A p-alanine

Many variations of K2K dendrons have also evolved. A symmetrical version with a p-alanine spacer 39 at the a-amine of Lys provides a core unit that has symmetrical branching. To limit the flexibility of the branched lysyl template, ornithine, the lower homologue of Lys, as well as more constrained diamino acids 23-25 have been used. 39 62,64 Nonbranched polylysine dendrons 26 that are linear, and helical 71 and cyclic peptides 27 have also been developed to impart different forms of dendrimeric architecture (Scheme 5). 

Choose a reaction sequence so that each of the Nc reactive sites adds a reactant B, possessing new Nb (Nb > 1) reactive sites (thereby introducing multiplicity) to obtain dendrimer D0 of generation 0. With ammonia as initiator core, a p-alanine derivative (Nb = 2) might be chosen as reactant. 

Aromatic cytokinins are found in poplar,379-381 anise,382 tomato,383 Cocos nucifera m and Arabidopsis,381 In addition to BA, aromatic cytokinins are found as ortho-topolins, wc/ -topolins, hydroxylated BAs, ortho-meth-oxytopolins, and rwfto-methoxytopolins (Figure 1 1).380,381 Other derivatives have been isolated as N3-, N7-, and /VP-glucosides and A P-alanine on the adenine ring,385 and nucleosides and a glucoside linked to the ribosyl moiety.386 In spite of the several reports of their occurrence, it is not clear whether the aromatic species are common in plants. 

When stericaUy demanding peptide fragments are coupled in the presence of HOSu, a side reaction that leads to a P-alanine derivative becomes donninant (Scheme In this side reaction, HOSu is activated by DCC and attacked by a second equivalent of HOSu. The nitrene is probably not a real intermediate as it is rearranged conconoitantly to its formation to an isocyanate moiety, which is trapped by a third equivalent of HOSu.t By replacing the HOSu additive with A-hydroxy-5-norbornene-2,3-dicarboximide (18)t or other dinucleo-phUes, this side reaction is efficiently bypassed. 

Scheme 9 Formation of a P-Alanine Derivative by the Addition of A-Hydroxysuccinimide to Carbodiimidesl ...

Peptide cleavage from the allyl-linker resin is achieved with morpholine in large excess in the presence of tetrakis(triphenylphosphine)palladium (10mol% based on the allylic substitution of the resin). (3-HYCRAM resin is a modification of HYCRAM containing a P-alanine residue as a spacer between the crotonoyl unit and the resin. It has been used for the solid-phase synthesis of glycopeptides by the Boc and Fmoc strategies.b 1 Difficulties may be... 

Another interesting example of a linear 3-AP dimer is viscosaline (48), Fig. (12), a 1,3-dialkylpyridinium compound with a P-alanine moiety covalently bound to one alkyl chain. It was recently purified from the arctic sponge Haliclona viscose [21], and proposed as a biosynthetic precursor of cyclostellettamines (53-63), Fig. (14) and related molecules. 

Synthesis of the bicyclic dodecapeptide theonellamide F is achieved via cyclic peptide 224 which in turn is prepared from building block 223. The key intermediate 223 is prepared by coupling of tetrapeptide 221 and a p-alanine derivative (222).83... 

Pantothenic acid and pantothenates may also be analyzed following derivatization to extend the chromophore and hence allow UV detection at higher wavelengths or fluorometric detection. Hudson et al. (63) have attempted to analyze the vitamin as a P-alanine-fluorescamine complex. The derivatization procedure was lengthy and required extensive sample cleanup before the hydrolysis step due to the interference of riboflavin, niacinamide, and some minerals such as zinc, copper, manganese, and molybdenum. Although these interferences were eliminated, the method did not yield reproducible results. 

Miick S M, G V Martinez, W R Fiori, A P Todd and G L Millhauser 1992. Short Alanine-based Peptides Ma Form 3(10)-Flelices and not Alpha-helices in Aqueous Solution. Nature 359 653-655. 

Aminopropanoic acid known as 3 alanine It IS a p amino acid that makes up one of the stmctural units of coenzyme A... 

Fig. 10. Sequences (see Table 1) of betabeUins. In each case, only one-half of the P-sandwich is shown. The dimer is formed from identical monomeric sets of four P-strands. In the pattern sequence, e is for end, p is for polar residue, n is for nonpolar residue, and t and r are for turn residues. Lower case f is iodophenyialanine lower case a, d, k, and p are the D-amino acid forms of alanine, aspartic acid, lysine, and proline, respectively B is P-alanine (2,53,60,61).

R)-Pantothenic acid (1) contains two subunits, (R)-pantoic acid and P-alanine. The chemical abstract name is A/-(2,4-dihydroxy-3,3-dimethyl-l-oxobutyl)-P-alanine (11). Only (R)-pantothenic acid is biologically active. Pantothenic acid is unstable under alkaline or acidic conditions, but is stable under neutral conditions. Pantothenic acid is extremely hygroscopic, and there are stabiUty problems associated with the sodium salt of pantothenic acid. The major commercial source of this vitamin is thus the stable calcium salt (3) (calcium pantothenate). 

The metabohcaHy active form of pantothenic acid is coen2yme A. Pantothenic acid is produced only by microorganisms, starting from (R)-pantoate (22) and P-alanine. (R)-Pantoate is synthesi2ed by a set of en2ymatic reactions, as follows (63,64) ... 

Aspartic acid decarboxylase cataly2es the decarboxylation of asparatic acid to yield P-alanine (10), a precursor for the biosynthesis of pantothenic acid (67). FiaaHy, (R)-pantothenic acid is obtaiaed by coupling P-alaniae (10) with (R)-pantoate (22) ia the presence of pantothenate synthetase ... 

RS- P-Aminoisobutyric acid (a-methyl-P-alanine) [10569-72-9] M 103.1, m 176-178 , 178-180 , 181-182 , R -(-)- isomer [144-90-1] m 183 , [a] -21 (c 0.43, HjO), pKes,(,) 3.7, pKEst(2) 10.2. Colorless prisms from hot H O, were powdered and dried in vacuo. The purity is checked by paper chromatography (Whatman 1) using ninhydrin spray to visualise the amino acid Rp values in 95% MeOH and n-PrOH/5N HCOOH (8 2) are 0.36 and 0.50 respectively. [Kupiecki and Coon Biochem Prep 7 20 7960 Pollack J Am Chem Soc 65 1335 7943.] The R-enantiomer, isolated from iris bulbs or human urine was crystd from H2O and sublimed in vacuo [Asen et al. J Biol Chem 234 343 7959]. The RS-hydrochloride was recrystd from EtOH/Et20 m 128-129 , 130° [Bbhme et al. Chem Ber92 1258, 1260, 1261 7959]. 

R-(+)-Pantothenic acid sodium salt (7V-[2,4-dihydroxy-3,3-dimethylbutyryl] P-alanine Na salt) [867-81-2] M 241.2, [aJ +27.1 (c 2, H2O), pK 4.4 (for free acid). Crystd from EtOH, very hygroscopic (kept in sealed ampoules). The free acid is a viscous hygroscopic oil with [a] +37.5 (c 5, H2O), easily destroyed by acids and bases. 

Recently the Bohlmann-Rahtz synthesis has received greater attention. Baldwin has employed this method for the construction of heterocyclic substituted a-amino acids. Exposure of alkynyl ketone 39 to 3-aminocrotoyl ester 40 resulted in the Michael product 41. Thermolysis then gave rise to the desired pyridyl-P-alanines 42. 

CN (R)-A-(2,4-dihydroxy-3,3-dimethyl-l-oxobutyl)-P-alanine monosodium salt... 

N-(3-ethoxy-3-oxopropy])-A -(phenylmethyl)-P-alanine ethyl ester... 

C7H4N2O2 619-24-9) see Tazanolast A -(4-nitrobenzoyl)-p-alanine (CJ0H10N2O3 59642-21-6) see Balsalazide sodium /7-nitrobenzoyl chloride... 

Urbach, A. R., J.J. Love, S.A. Ross, and P.B. Dervan. Structure of a jS-alanine linked polyamide bound to a full helical... 

P-Alanine, a metabolite of cysteine (Figure 34-9), is present in coenzyme A and as P-alanyl dipeptides, principally carnosine (see below). Mammalian tissues form P-alanine from cytosine (Figure 34-9), carnosine, and anserine (Figure 31-2). Mammalian tissues transami-nate P-alanine, forming malonate semialdehyde. Body fluid and tissue levels of P-alanine, taurine, and... 

The P-alanyl dipeptides carnosine and anserine (A -methylcarnosine) (Figure 31-2) activate myosin ATPase, chelate copper, and enhance copper uptake. P-Alanyl-imidazole buffers the pH of anaerobically contracting skeletal muscle. Biosynthesis of carnosine is catalyzed by carnosine synthetase in a two-stage reaction that involves initial formation of an enzyme-bound acyl-adenylate of P-alanine and subsequent transfer of the P-alanyl moiety to L-histidine. 

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

Fig. 2. Agents controlling the opening of Cl -channels. The structural formula, the name, the respeetive Cl -channel, and an appropriate reference are provided. (A) Note the similarity of GABA, taurine, and P-alanine. Note also that DPC and its analogues such as NPPB contain a -alanine backbone. (B) The structure of torasemide comes close to both DPC and furosemide or buraetanide. It blocks the Na ZCPK" -cotransporter with very high affinity and with lesser affinity also the TAL-Cl -channel. Note that IAA-94 is related to phenoxyaeetic acids (e.g., ethacrynic acid). Amidine is related to IAA-94 but it has a positive net charge. Amidine as well as IAA-94 block the ICOR channel at around lO mol/1 [63].

Substantial attention has been devoted to the metabolism of 5-fluorouracil and related compounds. For example, F NMR was used successfully both in cell extracts and in whole mycelia to elucidate anabolic reactions involving pyrimidine nucleotides and degradation to a-fluoro-p-alanine in the fungus Nectria haematococca (Parisot et al. 1989,1991). 

Fluoro-2 -deoxyuridine has been extensively used in studies of the mechanism of action of thymidylate synthase, and 5-fluorouracil is an anticancer drug that has provided a lead to the development of others. The metabolism of 5-fluorouracil by the ascomycete fungus Nectria haematococca has been studied using F NMR (Parisot et al. 1991). a-Fluoro-P-alanine (2-fluoro-3-aminopropionate) was produced (Figure 10.27), while 5-fluorouridine-5 -mono-, di-, and triphosphate were found in acid extracts of the mycelia, and the 2 - and 3 -monophosphates were recovered from RNA. 

Many reports confirm notable reductions in reaction times when carrying out reactions under micro flow conditions. Concerning p-dipeptide synthesis, for example, a comparison between batch and micro-reactor processing was made for the reaction of Dmab-P-alanine and Fmoc-i-P-homophenylalanine [158]. While the micro reactor gave a 100% yield in 20 min, only about 5% was reached with the batch method. Even after 400 h, only 70% conversion was achieved. 

The second example of property space applications concerns the dipephde camo-sine (P-alanine-L-histidine, see Fig. 1.4) which represents the archetype of a series of histidine-containing dipeptides whose full physiological role remains poorly understood despite extensive studies in recent years [18-20]. Carnosine is synthesized by carnosine synthetase and hydrolyzed by dipeptidases (also called camosi-nases) which belong to the metalloproteases [21]. 

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