Acyclic pyrophosphate

Macrocychc bisphosphonates 165 and 166 were prepared from 2, 3 -0-isopropyhdene-5 -tosyladenosine 158 or -mesyladenosine 159 precursors, and the bis(tetrabutylammonium) salt of nicotinamide riboside 5 -methylbis (phosphonate) 160 (05JMC4177). Nucleophilic substitution of the precursors afforded the acyclic pyrophosphate 161 or 162 in modest yields. After deprotection with an aqueous hydrochloric acid solution, nicotinamide... 

Phosphonoformate is a pyrophosphate analog and inhibits both DNA polymerases and reverse transcriptase. However, toxicity may prevent longterm treatment of AIDS patients. Amantadine has a narrow antiviral specificity. It specifically inhibits initiation of the replication of influenza virus RNA of type A (but not of type B). Active only against retroviruses, 3 -azidothymidine is a reverse transcriptase inhibitor, which acts by a chain termination mechanism. It was synthesized in the early 1960s but only recently has been used in treatment of AIDS victims. More recently a series of 2, 3 -dideoxynucleosides, such as dideoxyinosine, have also been used.d Acyclic phosphonates, such as phosphonylmethoxypropyladenine, avoid the need for metabolic phosphorylation of the drug.6... 

Recently, Czamik et al. have reported the use of the acyclic protonated amine host 9 as a chemosensor of pyrophosphate. Typical fluorescence sensing methods rely on the ability of a complexed anion to quench the fluorophore. The fluorescence intensity of host 9, however, is actually increased upon complexation of anions and its 2200-fold selectivity of pyrophosphate over phosphate allows for real-time assay of pyrophosphate hydrolysis by inorganic pyrophosphatase.18... 

Croteau, R., Felton, M. and Ronald, R.C. (1980a) Biosynthesis of monoterpenes conversion of the acyclic precursors geranyl pyrophosphate and neryl pyrophosphate to the rearranged monoterpenes fenchol and fenchone by a soluble enzyme preparation from fennel (Foeniculum vulgare). Archives of Biochemistry and Biophysics 200(2), 524-533. 

The difficulties encountered in the untemplated synthesis of natural nucleic acids is one factor that has prompted many researchers to propose alternatives to RNA as the initial genetic material. For example, a derivative of 3 -aminoguanosine can form untemplated chains of up to 20 bases in length.25 In addition, both cyclic and acyclic nucleotide bisphosphate derivatives polymerize without the aid of a template to form nucleic acids with pyrophosphate linkages between the monomers, rather than the more natural phosphodiester linkages.26-29... 

The controversy over presqualene alcohol has been resolved in favour of Rilling s second structure (5), rather than the diester proposed by Popjak or the acyclic formulation suggested by Lynen. In the biosynthesis from farnesyl pyrophosphate one hydrogen atom is lost to the medium from C-1, and when the presqualene alcohol pyrophosphate is further metabolized to squalene (6) no further hydrogen atoms are lost. Final proof of the structure came from its synthesis by three groups the indicated absolute stereochemistry was based on a correlation with trans-chrysanthemyl alcohol. This structure is now also accepted by Popjak and co-workers. Thus the conversion of farnesyl pyrophosphate into squalene may be rationalized as shown (see also ref 29). 

The biogenesis of many cyclic terpenoids requires a cts-double bond in the acyclic precursor. A cis-double bond is frequently incorporated into the terminal isoprenoid unit via an allylic rearrangement mechanism. Alternatively, a cis unit could be incorporated directly (as rubber). Two results this year highlight some features of this problem. Both geraniol (22) and nerol (23) are derived from all-trans units (i.e. retention of the 4i -proton of mevalonate) so that the cis-double bond of nerol is derived by isomerization. The sesquiterpenoid gossypol (34) is derived from c/s,cis-farnesyl pyrophosphate. Hence in its biosynthesis either... 

A non-specific bacterial acid phosphatase from Shigella flexneri (PhoN-Sf) has been screened for regioselective phosphorylation of primary alcohol(s) of more than 20 different cyclic and acyclic monosaccharides using pyrophosphate as the phosphate donor (O Scheme 61) [368]. These studies have shown that PhoN-Sf is capable of phosphorylating a range of hexoses (D-glucose epimers, glycosides, and C-2 derivatives), pentoses, heptoses, ketoses, and acyclic carbohydrates. 

For HSV at least three mechanisms have been described that generate resistance to AC V deficiency or loss of viral TK activity, alteration in substrate specificity of the virus-encoded TK, and alteration in the substrate specificity of the viral DNA polymerase (1,8). Most of the ACVr mutants that have been isolated in vitro and recovered from clinical specimens are TK-deficient (TK). However, resistant clinical mutants that have an altered TK or altered DNA polymerase activity have occasionally been described too. Although TK mutants are crossresistant with drugs that also depend on viral TK for their activation (i.e., GCV, penciclovir and brivudin (BVDU), they remain sensitive to agents, such as PFA, vidarabine (Ara-A), and the acyclic nucleoside phosphonate (ANP) analogs. PFA, a pyrophosphate analog, is a direct inhibitor of the viral DNA poly-merase in which it binds to the site involved in releasing the pyrophosphate product of DNA synthesis. Phosphorylation of Ara-A to Ara-A triphosphate is carried out by cellular enzymes phosphorylation of ANP derivatives to their mono- and diphosphoryl derivatives is also carried out by cellular enzymes. 

Quite interesting and indicative in respect to the authentication of the compounds may also be their oxygen isotope characteristics. OH-groups of acyclic and of some mono-cyclic monoterpenes are introduced as OH" from water, substituting the pyrophosphate functionality of the biosynthetic precursor. This hydrolysis is probably accompanied by a kinetic isotope effect, from where a relative low 8 Q-value is to be expected. The 8 0-value of synthetic analogues will depend on the oxygen source... 

Cyclization of an allylic pyrophosphate is a key step in the biosynthesis of most monoterpenes. Early hypotheses concerning the nature of the acyclic precursor and the cyclization process are first described, and chemical models for the cyclization presented. Following a review of several representative cyclase enzymes and the reactions that they catalyze, a series of stereochemical and mechanistic experiments with partially purified cyclases are reported. The results of these studies have allowed a detailed description of events at the active site and the formulation of a unified stereochemical scheme for the multistep isomerization-cyclization reaction by which the universal precursor geranyl pyrophosphate is transformed to cyclic monoterpenes. 

Two pinene cyclases have been isolated from sage (19,35). Electrophoretically pure pinene cyclase I converts geranyl pyrophosphate to (+)-a-pinene and to lesser quantities of (+)-camphene and (+)-limonene, whereas pinene cyclase II, of lower molecular weight, converts the acyclic precursor to (-)-B-pinene and to lesser quantities of (-)-a-pinene, (-)-camphene and (-)-limonene. Both purified enzymes also utilize neryl and linalyl pyrophosphate as alternate substrates for olefin synthesis. The availability of enzyme systems catalyzing formation of enantiomeric products from a common, achiral substrate has provided an unusual opportunity to examine the stereochemistry of cyclization. 

Two elements of the cyclization have yet to be addressed the isomerization of geranyl pyrophosphate to linalyl pyrophosphate (or the equivalent ion-pair) and the construction of bicyclic skeleta. Studies on the biosynthesis of linalool (61), and on the analogous nerolidyl system in the sesquiterpene series (52), have shown this allylic transposition to occur by a net suprafacial process, as expected. On the other hand, the chemical conversion of acyclic or monocyclic precursors to bicyclic monoterpenes, under relevant cationic cyclization conditions, has been rarely observed (47,62-65) and, thermodynamic considerations notwithstanding (66), bicyclizations remain poorly modeled. 

Curiously, certain cyclases, notably (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase, are capable of cyclizing, at relatively slow rates, the 3S-linalyl pyrophosphate enantiomer to the respective antipodal products, (-)-bornyl pyrophosphate and (+)-endo-fenchol (74,75). Since both (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase produce the designated products in optically pure form from geranyl, neryl and 3R-linalyl pyrophosphate, the antipodal cyclizations of the 3S-linalyl enantiomer are clearly abnormal and indicate the inability to completely discriminate between the similar overall hydrophobic/hydrophilic profiles presented by the linalyl enantiomers in their approach from solution. The anomalous cyclization of the 3S-enantiomer by fenchol cyclase is accompanied by some loss of normal regiochemical control, since aberrant terminations at the acyclic, monocyclic and bicyclic stages of the cationic cyclization cascade are also observed (74). The absolute configurations of these abnormal co-products have yet to be examined. 

The pinene cyclases convert the anomalous linalyl enantiomer to abnormal levels of acyclic (e.g. myrcene) and monocyclic (e.g. limonene) terpenes, these aberrant products perhaps arising via ionization of the tertiary substrate in the transoid or other partially extended (exo) form (see below). In any event, for all "normal" cyclizations examined thus far, the configuration of the cyclizlng linalyl Intermediate has been confirmed to be that which would be expected on the basis of an anti-endo conformation. Scattered attempts at intercalating the cyclization cascade with analogs of proposed cyclic intermediates (e.g. a-terpinyl and 2-pinyl pyrophosphate) have been unsuccessful (20,35,36). 

Suga, T., Hirata, T., Aoki. T., and Shishibori, T., Interconversion and cyclization of acyclic allyhc pyrophosphates in the biosynthesis of cyclic monoterpenoids in higher plants. Phytochemistry, 25, 2769, 1986. 

The synthesis and biological activity of the new acyclic heterodinucleotide (113) that consists of both an antiherpetic (acyclovir) and an antiretroviral (2-(phosphonomethoxy)propyl-adenine) drug linked by a pyrophosphate bridge were reported. The heterodinucleotide (113), prepared from the reaction of a morpholidate derivative of PMPA and the tributylammonium salt of acyclovir monophosphate in the presence of pyridine, behaved as a pro-drug in macrophages. Anti-HIV and anti-HSV activity of this compound were demonstrated in HIV-lfia-L and HSV-1-infected macrophages. ... 

Steroids are formed from two sesquiterpene molecules—farnesyl pyrophosphate— which are attached to each other tail to tail to give the acyclic squalene (SOC-atoms) this undergoes complex reactions involving a cyclisation to tetracyclic or pentacychc ring systems, especially cholesterol. 

There are relatively few sesquiterpenoids which cannot be derived from a farnesyl precursor either directly or indirectly. Recent examples of this rare group are furoventalene (403), the keto-lactone (404), the phenol (405), and the revised structure of humbertiol (406). Proposed biogenetic schemes for these compounds involve the combination of a C o monoterpene unit (either acyclic or cyclic) with a C5 unit (e.g., dimethylallyl pyrophosphate). 

Several bacterial species produce C45 and C50 carotenoids which contain one or two extra isoprenyl groups. Although their biosynthesis has not been studied, it is probable that instead of proton-initiated cyclisation at the polyene termini, attack by dimethyl allyl pyrophosphate results in substances such as the symmetrical decaprenoxanthin (P439) (68). The stereochemistry of the isolated acyclic double bond was shown to be trans by the n.m.r. spectrum of the corresponding aldehyde. Other carotenoids present in Flavobacterium... 

The acyclic precursor of the monoterpenoids is normally assumed to be geranyl pyrophosphate (6 n = 1) but, clearly, this cannot directly cyclise to the foliamenthin skeleton. Two alternative precursors are" linalool pyrophosphate (28 R = P206 ) and nerol pyrophosphate (29 R = P206 ). Unfortunately,... 

H of loganin (35 R = Me). However, the first Cjo acyclic precursor must be geranyl pyrophosphate 6 n = 1) since two tritium atoms are incorporated" by the [2- C,3R,4R- H]isomer and none by the (4S)-isomer. The mechanism proposed by Arigoni for this cyclisation involves the trialdehyde (33). Potty et al. have isolated an enzyme from Citrus spp. which oxidises geraniol (27) to the corresponding aldehyde. 

The chemical structure of naturally occurring ais polyisoprenes was determined by 13C NMR spectroscopy using acyclic terpenes and polyprenols as model compounds. The arrangement of the isoprene units along the polymer chain was estimated to be in the order dimethylallyl terminal unit, three trans units, a long block of ais units, and ais isoprenyl terminal unit. This result demonstrates that the biosynthesis of cis-polyisoprenes in higher plants starts from trans,trans,trarcs-geranylgeranyl pyrophosphate. ... 

According to this mechanism, natural rubber chains are expected to have one dimethylallyl terminal unit and one isoprenyl pyrophosphate terminal unit the latter may give rise to a hydroxyl group by hydrolysis. From this point of view, acyclic terpenes in the generalized structure (II) may be appropriate models for the structural characterization of natural polyisoprenes by 13C NMR spectroscopy. 

Figure 29. Relationships h een the carbon positions in isopentenyl pyrophosphate and their sources. In the mevalonic-acid pathway, all five caibon positions in isopentenyl pyrophosphate derive from acetate and, in turn from the C-1 + C-6 and C-2 + C5 positions of glucose. In the methyierythritol-phosphate pathway, one carbon derives from the C-3 + C-4 position in glucose. Moreover, the mapping of positions from preciu ors into products of the two pathways differs sharply, as indicated by stmctures of acyclic and steroidal carbon skeletons based on the MVA (a, c) and MEP pathways (b, d).

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