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1.
J Am Chem Soc ; 146(8): 5375-5382, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38354320

ABSTRACT

Octafluorocyclopentene (OFCP) has found utility as a polyelectrophile in substitution cascades that form complex macrocyclic compounds. The Harran group synthesis of macrocyclic polypeptides depends on OFCP as a linker, combining with four different nucleophilic units of a polypeptide. We report a computational investigation of the origins of OFCP reactivity and a rationale for controlled mono-, di-, tri-, and tetrasubstitution of fluoride ions by heteroatomic nucleophiles. The roles of inductive, negative hyperconjugative, and resonance electron-donation by fluoride substituents are explored for the reaction of OFCP, less-fluorinated analogues, and common electrophilic alkenes with several different nucleophiles.

2.
J Am Chem Soc ; 145(29): 15888-15895, 2023 07 26.
Article in English | MEDLINE | ID: mdl-37441722

ABSTRACT

Octafluorocyclopentene (OFCP) engages linear, unprotected peptides in polysubstitution cascades that generate complex fluorinated polycycles. The reactions occur in a single flask at 0-25 °C and require no catalysts or heavy metals. OFCP can directly polycyclize linear sequences using native functionality, or fluorospiroheterocyclic intermediates can be intercepted with exogenous nucleophiles. The latter tactic generates molecular hybrids composed of peptides, sugars, lipids, and heterocyclic components. The platform can create stereoisomers of both single- and double-looped macrocycles. Calculations indicate that the latter can mimic diverse protein surface loops. Subsets of the molecules have low energy conformers that shield the polar surface area through intramolecular hydrogen bonding. A significant fraction of OFCP-derived macrocycles tested show moderate to high passive permeability in parallel artificial membrane permeability assays.


Subject(s)
Membranes, Artificial , Peptides , Peptides/chemistry
3.
Proc Natl Acad Sci U S A ; 117(40): 24679-24690, 2020 10 06.
Article in English | MEDLINE | ID: mdl-32948694

ABSTRACT

Peptidomimetic macrocycles have the potential to regulate challenging therapeutic targets. Structures of this type having precise shapes and drug-like character are particularly coveted, but are relatively difficult to synthesize. Our laboratory has developed robust methods that integrate small-peptide units into designed scaffolds. These methods create macrocycles and embed condensed heterocycles to diversify outcomes and improve pharmacological properties. The hypothetical scope of the methodology is vast and far outpaces the capacity of our experimental format. We now describe a computational rendering of our methodology that creates an in silico three-dimensional library of composite peptidic macrocycles. Our open-source platform, CPMG (Composite Peptide Macrocycle Generator), has algorithmically generated a library of 2,020,794,198 macrocycles that can result from the multistep reaction sequences we have developed. Structures are generated based on predicted site reactivity and filtered on the basis of physical and three-dimensional properties to identify maximally diverse compounds for prioritization. For conformational analyses, we also introduce ConfBuster++, an RDKit port of the open-source software ConfBuster, which allows facile integration with CPMG and ready parallelization for better scalability. Our approach deeply probes ligand space accessible via our synthetic methodology and provides a resource for large-scale virtual screening.

4.
Molecules ; 26(24)2021 Dec 15.
Article in English | MEDLINE | ID: mdl-34946685

ABSTRACT

Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site.


Subject(s)
Acyltransferases/antagonists & inhibitors , Acyltransferases/chemistry , Enzyme Inhibitors/chemistry , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/chemistry , Peptidomimetics/chemistry , Acyltransferases/metabolism , Animals , Enzyme Inhibitors/chemical synthesis , Gastric Mucosa/enzymology , Ghrelin/metabolism , Lipoylation , Membrane Proteins/metabolism , Mice , Peptidomimetics/chemical synthesis
5.
J Am Chem Soc ; 142(49): 20717-20724, 2020 12 09.
Article in English | MEDLINE | ID: mdl-33226803

ABSTRACT

Reaction pathways operative when pyridinophane N-oxides are photoirradiated have been studied using time course analyses and careful isolation of photolabile intermediates with support from DFT calculations. Based on the data and the isolation of two previously unknown heterocyclophanes, we outline a unified mechanistic scheme that explains competing processes under varying photochemical conditions.


Subject(s)
Aza Compounds/chemistry , Bridged-Ring Compounds/chemistry , Ultraviolet Rays , Aziridines/chemistry , Density Functional Theory , Molecular Conformation , Oxides/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry
6.
J Nat Prod ; 83(11): 3381-3386, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33151675

ABSTRACT

Callyspongiolide is a marine-derived macrolide that kills cells in a caspase-independent manner. NCI COMPARE analysis of human tumor cell line toxicity data for synthetic callyspongiolide indicated that its pattern of cytotoxicity correlated with that seen for concanamycin A, an inhibitor of the vacuolar-type H+-ATPase (V-ATPase). Using yeast as a model system, we report that treatment with synthetic callyspongiolide phenocopied a loss of V-ATPase activity including (1) inability to grow on a nonfermentable carbon source, (2) rescue of cell growth via supplementation with Fe2+, (3) pH-sensitive growth, and (4) a vacuolar acidification defect visualized using the fluorescent dye quinacrine. Crucially, in an in vitro assay, callyspongiolide was found to dose-dependently inhibit yeast V-ATPase (IC50 = 10 nM). Together, these data identify callyspongiolide as a new and highly potent V-ATPase inhibitor. Notably, callyspongiolide is the first V-ATPase inhibitor known to be expelled by Pdr5p.


Subject(s)
Enzyme Inhibitors/pharmacology , Macrolides/pharmacology , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Fluorescent Dyes/chemistry , Humans , Hydrogen-Ion Concentration , Macrolides/chemistry , Molecular Structure , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism
7.
Angew Chem Int Ed Engl ; 59(2): 674-678, 2020 01 07.
Article in English | MEDLINE | ID: mdl-31693283

ABSTRACT

Small peptides containing combinations of cysteine, tyrosine, histidine, and serine residues react with octafluorocyclopentene (OFCP) to afford atypically structured macrocycles through successive vinylic substitutions. The reactions proceed rapidly in air at 0 °C and are tolerant of spectating tryptophan, asparagine, glutamine, and threonine residues. Hexapeptides of consensus sequence YXCXXC displace four fluorine atoms from OFCP to generate fluorinated macrobicyclic compounds that display dual-turn surfaces. The method provides facile access to a wide range of previously unknown heterocyclic structures.


Subject(s)
Cysteine/chemistry , Histidine/chemistry , Macrocyclic Compounds/chemistry , Peptides/chemistry , Serine/chemistry , Tyrosine/chemistry , Vinyl Compounds/chemistry , Humans
8.
J Am Chem Soc ; 141(6): 2274-2278, 2019 02 13.
Article in English | MEDLINE | ID: mdl-30691264

ABSTRACT

An eight-step asymmetric synthesis of (+)-marineosin A is described. The route proceeds by condensing fragments of reversed polarity relative to conventional prodiginine constructions. The resultant unstable chromophore is disrupted by a unique cycloisomerization promoted at a tailored manganese surface. This provides a premarineosin and subsequently marineosin A in a particularly concise manner. A pyridinophane N-oxide photorearrangement in flow and structural isomers of premarineosin are discussed, as is the reassignment of marineosin stereochemistry. The route gives access to the natural product as well as diastereomers, congeners and analogs that are currently inaccessible by other means.


Subject(s)
Pyrroles/chemistry , Pyrroles/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Chemistry Techniques, Synthetic , Hydrogenation , Models, Molecular , Molecular Conformation , Photochemical Processes , Stereoisomerism
9.
Chem Rev ; 117(18): 11994-12051, 2017 Sep 27.
Article in English | MEDLINE | ID: mdl-28603978

ABSTRACT

This review examines the state of the art in synthesis as it relates to the building of complex architectures on scales sufficient to drive human drug trials. We focus on the relatively few instances in which a natural-product-based development candidate has been manufactured de novo, rather than semisynthetically. This summary provides a view of the strengths and weaknesses of current technologies, provides perspective on what one might consider a practical contribution, and hints at directions the field might take in the future.


Subject(s)
Biological Products/chemical synthesis , Pharmaceutical Preparations/chemical synthesis , Biological Products/chemistry , Drug Design , Humans , Molecular Structure , Pharmaceutical Preparations/chemistry
10.
J Am Chem Soc ; 140(4): 1280-1284, 2018 01 31.
Article in English | MEDLINE | ID: mdl-29332397

ABSTRACT

An asymmetric synthesis of (-)-callyspongiolide is described. The route builds the macrolide domain atypically from a disaccharide and a monoterpene without passing through a seco-acid. Chiral iridium catalysis selectively joins fragments. Subsequent degradation of an imbedded butyrolactone via perhemiketal fragmentation affords a stereo- and regio-defined homoallylic alcohol that is engaged directly in a carbonylative macrolactonization. Further elaboration of the polyunsaturated appendage provides the natural product in a particularly direct and flexible manner.

11.
J Org Chem ; 83(13): 7231-7238, 2018 07 06.
Article in English | MEDLINE | ID: mdl-29708748

ABSTRACT

A nickel catalyzed synthesis of isomeric 3,3'-biproline esters is described. When those materials are doubly acylated with the acid chloride of pyrrole-2-carboxylic acid, they become susceptible to auto-oxidation in the presence of guanidine. Through proper staging of reaction conditions, it is possible to initiate two consecutive oxidative guanylations prior to in situ cycloisomerization to afford spirocyclic bis-glycocyamidines. This unique outcome reflects a cascade of no fewer than 10 reactions occurring sequentially in one flask. The chemistry provides rapid access to advanced intermediates useful for the preparation of complex, optically active pyrrole/imidazole alkaloids.

12.
J Org Chem ; 83(6): 3090-3108, 2018 03 16.
Article in English | MEDLINE | ID: mdl-29494773

ABSTRACT

We describe the asymmetric synthesis of a highly substituted ω-octynoic acid derivative and demonstrate its utility for generating complex macrocycles from unprotected peptides. The molecule harbors an isolated quaternary center that displays four uniquely functionalized arms, each of which can be reacted orthogonally in sequence as the molecule is integrated into peptide structure. These processing sequences entail (1) scaffold ligation, (2) macrocyclization via internal aromatic alkylations or catalyzed etherifications, (3) acyliminium ion mediated embedding of condensed heterocycles, and (4) terminal alkyne derivatization or dimerization reactions. Numerous polycycles are prepared and fully characterized in this study. Factors that influence reaction efficiencies and selectivity are also probed. We construct a novel mimic of the second mitochondria derived activator of caspase using these techniques, wherein subtle variations in macrocycle connectivity have a marked impact on performance. In general, the chemistry is an important step toward facile, systematic access to complex peptidomimetics synthesized by directly altering the structure and properties of machine-made oligomers.


Subject(s)
Macrocyclic Compounds/chemistry , Peptides/chemistry , Cyclization
13.
Proc Natl Acad Sci U S A ; 110(40): E3753-60, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-24043790

ABSTRACT

Peptide-protein interactions are important mediators of cellular-signaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification.


Subject(s)
Macrocyclic Compounds/chemistry , Macrocyclic Compounds/chemical synthesis , Peptides, Cyclic/chemistry , Catalysis , Chromatography, High Pressure Liquid , Magnetic Resonance Spectroscopy , Molecular Structure , Palladium/chemistry , Protein Conformation
14.
Tetrahedron Lett ; 56(23): 3612-3616, 2015 Jun 03.
Article in English | MEDLINE | ID: mdl-26019371

ABSTRACT

We have discovered a fragment of the natural product roseophilin, a member of the prodiginine family, that antagonizes Mcl-1 functions in a liposome-based assay for mitochondrial membrane permeabilization. By tailoring this substance such that it can participate in salt bridging with the protein surface, we have prepared the first prodiginine inspired structure that shows direct, saturable binding to a recombinant Bcl-2 family member in vitro.

15.
Angew Chem Int Ed Engl ; 54(16): 4818-22, 2015 Apr 13.
Article in English | MEDLINE | ID: mdl-25729008

ABSTRACT

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic.


Subject(s)
Amides/chemistry , Lactams, Macrocyclic/chemistry , Oxazoles/chemistry , Pharmaceutical Preparations/chemistry , Amides/chemical synthesis , Azo Compounds/chemistry , Crystallography, X-Ray , Cyclization , Graphite/chemistry , Lactams, Macrocyclic/chemical synthesis , Molecular Conformation , Oxazoles/chemical synthesis , Oxidation-Reduction , Surface Properties
16.
J Am Chem Soc ; 135(10): 3788-91, 2013 Mar 13.
Article in English | MEDLINE | ID: mdl-23452332

ABSTRACT

Ansa-bridged prodiginines are bioactive pigments produced by bacteria. Certain of these structures are reported to be antagonists of protein-protein interactions involved in apoptosis. We describe a new entry to alkaloids of this type, demonstrated with a concise asymmetric synthesis of (+)-roseophilin (3). Our route constructs the pyrrolophane motif via phosphoryl transfer-terminated macroaldolization and passes through a previously unexplored prototropic form of the natural product.


Subject(s)
Aza Compounds/chemistry , Cyclopentanes/chemistry , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Stereoisomerism
17.
Tetrahedron ; 69(36): 7683-7691, 2013 Sep 09.
Article in English | MEDLINE | ID: mdl-23976797

ABSTRACT

Macrocyclic peptidomimetics are valuable in research and serve as lead compounds in drug discovery efforts. New methods to prepare such structures are of considerable interest. In this pilot study, we show that an organic template harboring a latent cinnamyl cation participates in novel Friedel-Crafts macrocyclization reactions with tryptophan. Upon joining the template to Trp-Trp-Tyr, a single operation efficiently generates eight unique macrocycles. Each has been isolated and thoroughly characterized. Product distribution as a function of Brønsted and/or Lewis acidic conditions was explored, and outcomes were compared to rearrangements induced within a corresponding tyrosine-linked cyclic ether. The solution structure of a new macrocyclic pyrroloindoline was solved using a combination of two-dimensional NMR methods and molecular mechanics simulations. Template-induced structural diversification of peptide sequences harboring aromatic residues has potential to create myriad macrocycles that target surfaces involved in protein-protein interactions.

18.
Tetrahedron Lett ; 54(21): 2645-2647, 2013 May 22.
Article in English | MEDLINE | ID: mdl-23814321

ABSTRACT

We describe a new synthesis of the 3-chloro-(4'-methoxy)-2,2'-pyrrolylfuran segment (3) of (+)- roseophilin. The route exploits a isoxazoylpyrrole intermediate, wherein the isoxazole ring serves as a ß-diketone equivalent and a directing group for palladium catalyzed chlorination of the attached pyrrole. Subsequent reduction of the N-O bond and acid promoted cyclization afords roseophilin segment 3b in five steps and 19% overall yield. This strategy was extended to the synthesis of 3-chloro-(4'-alkoxy)-2,2'-pyrrolylfurans (16a-c) and 4-alkoxy-2,2'-bipyrroles (20a-c), which are building blocks to synthesize bioactive prodiginine natural products and their congeners.

19.
Org Lett ; 24(14): 2607-2612, 2022 04 15.
Article in English | MEDLINE | ID: mdl-35377667

ABSTRACT

Sequential organocatalytic additions of 2-furanone and dihydroxyacetone derivatives to a crotonaldehyde lynchpin provide polyhydroxylated chains reminiscent of lactonized deoxo Kdn type sugars. Further homologation via Kulinkovich ring opening of the butyrolactone and acylation of the zinc homoenolate derived from the incipient cyclopropanol allows assembly of functionalized chain precursors to portimine. Our experiments probe the stability and reactivity of monosubstituted methylidene pyrrolines and generate advanced intermediates useful for exploring the biosynthesis and de novo synthesis of portimine.


Subject(s)
Imines , Spiro Compounds , Organic Chemicals
20.
J Org Chem ; 74(16): 5909-19, 2009 Aug 21.
Article in English | MEDLINE | ID: mdl-19603820

ABSTRACT

A synthetic approach to palau'amine is described that exploits veiled symmetry in the structure. Bis-alkylidenes i have been prepared and found susceptible to halogenative desymmetrization using t-BuOCl. This oxidation forms the imbedded spirocyclopentane motif observed in the natural product. A host of atypical reactions and processes developed during these studies are discussed, as are plans for completing total syntheses of this compound class.


Subject(s)
Guanidines/chemistry , Guanidines/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Alkaloids/chemistry , Cyclization , Dimerization , Reproducibility of Results , Stereoisomerism , Substrate Specificity
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