Thymine discovery

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

Same of the common names of these bases reflect the circumstances of their discovery. Guanine, for example, was first isolated from guano (bird manure), and thymine was first isolated from thymus tissue. 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

The discovery of a small proportion of a nucleoside containing thymine42 in the ribonucleic acid of two strains of Escherichia coli, in Aerobacter aero-genes, and in commercial, yeast-ribonucleic acid emphasizes the point made previously,26-28 namely, that the nucleic acids may contain constituents other than those heretofore identified. Alkaline hydrolysis of the ribonucleic acid from E. coli gave nucleotides42 (probably the 2- and 3-phosphate esters) which were converted to the nucleoside with prostatic phospho-monoesterase.62 Enzymic hydrolysis of the nucleic acid preparation also led to the nucleoside, which was degraded further to thymine by hydrolysis with perchloric acid.42 There can be little doubt that this carbohydrate derivative of thymine is intimately bound as part of the polynucleotide chain of this particular ribonucleic acid. 

Erwin Chargaff s discovery that DNA contains equimolar amounts of guanine and cytosine and also equimolar amounts of adenine and thymine has come to be known as Chargaff s rule ... 

In 1933, Klein discovered that sodium arsenate inhibits the action of the nucleotidase" of intestinal mucosa. Consequently, Klein and Thannhauser were enabled to hydrolyze thymus nucleic acid by means of intestinal desoxyribonucleinase without subsequent dephosphorylation of the liberated nucleotides. Making use, also, of Klein s discovery of the deaminase-inhibiting activity of silver ions, they were successful in isolating the adenine nucleotide. Hence the phosphodesoxyribosyl nucleotides of adenine, guanine, thymine, and cytosine were isolated and characterized. 

Interest in G C tetrad forming base-pairs comes from the discovery of the fragile X syndrome and the associated d(CGG)n d(CCG) repeats. Initial structural prediction for the CG rich repeat sequences identified a parallel stranded motif stabilized by the methylation of the cytosine residues. Subsequent structural analyses by NMR methods on a sequence that contained CG2 repeats, linked by thymine bases, revealed a head-to-tail hairpin arrangement... 

Because of complementary base pairing, the amount of adenine in a molecule of DNA always equals the amount of thymine, and the amount of cytosine always equals the amount of guanine. In 1953, James Watson and Francis Grick used this observation to make one of the greatest scientific discoveries of the twentieth century when they determined the double-helix structure of DNA. They accomplished this feat without performing many laboratory experiments themselves. Instead, they analyzed and synthesized the work of numerous scientists who had carefully carried out studies on DNA. 

One of the most important discoveries of modern science was the elucidation of the structures of DNA and RNA as the famous double helix by Watson and Crick in 1953. They realized that the basic structure of base-sugar-phosphate was ideal for a three-dimensional coil. The structure of a small part of DNA is shown on the right. Notice that the 2 (pronounced two prime ) position on the ribose ring is vacant. There is no hydroxyl group there that is why it is called deoxyribonucleic acid. The nucleotides link the two remaining OH groups on the ribose ring and these are called the 3 - and 5 -positions. This piece of DNA has three nucleotides (adenine, adenine, and thymine) and so would be called -AAT- for short. 

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