Abstracts E1-E16

Category E. Drug Target Identification and Drug Design

 

E1.  Small molecule disruptors of HuR-mRNA interaction as novel cancer therapy

Xiaoqing Wu1, Lan Lan1, Rebecca Marquez1, Bryan Tsao1, Jia Yu1, Amber Smith1, Philip Gao2, Na Zhang2, David Wilson3, Scott Lovell 4, Kawaljit Kaur1, Roberto  De Guzman1, Ragul Gowthaman1,5, John Karanicolas1,5, Jeffrey Aubé6, Dan Dixon7 and Liang Xu1
1Department of Molecular Biosciences, 2COBRE-PSF Protein Purification Group, 3Laboratory for Early Stage Translational Research, 4COBRE-PSF Protein Structure Core,  5Center for Bioinformatics, 6Department of Medicinal Chemistry, 7Department of Cancer Biology, The University of Kansas Medical Center, The University of Kansas.

 

Post-transcriptional gene regulation is essential for normal development, but when dysregulated, has many implications in disease conditions, including cancer. The RNA-binding proteins (RBPs) are critical trans factors, they associate with specific cis elements present in mRNAs to regulate the stability and translation of target mRNAs. The RBP Hu antigen R (HuR) is highly abundant in many types of cancer. HuR promotes tumorigenesis by interacting with a subset of mRNAs, which encode proteins that are implicated in different tumor processes including cell proliferation, cell survival, angiogenesis, invasion, and metastasis. Our hypothesis is that small molecule compounds that disrupt the HuR-mRNA interaction will block HuR function, leading to the decay and reduced translation of mRNAs of the target genes critical for cancer cell growth and progression. High throughput screening (HTS) was carried out in several chemical libraries (~ 10,000 compounds) using fluorescence polarization (FP) assay and identified a series of initial hits with sub-micromolar inhibitory constants (Ki).  Those potential disruptors were then validated by Alpha assay (Amplified Luminescent Proximity Homogeneous Assay), confirmed by Surface Plasmon Resonance (SPR). We are now performing NMR and X-ray crystallization to further confirm the binding of the lead compounds with HuR. In cell-based assays, one of the top hits, ST-3, specifically shortened HuR target mRNAs’ half-life and decreased the levels of corresponding proteins (Bcl-2, XIAP and Msi1). ST-3 significantly inhibited proliferation of cancer cells with high levels of HuR.  More cell-based assays are carrying out to validate the target specificity and investigate the mechanism of action using cell lines with HuR knock-in/down. In conclusion, we identified potential small molecule disrupters of HuR-mRNA interaction as novel cancer therapy that inhibited cancer with HuR overexpression.

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E2.  Applications of Si-ROMP Reagents and Magnetic Nanoparticles (Co/C) in Synthesis

Pradip K. Maity,a Saqib Faisal,a Quirin M. Kainz,b Oliver Reiser,b and Paul R. Hanson*a
aDepartment of Chemistry, 1251 Wescoe Hall Dr., University of Kansas, Lawrence, KS 66045.  NIH Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), 2034 Becker Drive, Del Shankel Structural Biology Center, Lawrence, KS 66047. bInstitute for Organic Chemistry, University of Regensburg, Universitatsstr. 31, D-93053 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 in purification-free processes are reported. An array of high load, hybrid Si-immobilized oligomeric benzyl phosphates (Si-OBP) and their corresponding Si-immobilized oligomeric triazole phosphate (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 and conveniently polymerized to afford free-flowing solids on multi-gram scale and in excellent yield. Utilization in benzylation and triazolation reactions with a variety of nucleophiles is reported. 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 discussed.

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E3.  Copper-Catalyzed Decarboxylative Trifluoromethylation of Allylic Bromodifluoroacetates

Brett R. Ambler and Ryan A. Altman*
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States

 

The development of new synthetic fluorination reactions has important implications in medicinal, agricultural and materials chemistries. Given the prevalence and accessibility of alcohols, methods to convert alcohols to trifluoromethanes are desirable. However, this transformation typically requires four-step processes, specialty chemicals, and/or stoichiometric metals to access the trifluoromethyl-containing product. We recently developed a two-step copper-catalyzed decarboxylative protocol for converting allylic alcohols to trifluoromethanes. Preliminary mechanistic studies distinguish this reaction from previously reported Cu-mediated reactions. Beneficial aspects of this transformation include the: 1) employment of a mild, inexpensive and atom-economical source of CF3 in near-stoichiometric quantity; 2) development of a shortened strategy for converting readily available allylic alcohols into trifluoromethyl analogs; 3) ability to conduct trifluoromethylation reactions using only a catalytic quantity of metal. Functionalization of allyl trifluoromethane-based products should be useful for accessing more complex fluorinated compounds. Ongoing research aims to expand the scope of the reaction to include alternate classes of alcohols and to develop shorter, more robust routes to access trifluoromethane containing compounds.

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E4.  Exploring One-pot Sequential Multicomponent Reaction Pathways - A Formal “4+4” CAP Strategy Employing in-situ Generated ortho-Quinone Methides

Moon Young Hur, Thiwanka Samarakoon, Paul R. Hanson
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582

 

A one-pot, sequential multicomponent reaction strategy employing in situ generated orthoquinone methide enabling the production of highly functionalized eight membered benzofuzed sultams is reported.  This strategy entails the use of complementary ambiphilic pairing (CAP) protocol for the facile assembly of core dibenzo[b,g][1,4,5]oxathiazocine 5,5-dioxides bearing reactive and orthogonal functional groups which are subjected to selective functionalization in a sequential manner.

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E5.  Evaluation of the properties of a PEG modified PDMS for μTAS: wettability, nonpolar adsorption and electroosmotic flow

Richard P. S. de Campos1*, José A. F. da Silva1,2, Inez V. P. Yoshida1.
1 Instituto de Química, Universidade Estadual de Campinas, Campinas, SP. rpiffer@ku.edu
2 Instituto Nacional de Ciência e Tecnologia em Bioanalítica, INCTBio, Campinas, SP.

 

One of the most growing areas in analytical chemistry in the recent years is the development of micro total analysis systems (μTAS). Such μTAS have the integration of several analytical steps into one chip as their ultimate goal, combining the reduced analysis time, low reagent consumption and low residue generation with the possibility of high throughput integration. Nowadays those characteristics are interesting for a wide variety of applications, especially for studies concerning cell heterogeneity: the so called single cell analysis. Thus, the properties of the substrate of which those microdevices are made is of utterly importance.

Among all substrate materials used in μTAS fabrication, poly(dimethylsiloxane) (PDMS) is by far the most important polymer due to its elastomeric properties, optical transparency, biocompatibility, easy molding and low fabrication cost. However, its application for aqueous systems can be troublesome due the intrinsic hydrophobicity presented by the material. This hydrophobic characteristic can also cause nonpolar analytes to be adsorbed on PDMS surface or even be absorbed into its bulk. As an alternative to overcome this problem, several methods to modify PDMS surface and bulk were proposed in the literature. The objective of this work was to study and characterize the PDMS modification by covalently bonding it with poly(ethylene glycol) divinyl ether (DVE-PEG), following the structural changes by FT-IR spectroscopy, water contact angle (WCA) measurements and fluorescence microscopy. The electroosmotic flow for the device with T injection/separation microchannels during an electrophoretic separation using a contactless conductivity detector (C4D) was also evaluated.

The reaction route led to a satisfactory modification, as confirmed by the IR spectra. We obtained the DVE-PEG modified PDMS substrate and it showed a hydrophilic characteristic due to the formation of a well-spread film of water over its surface in the day after the modification, showed by the WCA measurements. This hydrophilic characteristic was maintained for approximately 10 days, with the gradual return to a hydrophobic state. The fluorescence assays showed that the nonpolar adsorption property of PDMS was significantly decreased, as shown by rhodamine-B solution monitoring. The EOF obtained was 3,6 x 10-4 cm2 V-1, higher than the typical values found for native PDMS, which once more states the difference between the modified and the raw material. Finally, in the practical point of view, the obtained material showed lower bubble formation when filling the microchannels with electrolyte, in addition to a better wettability then native PDMS. Devices were irreversible sealed after the modification using plasma oxidation, and the electrophoretic separation of three standard cations (Na+, Li+ and K+) was performed in less than 1 minute using an applied voltage of 1 kV .

Acknowledgments: INCTBio, FAPESP, CNPq, CAPES

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E6.  High-Load, Immobilized Si-ROMP and Co/C Magnetic Reagents and Scavengers: Development and Application in Sequestration and Parallel Synthesis

Saqib Faisal,a Pradip K. Maity,a Diana S. Stoianovab and Paul R. Hansona*
aDepartment of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence,  KS, 66045. The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), 2034 Becker Drive, Shankel Structural Biology Center, West Campus, Lawrence, KS 66047.
bMateria, Inc. 60 N. San Gabriel Blvd, Pasadena, CA 91107

 

The development of new ROMP-derived oligomeric phosphorus reagents for application in purification-free diversification protocols is reported. These hybrid Si-immobilized oligomeric benzylic and heterocyclic phosphates (Si-OBP & Si-OHP), and their corresponding oligomeric triazole phosphate (Si-OTP) derivatives were successfully synthesized as free flowing solid for efficient benzylation and triazolation of nucleophilic species. These oligomeric reagents were conveniently utilized in one-pot processes affording pure products. The applications of these reagents for the diversification of N, O and S-nucleophilic species, including the generation of a library protocol are reported. Further development of ROMP-derived oligomeric, reagents and scavengers immobilized on Co/C magnetic nanoparticles utilizing surface-initiated ROM polymerization. Utilization of these hybrid magnetic reagents in synthetic transformations for the facilitated synthesis of small molecules, applications in parallel synthesis and potentially automated/flow-through technologies.

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E7.  Minimizing Side Reactions in Novel Peptide Ring Closing Metathesis Reactions

Solomon A. Gisemba and Jane V. Aldrich
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS, 66045-7582, USA

 

The opioid receptors, consisting of mu (μ), kappa (κ), and delta (δ) opioid receptors, are important therapeutic targets. Mu opioid receptor (MOR) agonists such as morphine are the most widely used pharmaceutical agents in pain management despite their severe side effects, such as respiratory depression and addiction liability. Kappa opioid receptor (KOR) antagonists initially found utility as pharmacological tools, but more recently have shown potential for the treatment of depression and drug addiction. However, prototypical small molecule selective KOR antagonists such as norBNI and JDTic show prolonged duration of action in vivo, which has slowed their development. In contrast, peptide antagonists, such as the cyclized dynorphin (Dyn) A analog zyklophin, show a shorter duration of action along with preventing stress-induced reinstatement of cocaine seeking behavior following systemic administration.1 Thus KOR selective peptide antagonists offer a promising profile for potential further development.

Arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]Dyn A(1-11)-NH2, Figure 1), an acetylated Dyn A analog, has shown potent and selective KOR antagonism.2 Novel cyclization strategies via ring closing metathesis (RCM) are being pursued to enhance the metabolic stability and potentially stabilize the bioactive conformation of arodyn.3 RCM is compatible with peptide synthesis and standard amino acid protecting groups. While RCM of Dyn A analogs involving allylglycine (AllGly) residues showed moderate to high yields,4 reactions involving O-allyl groups resulted in low yields due to a side reaction.3

The initial focus of this research is to develop synthetic methodology to enhance peptide RCM reaction yields to facilitate the synthesis of arodyn analogs for pharmacological evaluation. A model dipeptide RCM precursor was synthesized to probe strategies to minimize side reactions and enhance reaction yields. Different reaction parameters such as temperature, catalyst concentration, catalyst equivalents, inclusion of reagents reported to suppress side reactions,5,6 and reaction time were examined. High temperature and high catalyst concentration generally increased side product formation, whereas lower catalyst concentration in the presence of phenol promoted formation of the desired RCM product. The results of these different side reaction minimization strategies and the application of the modified reaction conditions to the synthesis of novel arodyn analogs will be presented. This research is funded by NIDA grant R01 DA018832.

Ac-Phe-Phe-Phe-Arg-Leu-Arg-Arg-D-Ala-Arg-Pro-Lys-NH2
Figure 1. The sequence of arodyn.

1. Aldrich, J. V.; Patkar, K. A.; McLaughlin, J. P. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 18396.
2. Bennett, M. A.; Murray, T. F.; Aldrich, J. V. J. Med. Chem. 2002, 45, 5617.
3. Fang, W. J.; Kulkarni, S. S.; Murray, T. F.; Aldrich, J. V. Adv. Exp. Med. Biol. 2009, 611, 279.
4. Fang, W.J.; Cui, Y.; Murray, T. F.; Aldrich, J. V. J. Med. Chem. 2009, 52, 5619.
5. Schmidt, B.; Hauke, S. Org. Biomol. Chem. 2013, 11, 4194.
6. Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160.

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E8.  One-pot sequential protocols towards sultam library synthesis 

Naeem Asad, Joanna Loh, and Paul R. Hanson
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582

 

A one-pot, sequential protocol is reported that involves complementary ambiphile pairing (CAP) of a vinyl sulfonamide with a variety of unprotected amino acids via aza-Michael addition and subsequent intramolecular amidation.  The method generates diverse, sp3-rich mono- and bicyclic acyl sultams in a highly scalable manner.  Modular pairing of stereochemically rich building blocks allows quick access to all possible isomers.  Extension to include one-pot, sequential 3-, 4- and 5-multicomponent protocols is also discussed.

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E9.  Phosphate Tethered-Mediated Approach Towards the Total Synthesis of IKD-8344

Cornelius N. Ndi, Susanthi Jayasinghe and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582

 

Efforts toward the total synthesis of the monomeric  seco-acid of IKD-8344 employing a phophate tether-mediated approach are presented. IKD-8344 is a novel 28-membered C2 symmetric macrolide which was found to possess potent anthelmintic activity against the parasitic worm Trichinella spiralis as well as strong cytotoxicity against L5178Y mouse leukemia cells with an IC50 value of 0.54 ng/mL. More recently, it also was found to possess selective antifungal activities against the mycelial form of Candida albicans, a diploid human fungal pathogen that frequently infects immunocompromised and immunosuppressed patients. Current synthetic approach highlights a one pot sequential RCM/CM/H2 and a subsequent O-alkylation to form a threo-trans oxolane ring; an advance unit of the monomeric seco-acid.

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E10.  Structure informs on function: A thiazolinyl imine reductase of siderophore biosynthesis

Kathleen M. Meneely1, Andrew P. Riley2, Thomas E. Prisinzano2,3, Audrey L. Lamb1
Molecular Biosciences1, Chemistry2 and Medicinal Chemistry3, University of Kansas, Lawrence, KS

 

Iron is an essential element for most pathogenic bacteria that must obtain this nutrient from the environment. Many of these bacteria acquire iron by synthesizing low molecular weight chelating molecules termed siderophores. Yersiniabactin is produced by Yersinia enterocolitica in iron-limiting environments and is composed of salicylate, three cyclized cysteines and one malonyl moiety. The thiazolinyl imine reductase (Irp3) catalyzes the NADPH-dependent reduction of one of the three thiazoline rings of a yersiniabactin intermediate. The apo form of Irp3 was solved to 1.85 Å resolution by selenomethionine MAD with 23 seleniums in the asymmetric unit and a final Rcryst of 19.6% and an Rfree of 24.2%. An NADP+ bound form of Irp3 was determined by molecular replacement to 2.31 Å resolution with apo-Irp3 as the model and final Rcryst and Rfree of 19.7% and 26.0%, respectively. The NADP+-bound Irp3 structure shows clear density for NADP+ in each of the four monomers of the asymmetric unit. Irp3 is a homodimer consisting of two domains, an N-terminal NADPH binding domain and a C-terminal dimerization domain and shows structural similarity to sugar oxidoreductases and biliverdin reductase. A reaction mechanism is proposed for the donation of a proton from a general base (either His101 or Tyr128) and hydride donation from the C4 of the NADPH cofactor for the reduction of the carbon-nitrogen double bond of the thiazoline ring. A homology model of the functionally similar thiazolinyl reductase in Pseudomonas aeruginosa (PchG) was generated. An extensive loop is found in Irp3 and PchG but not in other structural homologues. This loop is hypothesized to be involved in binding to the nonribosomal peptide synthetase modules to which the substrate is covalently attached. Hot off the press: A holo structure and initial kinetics with a substrate analogue.

 

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E11.  Structure-based design of novel cytochrome P450 17A1 inhibitors for sex steroid driven cancers

Charlie Fehl, Elyse M. Petrunak, Emily E. Scott, and Jeffrey Aubé
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66047-3761

 

Androgenic and estrogenic sex steroids drive proliferation in prostate and breast tissues, the two most commonly diagnosed cancer types in men and women, respectively.  The human cytochrome P450 17A1 (CYP17A1) enzyme is essential for the production of both androgenic and estrogenic sex steroid hormones.  Thus inhibition of CYP17A1 is a new approach to treating breast and prostate cancer, as validated by the approval of abiraterone for prostate cancer treatment.

Selectivity is an ongoing challenge in the design of CYP17A1 inhibitors, not currently met by abiraterone.  Ideal inhibitors must first discriminate between CYP17A1 and several other highly related steroidogenic cytochrome P450 enzymes to limit off-target side effects.  Secondly, ideal inhibitors would inhibit only the CYP17A1-mediated lyase reaction that is essential for sex steroid production, but permit a CYP17A1-mediated hydroxylation reaction that occurs in the same active site and is essential for both sex steroid and corticosteroid synthesis.

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E12.  Synthetic Efforts Towards the Synthesis of the C26-C40 Northern Hemisphere of Spirastrellolide B

Salim Javed, Rambabu Chegondi, Soma Maitra, and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS, 66045

 

Synthetic efforts towards an efficient synthesis of the C26-C40 northern hemisphere of spirastrellolide B is reported.  Spirastrellolide B is a member of the bioactive spirastrellolide family of polyketides possessing unique molecular architecture and represents a daunting synthetic challenge.  Currently, a number of reports detailing routes to this Northern Hemisphere exist in the literature.  A synthetic strategy employing a newly crafted Mukaiyama aldol/relay cross metathesis protocol in conjunction with a phosphate-mediated desymmetrization method will be discussed.

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E13.  Synthetic Studies Towards the C1-C25 Southern Hemisphere of Spirastrellolide B

Soma Maitra, Rambabu Chegondi, Salim Javed and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582

 

Efforts towards the synthesis of the C1-C25 fragment of spirastrelolide B, a polyketide natural product isolated in 2007, will be reported.  Interesting biological activity and structural complexity has led to several synthetic efforts towards this family of natural products.  A synthetic strategy involving a late-stage union of two key fragments via Suzuki-Miyaura coupling and phosphate tether-mediated one-pot processes to streamline the synthetic plan will be discussed.

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E14.  The Development of a Pyrrolopyrimidine Chemotype to Reduce Perinucleolar Compartment Prevalence in Metastatic Prostate Cancer Cells

Kevin Frankowski,a Samarjit Patnaik,b Frank Schoenen,a Sui Huang,c John Norton,c Chen Wang,c Steve Titus,b Marc Ferrer,b Wei Zheng,b Noel Southall,b Victor Day,a Jeffrey Aubé,a Juan Jose Maruganb
a
Specialized Chemistry Center, The University of Kansas, Lawrence, KS 66047.
b
National Center for Advancing Translational Sciences,  NIH, Rockville, MD, 20850.
c
Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois
 

Metastatic tumor cells have previously been shown to display an unusually high prevalence of perinucleolar compartment (PNC) bodies in the nucleus. While the precise function of the PNC is not known, this phenotypic marker could be used to identify chemotherapeutic compounds with novel modes of action. Utilizing a high content assay we have identified and further optimized a pyrrolopyrimidine chemotype that disrupts assembly of the PNC in cells while not effecting cell viability. The efficient synthesis of this chemical series enabled the ten-fold optimization of potency to 90 nM as well as exploration into the structural elements necessary for activity. Active analogues were subsequently found to also inhibit tumor cell migration and anchorage-independent growth.

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E15.  The Optimized and Improved Larger Scale Synthesis of Opioid Macrocyclic Tetrapeptides with Potential for Drug Development

Sanjeewa N. Senadheeraa Shainnel O. Eans,b Jay P. McLaughlin,b Jane V. Aldricha
aDepartment of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA, b Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, USA

 

Narcotic analgesics such as morphine, which act primarily through mu opioid receptors (MOR), have been widely used clinically for the treatment of severe pain. However, their use is limited by severe side effects such as respiratory depression and drug dependence. Kappa opioid receptor (KOR) ligands have demonstrated potential as therapeutic agents in the treatment of various diseases including drug abuse and pain. The natural product macrocyclic tetrapeptide KOR ligand CJ-15,208 (Figure 1, Saito et al., J. Antiobiot. 2002, 55, 847) can prevent reinstatement of cocaine seeking behavior in vivo following oral administration (Aldrich et al., J. Nat. Prod. 2013, 76, 433). These macrocyclic peptides are potential candidates for drug development because of their low molecular weight and expected metabolic stability in vivo, but the small 12-membered ring size can make their synthesis difficult, resulting in low yields and dimeric macrocyclic octapeptides as the major products. We are synthesizing analogs of CJ-15,208 by modifying our initial synthetic protocol (Ross et al., Tetrahedron Lett. 2010, 51, 5020) to prepare larger quantities of these macrocyclic tetrapeptides for detailed pharmacological evaluation in vivo following systemic administration. The macrocyclic tetrapeptides were synthesized by a combination of solid phase synthesis of the linear peptide precursors, followed by cyclization in solution. Optimization of the crucial cyclization step and the use of normal-phase column chromatography increased the yields of the final products, providing sufficient material for extensive characterization in vivo. Pharmacological results for selected macrocyclic tetrapeptides will also be presented. These novel macrocyclic tetrapeptides are promising candidates for the development of potential peptide KOR therapeutic ligands. Research supported by NIDA grants R01 DA018832 and R01 DA 023924.

macrocyclic tetrapeptide KOR ligand CJ-15,208

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E16.  The Shapiro Fluorination: Direct Access to Fluorinated Peptidomimetics

Ming-Hsiu Yang, Siddharth S. Matikonda, and Ryan A. Altman*
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045

 

Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Strategic incorporation of a fluoroalkene group can alter the pharmacokinetic properties of amide-based probes including lipophilicity and membrane permeability, as well as metabolic stability towards proteolysis. Moreover, selective preparation of E- and Z-fluoroalkene isomers can provide fluorinated probes for conducting conformational analyses of amides.

Current preparations of this functional group include elimination of difluoroallyl functional groups, fluoroolefination of carbonyl-containing compounds, and metal-catalyzed fluorination reactions of organometallic substrates; however, most of these methods provide mixtures of E- or Z-fluoroalkene diastereomers (dr < 3:1), and/or mixtures of nonfluorinated products.

To directly access fluoroalkenes in good stereoselectivity, a Shapiro fluorination reaction was developed. Fluoroalkene products can be accessed in one- or two-step sequences from widely available ketones. The reaction employs inexpensive and readily available reagents, and no metal catalysts and ligands are required. Compared with current methods, the Shapiro fluorination reaction provides improved diastereoselectivities (dr > 5.5:1). This strategy should be useful for the preparation of fluorinated analogs of peptide-based therapeutics, many of which would be challenging to prepare by alternate strategies.

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