Rational Design and Synthesis of AT1R Antagonists

Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efficient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the first sartan, Losartan.     

Combinatorial solid-phase synthesis of hapalosin mimetics

The solid-phase synthesis of a small library of mimetics of the cyclic depsipeptide hapalosin is described. 3-Amino-4-hydroxy-5-nitrobenzoic acid was anchored through the anilino moiety to a backbone amide linker (BAL) handle support. Using chemoselective reactions and without the need for protecting group manipulations, the benzoic acid group was first amidated, then the aniline nitrogen was acylated, and finally the nitro group was reduced to an amine and acylated or reductively alkylated, to generate a 12-member library.     

Influence of steric effects in solid-phase aza-peptide synthesis

Aza-peptides are peptide analogs with potential applications as drug candidates. However, due to difficulties associated with the synthesis of these compounds, information regarding their bioactivity is very limited. Herein, we identify steric hindrance as one reason for the slowness of the aza-peptide bond formation reaction. The steric effect of the side group of amino acids in their coupling with the semicarbazide moiety in the synthesis of a model peptide, H-AA-AzAla-Phe-NH₂, was studied and quantified using COMU as a coupling reagent. Characterization of the role of this structural factor in aza-peptide bond synthesis is essential for outlining a new and efficient synthesis protocol.     

A novel linker for solid-phase synthesis cleavable under neutral conditions

A novel linker cleavable under neutral conditions has been developed for the solid-phase synthesis of base-labile compounds. The linker is comprised of a 3-azidomethyl-4-hydroxybenzyl alcohol moiety, and the azidomethyl group in the linker is readily converted to an aminomethyl group by treatment with a phosphine reagent in the presence of water to result in an intramolecular cyclization to release the compounds. Using the linker, a base-labile dinucleoside methyl phosphate was synthesized on a highly cross-linked polystyrene (HCP) support and cleaved successfully from the resin without decomposition of the product.     

Tartric acid-based linker for the solid-phase synthesis of C-terminal peptide alpha-oxo aldehydes

A novel linker, based on the anchoring of (+)-dimethyl 2,3-O-isopropylidene-D-tartrate to PEGA or PEG-PS solid supports, was developed for the solid-phase synthesis of C-terminal peptide alpha-oxo aldehydes. Peptide elongation was performed using the 9-fluorenylmethoxycarbonyl/t-Bu chemistry. The peptide and the 1,2-diol were deprotected on the solid phase. Then, a periodic oxidation of the fully deprotected peptidyl-resin led to the simultaneous cleavage of the product from the solid support and to the generation of the alpha-oxo aldehyde moiety. The methodology allowed the distance between the alpha-oxo aldehyde and the peptide to be easily modulated. The C-terminal peptide alpha-oxo aldehydes synthesized in this study were found to be useful partners in hydrazone, thiazolidine, and oxime chemical ligations.     

Continuous-flow solid-phase peptide synthesis

We describe a simple manually operated synthesizer for solid-phase peptide synthesis (SPPS). The synthesis is performed on standard polystyrene-based resin in a flow reactor under low-pressure conditions. The usefulness of the present configuration of SPPS is exemplified on the synthesis of two octapeptide and one decapeptide amides.     

Microwave-assisted solid-phase synthesis of hydantoin derivatives

A microwave-assisted synthesis of 3,5- and 1,3,5-substituted hydantoins starting from various resins for solid-phase combinatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and the nucleofuge properties of the resin.     

Total solid-phase synthesis of the azathiocoraline class of symmetric bicyclic peptides

Thiocoraline is a potent antitumor agent isolated from the marine organism Micromonospora sp. This symmetric bicyclic depsipeptide binds the minor groove of DNA. Here we report two solid-phase strategies for the syntheses of azathiocoraline and its analogues. The thioester linkage was replaced by an amide bond to improve the compound's pharmacokinetic properties. The first strategy is based on a convergent (4+4) approach, whilst the second is a stepwise synthesis, cyclizations in both approaches occurring on the solid support. These two strategies were designed to overcome problems caused by the presence of consecutive noncommercial N-methyl amino acids, to avoid epimerization during cyclization and/or fragment condensation, and to form the disulfide bridge under solid-phase conditions. The heterocyclic moiety was added in the last step of the synthesis to assist the preparation of libraries of new compounds with potential therapeutic applications.     

Application of Validated TLC—Densitometric Method for Simultaneous Identification and Determination of Losartan Potassium,Telmisartan, and Valsartan in Tablets

JPC – Journal of Planar Chromatography – Modern TLC - The antihypertensive effect of sartans is a result of inhibition of the binding of angiotensin (AT) II to the AT1 receptor in...     

Comparison of various coupling reagents in solid-phase aza-peptide synthesis

Aza-peptides are promising drug leads, however extensive study of their properties is hampered by low yielding aza-peptide bond formation during conventional Fmoc SPPS. The kinetics of aza-peptide bond formation in the model peptide H-Ala-AzAla-Phe-NH₂ was compared with various conventional amino acid activators. The reaction rates and yields were dependent on the activator structure. The reaction time of aza-peptide formation using oxyma-based agents was approximately 30 times longer than in typical peptide synthesis. Therefore, new activators are required to increase the reactivity of the activated amino acid to achieve effective acylation of the semicarbazide moiety during aza-peptide bond formation.     

THAL, a sterically unhindered linker for the solid-phase synthesis of acid-sensitive protected peptide acids

The 5-(4-hydroxyphenyl)-3,4-ethylenedioxythienyl alcohol (THAL, Thiophene Acid Labile) is described as a new linker for the solid-phase synthesis of peptide carboxylic acids. It is based on the electron-rich 3,4-ethylenedioxythenyl (EDOTn) moiety and allows the obtention of free and tert-butyl-protected peptides by cleavage with 90% and 0.5% TFA, respectively. This very high acid lability makes it useful for the synthesis of sensitive peptides. Free and tert-butyl-protected Leu-enkephalins have been synthesized as models to demonstrate the utility of the linker.     

Diastereoselectivity in the solid-phase synthesis of peptide heterocycle hybrids

Sixteen compounds containing the bicyclic moiety (3,8,10-trisubstituted 2,9-dioxo-5-thia-1,8-diazabicyclo[4.4.0]decane) were produced via solid-phase synthesis. Differing substitution at the 3- and 10-positions was used. These were analyzed using 2-D NMR techniques (ROESY) to determine the stereoselectivity of ring formation in the core heterocycle. Conformational analysis of the proposed transition state structure using Sybyl 6.8^® was used to rationalize the stereochemical outcome of ring formation.     

Facile solid-phase synthesis of an antifreeze glycoprotein

The antifreeze glycoproteins (AFGPs) 1 are composed of a repeating tripeptide unit (Ala-Thr-Ala) in which the threonine residue is glycosylated with the disaccharide beta-D-Gal-(1-->3)-alpha-D-GalNAc. A new procedure for synthesizing AFGPs using Fmoc-(Ac4-beta-D-Gal-(1-->3)-benzylidene- alpha-D-GalNAc)Thr-OH (10) as a building block has been developed. Total synthesis of the AFGPs (n = 4, 8) in overall yields of 61% and 33 %, respectively, has demonstrated the usefulness of the method. The synthetic AFGPs 1 (n = 4, 8) showed a similar conformation to the native AFGPs in their circular dichroism spectra.     

Total synthesis of GEX1A

An efficient and readily modifiable synthesis of GEX1A/herboxidiene/TAN-1609 ( 1) was developed. This modular synthesis featured a Suzuki coupling to install the conjugated diene and a Ru-catalyzed lactonization and Roush crotylation to construct the functionalized tetrahydropyran moiety. Myers' alkylation, cross-metathesis, and Keck crotylation were employed for assembly of the biologically essential side-chain domain.     

Recent progress in the synthesis of diclofenac based NSAIDs analogs/derivatives

Non-steroidal anti-inflammatory drugs (NSAIDs) are known for inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Diclofenac and its analogs, having phenylacetic acid moiety, are important NSAIDs. In this review article, various methodologies developed after 90?s for the synthesis of various analogs/derivatives of diclofenac sodium have been discussed and summarized.     

Improved method for the solid-phase synthesis of oligoribonucleotide 5'-triphosphates

We have developed an improved solid-phase method for the synthesis of 5'-triphosphates (5'-TPs) of oligoribonucleotides. The method is based on the use of salicyl phosphorochloridite as the phosphitylating reagent and the improvement is characterized by the use of the highly reactive pyrophosphorylating reagent tris(tetra-n-butylammonium) hydrogen pyrophosphate instead of the conventional tri-n-butylammonium salt for the nucleophilic substitution reaction to form the cyclic ester intermediate. The improved method can be used to generate oligoribonucleotide 5'-TPs efficiently and reproducibly.     

An efficient protocol for the solid-phase synthesis of malondiamides

A novel and straightforward solid-phase synthesis of malondiamides containing a free nitrogen has been developed. These intermediates, which can be directly obtained in good yield and purity, can be further derivatised. This approach can be used for the synthesis of large split-and-mix-libraries.     

Solid-phase synthesis of alkanethiols for the preparation of self-assembled monolayers

Self-assembled monolayers (SAMs) of alkanethiols (ATs) on gold can be used to fabricate surfaces for nanoscience and biology. The chemical structure of the interface can be tailored simply by modifying the AT headgroup. To streamline access to different precursor ATs, we developed a general solid-phase synthetic route. A key feature of this route is the use of a modified resin containing an AT linker ("AT resin") because it minimizes purification steps. The precursor to the AT resin was prepared in five steps, and all of the synthetic intermediates are stable solids that can be purified by crystallization. Accordingly, the AT resin can be prepared on a multigram scale. The utility of the AT resin was evaluated by using it to generate a variety of ATs. For example, ATs presenting different types of integrin-binding ligands (linear and cyclic RGD derivatives) were prepared and used to form arrays of SAMs that support cell adhesion. Additionally, the AT resin also provides a starting point for the synthesis of ATs presenting reactive groups (e.g., an amine-reactive AT or a maleimide-containing alkanedisulfide) or protein immobilization tags (e.g., biotin-AT). Thus, our synthetic strategy provides a convenient and flexible means for the synthesis of the necessary building blocks for custom SAMs and SAM arrays.     

Asymmetric synthesis of 6'-hydroxyarenarol: the proposed biosynthetic precursor to popolohuanone E

The first synthesis of (+)-6'-hydroxyarenarol 3, the proposed biogenetic precursor to popolohuanone E (1), is described. An enantioselective route to key iodide intermediate 12 has been developed allowing the asymmetric synthesis of the known cis-decalin 22. Conditions which allow the removal of the methyl ether protecting groups on the hydroxyarene leaving the exocyclic methylene moiety in tact have also been developed to complete this synthesis.     

Highly enantioselective synthesis of tertiary boronic esters and their stereospecific conversion to other functional groups and quaternary stereocentres

Organoboron compounds are useful in asymmetric synthesis. We have developed an efficient methodology for the highly enantioselective synthesis of tertiary boronic esters from the corresponding secondary benzylic alcohols. Further stereospecific transformations of the boronic ester moiety are described including the preparation of tertiary alcohols, C-tertiary amines and tertiary arylalkanes. Several homologations of tertiary boronic esters have also been developed for the construction of quaternary stereocentres.