. Maity1,Saqib Faisal1, Patrick C. Kearney1, Oliver Reiser2, and Paul R. Hanson*1

1Department of Chemistry and NIH Center for Chemical Methodologies and Library Development(CMLD), University of Kansas, Lawrence, KS, USA;  2Institute for Organic Chemistry, University of Regensburg, Regensburg, Germany.

The development and application of silica-supported ROMP reagents and Nb-tagged Cobalt-graphite (Nb-Co/C) magnetic nanoparticles for the synthesis of small molecules are reported under purification-free processes. An array of high load, hybrid Si-immobilized oligomeric benzyl phosphates (Si-OBP) and triazole phosphates (Si-OTP) derivatives were successfully synthesized for the efficient benzylation and triazolation of nucleophilic species. These reagents are readily synthesized from commercially available starting materials to afford free-flowing solids on multi-gram scale in excellent yield and utilized in benzylation and triazolation reactions with a variety of nucleophiles. Additional efforts utilizing surface-initiated polymerization from Nb-tagged silica (Nb-Si) and Nb-tagged Cobalt-graphite (Nb-Co/C) magnetic nanoparticles for purification-free Intermolecular Monomer-on-Monomer (MoM) Mitsunobu protocol on sulfonamide scaffolds is also diccussed.



E7.  Phosphate Tether-Mediated Ring-Closing Metathesis for the Formation of P-Chiral, Z-Configured Bicyclo[7.3.1]- and Bicyclo[8.3.1]phosphates

Jana L. Markley, Soma Maitra, Paul R. Hanson*

Department of Chemistry, University of Kansas, Lawrence, KS, USA

Phosphate tether-mediated diastereoselective ring-closing metathesis studies to provide a variety of bicyclo[7.3.1]- and bicyclo[8.3.1]phosphates are reported. Discussion will focus on the formation of medium and large ring systems (10- to 11-membered rings) and emphasize the effects of ring size and olefin substitution on the success and stereochemical outcome of each P-tether-mediated RCM event. Taken collectively with previous reports carried out in our laboratory, this work will highlight the ability of phosphate tethers to mediate the desymmetrization of C2-symmetric diene-containing diols and provide unique P-chiral heterocycles with potential synthetic and biological utility.



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