Conformationally rigid cyclic α-amino acids in the design of peptidomimetics, peptide models and biologically active compounds

Komarov, Igor V.; Grigorenko, A. O.; Туров, А. В.; Khilya, V. P.

doi:10.1070/rc2004v073n08abeh000912

Cited by 73 publications

(28 citation statements)

References 168 publications

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“…Both non-natural amino acids 10a and 11a can be used for synthesis of isomeric peptidomimetics, providing the rigid scaffolds for unusual secondary structure elements. 16 In conclusion, we have developed a practical synthetic procedure leading to functionalized 3-aza-, 3-oxa-, and 3-thiabicyclo[3.3.1]nonanes 1a,b,d-l. The overall yield of the key intermediate products 6a-c is 40%, and these are readily transformed further to generate chemically very diverse libraries of compounds for biological screening.…”

Section: Paper Syn Thesismentioning

confidence: 99%

An Expedient and Practical Approach to Functionalized 3-Aza-, 3-Oxa-, and 3-Thiabicyclo[3.3.1]nonane Systems

et al. 2014

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The synthesis of a number of heterobicyclo[3.3.1]nonane derivatives possessing carbonyl, amino, or carboxyl groups is reported. The synthetic scheme is concise and practical, based on optimized reaction conditions for each step and an orthogonal protection group strategy. Procedures for the key synthetic steps (double annulation of α-bromomethyl acrylates to enamines and a Caglioti reaction) were improved significantly. This makes the compounds attractive for medicinal chemistry as potential chemically diverse 3D-scaffolds applicable in drug design.Saturated carbo-and heterobicyclic systems are used frequently in contemporary drug design. These systems represent the so-called 3D-scaffolds; 1 when functionalized at appropriate positions they can interact efficiently with biological targets. In principle, bicyclic scaffolds allow for wide variations of the functional group disposition in space, enhancing the chances of finding derivatives with optimal pharmacological characteristics. In order to exploit this potential to the full, chemists have developed flexible and practical synthetic approaches to bicyclic scaffolds functionalized at different positions. 2 We report here on the synthesis of a library of bicyclo[3.3.1]nonane-derived compounds possessing heteroatoms N, O, and S in the bicyclic skeleton (target compounds 1). Structural and chemical diversity of the synthesized library could be of great value for finding derivatives with improved pharmacokinetic properties, and enhanced efficiency and selectivity of interaction with biological targets. Such diversity has been the focus of the drug discovery process over the past decade. 3 The concept of diversity-oriented synthesis (DOS) was introduced, designating preparation of collections of structurally complex and diverse compounds from simple starting materials. 4 The bicyclic compounds described in this paper could be introduced into DOS by linear or branching functionalization methodology. 5 We explore this potential, aiming at improvements of known synthetic procedures and designing new ones.Construction of the [3.3.1]bicyclic system was performed by a well-documented strategy, based on the double annulation of α-bromomethyl acrylates 2 to enamines 3 (Scheme 1). The strategy was elaborated almost a half a century ago for synthesis of carbo-bicyclic derivatives, 6 and has already proved its efficiency in preparations of 3-azabicyclo[3.3.1]nonanes, 7 3-oxabicyclo[3.3.1]nonanes, 8 and 3-phenyl-3-phosphabicyclo[3.3.1]nonane-3-oxide. 9 A formal [3+3] cycloaddition annulation was also reported recently for rapid direct construction of the bicyclo[3.3.1] skeleton. 10

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Section: Paper Syn Thesismentioning

confidence: 99%

An Expedient and Practical Approach to Functionalized 3-Aza-, 3-Oxa-, and 3-Thiabicyclo[3.3.1]nonane Systems

et al. 2014

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“…To date, nearly two dozen isoxazole‐containing pharmaceuticals, including semisynthetic β‐lactam antibiotics (e.g, oxacillin, dicloxacillin, flucloxacillin, and cloxacillin), sulfonamide antibacterials, antidepressants, antirheumatic drugs, anti‐inflammatory agents, antiviral drugs, fungicides, and hypoglycemic agents, have been approved by the FDA (Figure ). The use of conformationally restricted amino acids that contain heterocyclic rings for the preparation of peptidomimetics has recently been explored An interesting application in this field includes our recent reported on the preparation and use of 5‐aminoisoxazole restricted amino acids . This heterocyclic fragment is also present in the molecules of the above‐mentioned sulfonamide antibiotics (e.g., sulfametoxazole, sulfafurazole, and sulfisoxazole) as well as quirzatinib, which is currently under investigation for the treatment of acute myeloid leukemia …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Bi‐ and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles

et al. 2018

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The reaction of chloroximes that have a protected amino group and active methylene nitriles under basic conditions has been shown to give functionalized 5‐aminoisoxazoles in yields of 37–81 %. This method has a broad substrate scope, including nitriles that contain either an electron‐withdrawing (i.e., CO2Me, CN, or SO2Me) or a heteroaryl group at the α‐position. Moreover, a malononitrile dimer was employed in analogous transformations, which led to the formation of polyfunctional isoxazolo[5,4‐b]pyridines. The selective removal of the protecting groups contained in the product demonstrated the utility of these compounds as advanced building blocks in early drug discovery programs.

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“…In view of the importance of the aforementioned classes of amino acids, the development of pathways to new three-and four-membered azaheterocyclic α-and β-amino acid derivatives is a challenging research field in modern synthetic chemistry at the biological interface (Hughes 2009a;Kiss and Fülöp 2010;Fülöp et al 2006;Kuhl et al 2005;Miller and Nguyen 2005;Cativiela and Ordóñez 2009;Komarov et al 2004;Cowell et al 2004;Gelmi and Pocar 2003;Park and Kurth 2002). Following a preliminary communication (Mangelinckx et al 2008), in the present paper, in-depth results are described on the synthesis and study of the reactivity of 2-(bromomethyl)aziridine-2-carboxylic esters and 3-bromoazetidine-3-carboxylic esters, the structures of which incorporate the synthetically important 2-(halomethyl)aziridine (Abbaspour Tehrani et al 2002;De Smaele et al 1998;De Kimpe et al 1997;D'hooghe et al 2006a;Mangelinckx et al 2009;Vervisch et al 2010), or 3-haloazetidine structural motif (Van Driessche et al 2006;Van Brabandt et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives of potential interest for biological and foldameric applications

et al. 2011

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A short synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-carboxylates was developed involving amination, bromination and base-induced cyclization of alkyl 2-(bromomethyl)acrylates. The aziridines are the kinetically favored cyclization products and could be transformed into 3-bromoazetidine-3-carboxylic acid derivatives via thermal isomerization. The new small-membered azaheterocyclic α-and β-amino acid derivatives contain a bromo-substituted carbon center as a useful moiety for functionalization.Transformation of these functionalized azaheterocycles via nucleophilic substitution with carbon, sulfur, oxygen and nitrogen nucleophiles and via elaboration of the amino and carboxyl group provided a broad range of new conformationally constrained aziridine-2-and azetidine-3-carboxylic acid derivatives which are of interest from a biological point-of-view as well as for applications in the field of foldamers.

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Conformationally rigid cyclic α-amino acids in the design of peptidomimetics, peptide models and biologically active compounds

Cited by 73 publications

References 168 publications

An Expedient and Practical Approach to Functionalized 3-Aza-, 3-Oxa-, and 3-Thiabicyclo[3.3.1]nonane Systems

An Expedient and Practical Approach to Functionalized 3-Aza-, 3-Oxa-, and 3-Thiabicyclo[3.3.1]nonane Systems

Synthesis of Bi‐ and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives of potential interest for biological and foldameric applications

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