Substituted purines and pyrimidines

Substituted purines and pyrimidines can themselves be erroneously incorporated into the DNA sequence, leading to mutations. 

---

These relationships are general Hydroxyl substituted purines and pyrimidines exist in their keto forms ammo substituted ones retain structures with an ammo group on the ring The pyrimidine and punne bases m DNA and RNA listed m Table 28 1 follow this general rule Beginning m Section 28 7 we 11 see how critical it is that we know the cor rect tautomeric forms of the nucleic acid bases... 

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

Pyrimidine is a six-membered aromatic heterocyclic compound that contains two nitrogen atoms, separated by a carbon atom, in the ring. Nucleic acids, DNA and RNA, contain substituted purines and pyrimidines. Cytosine, uracil, thymine and alloxan are just a few of the biologically significant modified pyrimidine compounds, the first three being the components of the nucleic acids. 

Accepted trivial names are given to the substituted purines and pyrimidines 144-148, which are the principal component bases of nucleic acids. 

Structural characterization, recognition patterns, and theoretical calculations of long-chain N-alkyl substituted purine and pyrimidine bases as ligands On the importance of anion—tt interactions 13CCR2705. Structure, functionalization, and apphcations of giant hollow spher-... 

Nucleotides are expressed as phosphoric esters, such as Ado-3 -P for adenosine-3 -monophosphate. S3mibols for monomers containing substituted purine and pyrimidine bases and sugar residues other than ribose are formed in accord with rules subsequently described for one-letter s3nnbolSo... 

The identification of DNA as a primary target for metal-based drugs, especially cisplatin, has focused attention on the interactions of metal complexes with nucleic acid constituents, which include the simple purine and pyrimidine bases and their nucleoside and nucleotide derivatives. The structures, with abbreviations, are represented in Appendix 1. Simple complexes can represent models for cross links in DNA, which can be studied in more detail with small polynucleotides, from the simpler dinucleotides to oligonucleotides and this topic is covered in Section 4.4. There has been extensive use of substituted purines and pyrimidines as models for the DNA bases and in the examination of steric and electronic effects. The structures of many of these analogues are also collected in Appendix 1. 

A major recent growth point in substitution reactions has been the synthesis of pteridine glycosides, especially ribosides for study as probes in DNA chemistry taking advantage of the fluorescent properties of pteridines (see Section 10.18.12.4). Typically these reactions are developments of standard methods of glycosylation used with purines and pyrimidines as nucleophiles. In these and in other cases, the ambident nucleophiles within the pterin... 

Many of the simple heterocycles occur naturally within human biochemistry. For example, the amino acids proline, histidine, and tryptophan contain, respectively, a pyrrolidine, an imidazole, and an indole ring. The nucleic acids contain purine and pyrimidine rings. Vitamins are heterocyclic compounds vitamin Bg (8.8) is a substituted pyridine vitamin Bj (8.9) contains a pyrimidine ring. Simple heterocycles are therefore important to human biochemistry and thus to drug design. 

Unusual features of riboflavin as recorded by some researchers include (1) High levels in liver inhibit tumor formation by azo compounds in animals (2) free radicals are formed by light or dehydrogenation flavine semiquinone dihydroflavin+ (3) free vitamin is found only in retina, urine, milk, and semen (4) substitution of adenine by other purines and pyrimidines destroys activity of flavin adenine dinucleotide (FAD) ... 

Modified nucleic acid bases. These are derived from the purines and pyrimidines given in Fig. 15.1. They either occur naturally, mostly as rare (minor) components of the transfer RNA s [523], or they are synthesized as mimics of or substitutes for the nucleic acid bases. They are of considerable biochemical and pharmaceutical interest, but we can consider only some of the more important compounds (Fig. 15.2). 

X-Ray crystallographic studies of purine and its various substituted derivatives have been of special value in providing (a) fine structural details of the ring system of simple molecules in their various neutral and protonated, and to a lesser extent, deprotonated forms (b) a source of molecular geometries for theoretical calculations and related purposes and (c) information about the precise arrangement of purine (and pyrimidine) bases in the various nucleic acids, and the way in which interaction of such bases with extraneous materials including intercalated or absorbed compounds occurs. 

Novel congeners of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, 32), the dialkyl esters of purine and pyrimidine A-[2-(phosphonomethoxy)ethyl] derivatives substituted at position 2, 6 or 8 of the purine base (33) or position 2, 4 or 5 of the pyrimidine base (34), were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate diester. Except for the 5-bromo-cytosine derivative (34a), no activity against DNA viruses or retroviruses was observed for the novel pyrimidine analogues. However, modifications to the purine led to compounds highly active against HSV-1 and -2, VZV, CMV, W, MSV and HIV. 

E. S. D. Chen was primarily responsible for the study of properties of biologically significant molecules. The Ea of the purines and pyrimidines were predicted using substitution and replacement effects and subsequently measured experimentally. Quantum mechanical calculations of the Ea supported these determinations. These studies led to a theory of electron transport through DNA [105-111]. These... 

The syntheses of the 6 -0-(bromopentyl)-substituted allofuranosyl-purine and -pyrimidine phosphoramidite (40a-c) and the 2 -0-[(3-bromopropoxy)methyl] substituted allofuranosyl-purine and -pyrimidine phosphoramidite (41a-c) have been reported. Such modifications of the sugar moiety presented opportunities for the functionalisation of oligonucleotides with a variety of soft nucleophiles while the fully protected sequence was still on the solid support. ... 

There is, for example, no end-of-text chapter entitled Heterocyclic Compounds. Rather, heteroatoms are defined in Chapter 1 and nonaromatic heterocyclic compounds introduced in Chapter 3 heterocyclic aromatic compounds are included in Chapter 11, and their electrophilic and nucleophilic aromatic substitution reactions described in Chapters 12 and 23, respectively. Heterocyclic compounds appear in numerous ways throughout the text and the biological role of two classes of them—the purines and pyrimidines—features prominently in the discussion of nucleic acids in Chapter 27. 

Several examples of prodrugs are found in the purine and pyrimidine analogs that substitute for natural nucleotides and inhibit nucleic acid formation. For example, 5-fluorouracil is essentially harmless to mammalian host and tumor cells. Upon administration, the drug is subject to one of two opposingmetabolicfates (10). Inactivation and elimination are accomplished by catabolism (about 80% of the dose) and by urinary excretion of unchanged drug... 

---