Solid-phase synthesis of HTLV-1 protease inhibitors containing hydroxyethylamine dipeptide isostere

An efficient method has been developed for the first solid-phase synthesis of HTLV-1 protease inhibitors that contain hydroxyethylamine isostere as a transition-state mimetic. The synthetic procedure was designed to allow the evaluation of stereostructure-activity relationships at the scissile site. All the possible configurations at the hydroxy- and side chain-bearing asymmetric centers of the isostere were constructed by an ester-derived asymmetric aldol reaction. Each inhibitor containing the isostere backbone was synthesized on solid support by using the newly developed succinate ester linker. The configuration at the hydroxy- and side chain-bearing asymmetric center showed remarkable effects on the inhibitory activity; the K(i) value changed with approximately 2 orders of magnitude. The described approach enables an efficient preparation of the inhibitors containing secondary alcohol as a transition-state mimetic.     

A concise synthesis of silanediol-based transition-state isostere inhibitors of proteases

[reaction: see text] An efficient synthesis of silanediol-based transition-state inhibitors of proteases is described. A new convergent synthesis has been optimized by using a two-step sequence of hydrosilylation followed by the addition of a silyllithio species to an imine. The method should be applicable to the synthesis of a wide variety of silanediol isosteres to probe the utility of this unique transition-state isostere.     

Design and synthesis of a conformationally restricted trans peptide isostere based on the bioactive conformations of saquinavir and nelfinavir

The design and synthesis of a new peptide isostere which contains a trans alkene core is described. The key step involves a Wadsworth-Emmons reaction between chiral aldehyde (2S)-9a and chiral phosphonate 7 under base-sensitive conditions to give a chiral enone (2R)-24a which was reduced to afford the desired trans alkene isosteres (2R,5R)-6a and (2R,5S)-6b (Scheme 6). A potential application of this isostere in the synthesis of HIV protease inhibitors is also discussed.     

E-olefin dipeptide isostere incorporation into a polypeptide backbone enables hydrogen bond perturbation: probing the requirements for Alzheimer's amyloidogenesis

Herein, we report a stereospecific E-olefin dipeptide isostere synthesis that can be used to make gram quantities of the Phe-Phe isostere desired for eliminating a specific backbone H-bond donor and acceptor in the Alzheimer's disease related Abeta peptide. The Phe19-Phe20 E-olefin analogue of Abeta(1-40) was prepared by solid-phase peptide synthesis and was subjected to amyloidogenesis conditions. This analogue can aggregate into spherical morphologies but does not progress on to form protofibrils or fibrils as is the case for the all-amide sequence, providing insight into the structural requirements for amyloidogenesis.     

Design and synthesis of isoxazole containing bioisosteres of epibatidine as potent nicotinic acetylcholine receptor agonists.

An efficient synthesis of isoxazole containing isosteres of epibatidine is described. The synthesis proceeded from N-tert-butoxycarbonyl (Boc)-exo-2-(methoxycarbonyl)-7-azabicyclo[2.2.1]heptane (9). Compound 9 was reacted with the dilithium salt of an appropriately substituted oxime in tetrahydrofuran (THF). Cyclodehydration of the resultant beta-keto oxime and deprotection of the N-Boc group in 5 N aqueous HCl afforded the isoxazole containing isosteres of epibatidine (6-8). The binding affinities of these compounds were determined at the nicotinic acetylcholine receptor for the displacement of [3H]cystisine. The unsubstituted isoxazole containing isostere (6) showed the lower binding potency compared to the 3'-methylisoxazole isostere (7). Substitution with a phenyl group at the 3'-position of the isoxazole significantly reduced the binding potency. The in vivo toxicological studies of these analogs were also performed. The LD50 of the analogs ranged in the order: Me > H > Ph.     

Synthesis of oxacalothrixin B and its analogues involving iodine/TBHP-mediated electrocyclization

The total synthesis of oxacalothrixins, an isostere of biologically important carbazoloquinone alkaloid, calothrixin B was achieved from 2-acetyl-3-methylbenzofuran. An iodine/TBHP-mediated oxidative cyclization of benzofuranyl-enamine has been employed as a key step to synthesize, the crucial intermediate 1-hydroxy dibenzofurancarbaldehyde. The latter upon reductive cyclization followed by PIDA-mediated oxidation furnished oxacalothrixin B and its analogues.     

Synthesis of thia-ellipticine, 5,11-dimethylbenzothieno[2,3-g]isoquinoline

1,4-Dimethyldibenzothiophene (VII) was synthesized and was converted with butyl dichloromethyl ether to the 2-aldehyde (VIII). The structure was confirmed by an independent synthesis of the 2-ester (XI) derived from it. The 2-aldehyde (VIII) with aminoacetaldehyde diethylacetal formed the Schiff′s base (IX), and Pomeranz-Fritsch cyclization with 105% superphosphoric acid then formed thia-ellipticine (II), an isostere of the antitumor alkaloid, ellipticine.     

Aromatic Nonpolar Nucleosides as Hydrophobic Isosteres of Pyrimidine and Purine Nucleosides

Described are the design, synthesis, and structures of three nonpolar nucleoside isosteres to be used as probes of noncovalent bonding in DNA and as isosteric replacements for the natural nucleosides in designed nucleic acid structures. Reaction of substituted aryl Grignards with 3',5'-bis-O-toluoyl-α-deoxyibofuranosyl chloride and subsequent deprotection with sodium methoxide in methanol afforded the two β-C-nucleoside pyrimidine analogs 1 and 2. The dimethylindolyl nucleoside 3, a purine isostere, was obtained by a nucleophilic displacement on α-chlorodeoxyribofuranose by the sodium salt of 4,6-dimethylindole, followed by deprotection. Regio- and stereochemistry of the products were established with NOE difference spectra and (1)H NMR splitting patterns. Analogs 1 and 2 are nonpolar isosteres of thymidine, and nucleoside 3 is an isostere of 2-aminodeoxyadenosine, the triply-bonded Watson-Crick partner of thymidine. Semiempirical AM1 calculations were carried out to provide bond length information to assess structural similarities between the isosteres and their natural counterparts.     

Diastereoselective synthesis of the Leu-Pro type phosphinyl dipeptide isostere

A diastereoselective synthesis of the Leu-Pro type phosphinyl dipeptide isostere in its protected form was achieved from stereodefined α-amino-H-phosphinate. The methodology involved a cross-coupling reaction with alkenyl triflate and subsequent diastereoselective hydrogenation of the alkene moiety, which capitalized on the phosphorus chirality.     

Chemoenzymatic synthesis of ketomethylene tripeptide isosteres

A chemoenzymatic method is described for the synthesis of a desired ketomethylene tripeptide isostere. The key step is an enzymatic hydrolysis, which removes the C-terminal ester-protecting group under mild conditions without epimerizing the existing stereogenic center and produces the desired stereoisomer in high enantiomeric excess (98% de, 97% ee). The method is short with overall 15–20% yields after seven synthetic steps from readily available starting materials being obtained.     

Synthesis and evaluation of 8,9-amido analogs of geldanamycin

Amido analogs of geldanamycin, an ansamycin anticancer agent, were designed, synthesized, and assayed with SKBR3 cells, in which stability of HER2 receptor tyrosine kinase is dependent on the chaperone Hsp90. An amide was employed as a trisubstituted alkene isostere at the C8,9 position, which provided for a simplified, convergent synthesis through two major fragments, an aniline-amine left-hand portion and a dicarboxylic acid right-hand piece.     

Synthesis of the pro-gly dipeptide alkene isostere using olefin cross-metathesis

An approach to the synthesis of dipeptide olefin isosteres using intermolecular olefin cross-metathesis is presented. In particular, a synthesis of the Pro-Gly isostere (1) is reported. Conversion of N-BOC-proline into the corresponding vinyl-substituted carbamate provides the N-terminal cross-metathesis partner (2). Methyl 3-butenoate (3) is employed as the C-terminal component. Treatment of the two partners in an optimized molar ratio affords the cross product 1 (83% yield). Three other examples are demonstrated to evaluate the potential of the approach.     

Amino-alcohol dipeptide analogues: A simple synthesis of a versatile isostere for the development of proteinase inhibitors

Two simple approaches to an amino-alcohol isostere of proteolytically-cleavable dipeptide sequences are described, this isostere is incorporated into stereochemically-defined tetrapeptide analogues.     

Synthesis of a Gln-Phe hydroxy-ethylene dipeptide isostere

[structure: see text] The protected Gln-Phe hydroxyethylene dipeptide isostere 1 was synthesized as a precursor for preparation of potential inhibitors of Botulinum neurotoxin B metalloprotease. The method allows for the synthesis of additional hydroxyethylene dipeptide isosteres such as 2 with functionalized P1 side chains. The isosteres prepared were coupled with a dipeptide to produce protected pseudotetrapeptide derivatives.     

Stereoselective Synthesis of Hydroxyethylene Dipeptide Isostere from Sugar

Regioselective opening of the aziridine ring in the carbohydrate-based precursor led to the stereoselective synthesis of N-Boc-O-benzyl-(4S,5S)-5-amino-4-hydroxy-6-phenylhexanoic acid methyl ester, the hydroxyethylene dipeptide isostere moiety of potent HIV-1 protease inhibitor.     

Stereoselective synthesis of constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: dipolar cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone carboxylic acids

The synthesis of three vicinally substituted azacyclic carboxylic acids in enantiopure form was achieved from a common alpha-amino aldehyde originating from l-leucine. Pyrrolidines and pyrrolidinones were elaborated from alpha,beta-unsaturated gamma-hydroxy-delta-amino acids via azomethine ylide 1,3-dipolar addition and conjugate addition/cyclization strategies, respectively. The azacyclic amino acids were incorporated in a pseudopeptide now encompassing a hydroxyethylene isostere. Low nanomolar inhibition of BACE1, an enzyme implicated in the cascade of events leading to plaque formation in Alzheimer's disease, was found with a pyrrolidinone analogue.     

Selective functionalization of the 1H-imidazo[1,2-b]pyrazole scaffold. A new potential non-classical isostere of indole and a precursor of push–pull dyes

We report the selective functionalization of the 1H-imidazo[1,2-b]pyrazole scaffold using a Br/Mg-exchange, as well as regioselective magnesiations and zincations with TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl), followed by trapping reactions with various electrophiles. In addition, we report a fragmentation of the pyrazole ring, giving access to push–pull dyes with a proaromatic (1,3-dihydro-2H-imidazol-2-ylidene)malononitrile core. These functionalization methods were used in the synthesis of an isostere of the indolyl drug pruvanserin. Comparative assays between the original drug and the isostere showed that a substitution of the indole ring with a 1H-imidazo[1,2-b]pyrazole results in a significantly improved solubility in aqueous media.

A methodology for the selective functionalization of the 1H-imidazo[1,2-b]pyrazole scaffold has been developed and used in the synthesis of novel push–pull dyes and a non-classical isostere of the indolyl drug pruvanserin.     

The synthesis of N-acyl-2-hydroxymethyl aziridines of biological interest

A practical synthesis of the title compounds from protected amino acylazides is described. All the compounds might be considered as a novel class of dipeptide isostere precursors; they all induce lymphocyte proliferation and protein production as observed from preliminary biological tests.     

An efficient, stereoselective synthesis of the hydroxyethylene dipeptide isostere core for the HIV protease inhibitor A-792611

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.     

Transformation of Glucose into a Novel Carbasugar Amino Acid Dipeptide Isostere

The synthesis of a novel carbasugar amino acid (15), starting from D‐glucose and using the Ferrier rearrangement as a key step, is reported. Compound 15 is implemented as dipeptide isostere in the synthesis of a Leu‐enkephalin analog.