Daniel D. Long

An octameric carbopeptoid; secondary structure in octameric and tetrameric 5-aminomethyl-tetrahydrofuran-2-carboxylates

Abstract The efficient synthesis of an octameric furanose carbopeptoid, readily purified by chromatography in ethyl acetate:hexane (2:1), is reported. Extensive NMR studies suggest that two tetrameric 5-aminomethyltetrahydrofuran-2-carboxylates are prone to adopt solution conformations reminiscent of a repeating β-turn, a third tetramer and the corresponding octamer may tend towards a left-handed α-helix.

From sequencamers to foldamers? Tetrameric furanose carbopeptoids from cis- and trans-5-aminomethyl-tetrahydrofuran-2-carboxylates

Abstract The synthesis of three stereoisomeric cis - and trans -5-azidomethyl-tetrahydrofuran-2-carboxylates in which a ketal-protected cis -diol unit is present is described. The monomers undergo efficient oligomerisation to tetrameric carbopeptoids in which the diol protection facilitates ready purification by chromatography which augurs well for the formation of homogeneous higher polymers.

Complex tetrahydrofurans from carbohydrate lactones: THF amino acids as building blocks for unnatural biopolymers

The multi-gram syntheses of two epimeric six-carbon tetrahydrofurancarboxylates based upon a D-arabinofuranose template are described. An approach to 3-O-benzyl protected derivatives is also detailed. Introduction of nitrogen at C-6 of these scaffolds leads to the generation of building blocks suitable for the generation of oligomers which possess well defined secondary structures. Radical bromination facilitates introduction of nitrogen at C-2, to afford anomeric α-amino acid derivatives which are elaborated to two unnatural diastereomers of the potent herbicidal natural product hydantocidin. X-Ray crystal structures of N-methyl-2-azido-2-deoxy-α-D-arabino-hex-2-ulofuranosonamide and N-dodecyl-2-azido-2-deoxy-β-D-arabino-hex-2-ulofuranosonamide are also disclosed.

Absence of secondary structure in a carbopeptoid tetramer of a trans-5-aminomethyl-tetrahydrofuran-2-carboxylate

Abstract Whereas trimers and tetramers of β- C - d -arabinofuranosyl carbohydrate amino acids adopt well defined conformations based around a repeating β-turn like structure, stabilised by (i, i-2) inter-residue hydrogen bonds, there is no indication of any secondary structure in the tetramer of the epimeric α- C - d -arabinofuranosyl carbohydrate amino acid, where the C-2 and C-5 substituents of the tetrahydrofuran ring are trans to each other.

A solid phase approach to oligomers of carbohydrate amino-acids: Secondary structure in a trimeric furanose carbopeptoid

Abstract The synthesis of oligomers of a C -arabinofuranosyl carbohydrate amino acid on a polystyrene support functionalised with a Rink linker is reported. Cleavage from the solid support gives ready access to dimeric and trimeric carbopeptoids bearing a C -terminal carboxamide. Investigations into the solution structure of these novel carbopeptoids utilising 1 H NMR indicate that they adopt well difined conformations based around a repeating β-turn like structure stabilised by (i, i-2) inter-residue hydrogen bonds.

Exploring the Positional Attachment of Glycopeptide/β-lactam Heterodimers

Further investigations towards novel glycopeptide/β-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Grampositive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and β-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28∼36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.

A Multivalent Approach to Drug Discovery for Novel Antibiotics

The design, synthesis and antibacterial activity of novel glycopeptide/β-lactam heterodimers is reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, A and B respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and β-lactams. The antibiotics 8a˜f displayed remarkable potency against a wide range of Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA). Compound 8e demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and initial evidence supports a multivalent mechanism of action for this important new class of antibiotic.

Potential intermediates for incorporation of polyhydroxylated prolines into combinatorial libraries

Abstract Bicyclic 2 and monocyclic 6 2-amino-1,4-lactones provide divergent intermediates for subsequent incorporation of polyhydroxylated prolines into combinatorial amide libraries. The X-ray crystal structure of an azidolactone, combined with molecular modelling, rationalises the very different behaviour of two azidolactones which are epimeric at a remote side-chain carbon. The conversion of 2 and 6 into DGDP 4 secures the structural claims in the paper. The enantiomers of 2 and 6 may provide access to libraries of potential inhibitors of UDP-Gal mutase and thus of mycobacterial cell wall biosynthesis.

The in vivo pharmacodynamics of the novel opioid receptor antagonist, TD-1211, in models of opioid-induced gastrointestinal and CNS activity

The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.

Spirodiketopiperazines at the anomeric position of mannopyranose: Novel N- linked glycopeptides incorporating an α- amino acid at the anomeric position of mannopyranose

Abstract The first synthesis of a spirodiketopiperazine at the anomeric carbon of a pyranose sugar is described; an N-acylated bicyclic amino [2.2.2] lactone provides access to a new class of glycopeptide analogues of pyranoses and determines the anomeric configuration of the spirodiketopiperazine. The mannopyranose may be equilibrated to the more stable furanose form.