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Β-Amino Acids and Their Natural Biologically Active Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2011, vol. 80, p. 2-11 ISSN 0372-7025 DOI: 10.31482/mmsl.2011.001 REVIEW ARTICLE β- AMINO ACIDS AND THEIR NATURAL BIOLOGICALLY ACTIVE DERIVATIVES. 5. DERIVATIVES OF UNUSUAL ALICYCLIC AND HETEROCYCLIC β- AMIMO ACIDS Jiří Patočka Department of Radiology and Toxicology, Faculty of Health and Social Studies, University of South Bohemia České Budějovice Received 3 th December 2010. Revised 8 th March 2011. Published 6 th April 2011. Summary α- Amino carboxylic acids are one of five major classes of natural products and play a crucial role in diverse biological functions. Historically, the amino acids have been subdivided into proteinogenic and non- proteinogenic respresentatives. β- Amino acids are similar to alfa-amino acids in that they contain an amino terminus and a carboxyl terminus. However, in β- amino acids two carbon atoms separate these functional termini. β- Amino acids, with a specific side chain, can exist as the R or S isomers at either the α( C2 ) carbon or the β( C3 ) carbon. This results in a total of 4 possible diastereoisomers for any given side chain. β- Amino acids are not proteinogenic amino acids, but some of them are constituents of soma natural and biologically active compounds. Unusual β- amino acids are alicyclic β- amino acids and heterocyclic β- amino acids. Alicyclic β- amino acids, in which both the β- amino and the acids functionality are vicinally attached to an aliphatic ring, still represent a demanding challenge to the synthetic chemist. One reason for this lies in the intriguing difficulty associated with controlling the absolute and relative stereochemistry of two adjacent stereocenters. In heterocyclic β- amino acids the nitrogen of amino group is a part of nitrogen heterocycles. Some natural derivatives of alicyclic β- amino acids and heterocyclic β- amino acids, their chemical structures and biological activities are discussed in this mini-review. Key words: unusual amino acids; alicyclic β- amino acids; heterocyclic β- amino acids; alkaloids; peptides INTRODUCTION sipeptides, lactones, alkaloids, and other natural products, and in free form they show interesting β- Amino acids are not as common in nature as pharmacological effects. β- Amino acids are cur - their α- analogues. Some β- amino acids are found rently of growing interest, not only because of in more complex structures like peptides, dep - their natural roles, but also because of their use in the synthesis of peptide mimetics and in the syn - thesis of certain quite new biologically active sub - University of South Bohemia České stances (44). β- Amino acids are a constituent of Budějovice, Faculty of Health and Social some toxins and a special class of pore-forming Studies, Department of Radiology and lipopeptides which exhibit antibacterial and anti - Toxicology, Matice školské 17, fungal activity (5). Peptidomimetics containing 370 01 České Budějovice, Czech Republic β–amino acids represent one of the strategies in [email protected] developing therapeutic candidates with increased Patočka: β- Amino acids and their natural biologically active derivates oral bioavailability and resistance to metabolic β–amino acid substructures. The most important degradation (67). Consequently, β- amino acids β–amino acids are β- alanine (55), β- leucine (48), have potential as inducers of secondary structure β- lysine, β- arginine (49), β- glutamate, β- pheny - and even single β- amino acid residues stabilize lalanine and β- tyrosine (50). Furthermore, a lot of discrete conformations in cyclic peptides. Natural others unusual β- amino acids exist and these are derivatives of β- amino acids are often character - also components of natural products (51). Like ized by potent pharmacological and toxicological these compounds, alicyclic and heterocyclic amino activities that are often crucially based on their acids, are the aim of this article. ALICYCLIC β- AMINO ACIDS (Fig. 1) Fig. 1. Alicyclic β- amino acids. 2-Aminocyclopropane-1-carboxylic acid (I, n = 1), 2-aminocyclobutane-1-carboxylic acid (I, n = 2), cispentacin (II), PLD-118 (III), amipurimycin (IV) and oryzoxymycin (V). Alicyclic β- amino acids of the general formula I, in urational cis (R,S and S,R) and two configurational which both the β- amino and the acids functionality trans (R,R and S,S) forms. are vicinally attached to an aliphatic ring represent interesting group of compounds which alone or in - 2-Aminocyclopropane-1-carboxylic acid (I, n = 1) stalled to bigger molecule show some remarkable and 2-aminocyclobutane-1-carboxylic acid (I, biological effects (35). Alicyclic β- amino acids are n = 2) are known practically only as synthetically important synthons in drug research (17). The 3- prepared compounds (18) and may be used to pre - and 4-membered β- amino acids and its derivatives pare peptides and pseudopeptides which represent are rare in nature and usualy are toxic. For some 5- a group of compounds with conformationally con - and 6-membered β- amino acids a unique anti fungal strained β- amino acid residues (29, 39, 62, 70). The activity has been observed, 7-membered β- amino predominance of eight-membered hydrogen-bonded acid derivatives have been investigated for neuro - rings has been manifested for (trans,trans)- and logical disorders (35). Alicyclic β- amino acids are (trans,cis)-beta-dipeptides while the formation of one class of potent antifungals that have a dual six-membered rings is preferred for the (cis,trans) mode of action: These compounds inhibit protein beta-dipeptide similarly to the previously described synthesis after concentrative uptake and interfere (cis,cis)-diastereomer (71) . Likewise 2-aminocy - with self-regulatory mechanisms of amino acid me - clobutene-1-carboxylic acid was prepared (3) and tabolism (64). Alicyclic β- amino acids and their incorporated to some small peptides (40, 62) as well residues are amino acids with two chiral centers re - as unsaturated derivative, 2-aminocyclobutene-1- sulting in four possible configurations; two config - carbocylic acid (40) . 3 Patočka: β- Amino acids and their natural biologically active derivates 2-aminocyclopentane-1-carboxylic acid and deriv - (III ) (Bay-10-8888) which competitively inhibits atives isoleucyl-tRNA synthetase. PLD-118 disrupts fun - gal protein biosynthesis and cell growth (59). Be - Stereoisomer (1R,2S) of 2-aminocyclopentane- cause of its potent specific activity observed against 1-carboxylic acid is known as natural product Candida spp. including azole-resistant strains in named FR-109615 or cispentacin. Cispentacin was vitro and in vivo , in addition to its excellent phar - isolated from the culture broth of a Bacillus cereus macokinetics, solubility and safety, PLD-118 was strain, L450-B2. chosen for further development for systemic treat - Cispentacin (II) , water-soluble and ampho - ment of Candida infections (64). In 2000, PLD-118 teric compound, exhibits a strong antifungal in vitro was licensed to the Croatian pharmaceutical com - activity against various Candida strains, e.g. Can - pany PLIVA, where it is now named icofungipen dida albicans , Candida krusei and Candida utilis . (PLD-118) (58). Based on the very promising re - It showed weak in vitro activity against Trichophy - sults in preclinical and phase I clinical studies, a ton mentagrophytes , while no activity was observed phase II clinical study was initiated with this com - against Cryptococcus and Aspergillus species. In pound being the only new compound in develop - addition, cispentacin displayed a potent therapeutic ment for oral treatment of yeast infection. efficacy against a lethal lung Candida albicans in - Amipurimycin (IV ), a member of the complex fection in immuno-compromised mice (32). The peptidyl nucleoside family of antibiotics, is a Strep - 50% inhibitory concentration (IC 50 ) and IC 100 val - tomyces -derived potent antifungal agent. ues of cispentacin against clinical isolates of Can - Amipurimycin was isolated from the culture filtrate dida albicans were in the ranges 6.3-12.5 and of Streptomyces novoguineensis . It contains 6.3-50 μg/ml, respectively. This antibiotic demon - 2–aminopurine, cis-2-aminocyclopentane-1-car - strated good therapeutic efficacy against a systemic boxylic acid and a sugar moiety (21). Candida infection in mice by both parenteral and Amipurimycin is strongly active against Pyricu - p. o. administrations. The 50% protection dose laria oryzae (24), the microorganism that causes (PD 50 ) values after single i.v. and p.o. administra - rice blast disease. tions were 10 and 30 mg/kg, respectively. It was also effective in a systemic infection with Crypto - 2-aminocyclohexane-1-carboxylic acid and de - coccus neoformans and in both lung and vaginal in - rivatives fections with C. albicans in mice. Cispentacin did not induce acute lethal toxicity at 1.000 mg/kg by Enantiomerically pure, cis- and trans-2- i.v. injection and 1,500 mg/kg by i.p. and p.o. ad - aminocyclohexane-1-carboxylic acids were pre - ministrations in mice (45). I.v. administration of 50 pared synthetically (11, 60) as well as some higher mg/kg cispentacin led to a 100 % survival rate. In - 2-amino-cycloalkane-1-carboxylic acids (15) but in teresting cispentacin-derived bicyclic β- amino acid nature these amino acids were not found and their has been synthesized and incorporated into the 6- natural derivatives are rare. position of GnRH (36). Oryzoxymycin (V) is antibiotic (26) with un - Cispentacin and its stereoisomers, i.e. (1S,2R)- usual structure (25) with dihydro-3-hydroxyan - antipode and trans-diastereomer were tested for thranilic acid moiety. Oryzoxymycin was isolated their antifungal activity against C. albicans . Only from a soil sample of Streptomyces venezuelae , var. cispentacin showed antifungal activity. Both, its oryzoxymyceticus , and this compounds was shown (1S,2R)-antipode and its trans-diastereomer were to exhibit moderate activity against Xanthomonas inactive in vitro against C. albicans and C. tropi - oryzae , gram-positive bacteria that attack the leaves calis . To explore the structure activity retionship of rice plant (6). (SAR) of antifungal cispentacin β- amino acids Ohki et al.
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