Sulphonamides synthesis

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

Pioneering work on the desulphonylation of jS-ketosulphones was carried out by Corey and Chaykovsky - . This reaction was part of a sequence which could be used in the synthesis of ketones, as shown in equation (53). The main thrust of this work was in the use of sulphoxides, but Corey did stress the merits of both sulphones and sulphonamides for different applications of this type of reaction. The method soon found application by Stetter and Hesse for the synthesis of 3-methyl-2,4-dioxa-adamantane , and by House and Larson in an ingenious synthesis of intermediates directed towards the gibberellin skeleton, and also for more standard applications . Other applications of the method have also been madealthough it does suffer from certain limitations in that further alkylation of an a-alkyl- -ketosulphone is a very sluggish, inefficient process. Kurth and O Brien have proposed an alternative, one-pot sequence of reactions (equation 54), carried out at — 78 to — 50°, with yields better than 50%. The major difference between the two routes is that the one-pot process uses the desulphonylation step to generate the enolate anion, whereas in the Corey-House procedure, the desulphonylation with aluminium amalgam is a separate, non-productive step. 

Aromatic substitution by sulphonyl azides has been applied to the synthesis of cyclic sulphonamides not as readily available by other methods 16h For example, thermolysis of biphenyl-2-sulphonyl azide (60) in w-dodecane or in cyclohexane 78> at 150 °C gives high yields (partic-... 

An efficient synthesis of A-alkylated-4-substituted isothiazolidine-dioxides (sultams) 251 has been developed utilizing epoxides 248 <06TL4245>. Addition of a secondary sulphonamide 247 to epoxide 248 in hot 1,4-dioxane affords the amino alcohol 249, which is... 

Orthophosphoric and benzylphosphonic acids have been selectively alkylated with triethyl phosphite in a new synthesis of mono-, di-, and triethyl phosphates and of mono- and di-methyl phosphonates.62 A-Methylol carboxamides and sulphonamides react with trialkyl phosphites to give the phosphonate derivatives (78) and (80), respectively.63 However, the mechanism appears to be quite different in each case while the carboamides react by a transesterification-rearrange-ment pathway, the sulphonamides undergo elimination-addition via the imine (79). 

Synthesis of azocrown ethers from bis-sulphonamides and a.w-dibromoalkanes... 

Donald Woods discovered that sulphonamides exerted their action by inhibiting an enzyme used by bacteria to synthesise folic acid. The compound 4-aminobenzoic acid is the precursor for folic acid, and is structurally similar to sulphonamide. Bacteria that were unable to synthesise folic acid were unable to achieve de novo synthesis of purines for their DNA and RNA synthesis and hence could not proliferate. Such competitive inhibitors, which mimicked normal metabolites, became known as antimetabolites (many are used in cancer chemotherapy. Chapter 21). 

Marrow aplasia due to decreased nucleic acid synthesis, e.g. sulphonamides, ganciclovir... 

Toluene-o-sulphonamide is an intermediate in the synthesis of saccharin (Expt 6.42). Upon oxidising toluene-o-sulphonamide with potassium permanganate in alkaline solution, the sodium salt of o-sulphonamidobenzoic acid is formed, which on acidification with concentrated hydrochloric acid passes spontaneously into the cyclic imide of o-sulphobenzoic acid or saccharin. Saccharin itself is sparingly soluble in cold water, but the imino hydrogen is acidic and the compound forms a water-soluble sodium salt. The latter is about 500 times as sweet as cane sugar. 

Selective formation and elimination of sulphonamides permit synthesis of constitutional isomers ( dendro isomers ) of dendritic architectures of the kind shown in Fig. 2.20. 

MALDI-TOF spectra of the sulphonamide dendrimers erroneously suggest formation of defect structures during synthesis in fact, these are only generated during the ionisation process, primarily due to reaction of the peripheral sulphonamide groups with the acid matrix. An apparently unsatisfactory result should therefore always be checked by use of a second ionisation method or different MALDI matrices should be used to exclude misinterpretation of the spectra and to gain certainty about the true composition of the sample. 

Inhibition of tetrahydrofo-late synthesis Sulphonamides Competitive inhibitors of dihydro-pteroate synthetase... 

Scheme 2. Synthesis of sumatriptan (1) using a N-sulphonamide protecting group strategy.

A single pot synthetic protocol for the synthesis of 2-sulphonamide-l,3,4-oxadiazoles from 1,2-diacylhydrazine (xxix) under microwave irradiation using PS-BEMP (xxxi) and corresponding sulfonyl chloride (xxx) is reported by Baxendale et al. [33]. 

Proguardl (t) 17 h) inhibits dihydrofolate reductase which converts folic to folinic acid, deficiency of which inhibits plasmodial cell division. Plasmodia, like most bacteria and unlike humans, cannot make use of preformed foUc acid. Pyrimethamine and trimethoprim, which share this mode of action, are collectively known as the antifols. Their plasmod-icidal action is markedly enhanced by combination with sulphonamides or sulphones because there is inhibition of sequential steps in folate synthesis (see Sulphonamide combinations, p. 231). 

Sulphonamides Co-factor synthesis Differences in the target Plasmodium spp. 

Co-trimoxazole is a mixture of sulphamethoxazole (five parts) and trimethoprim (one part). The reason for using this combination is based upon the in vitro finding that there is a sequential blockade of folic acid synthesis, in which the sulphonamide is a competitive inhibitor of dihydropteroate synthetase and trimethoprim inhibits DHFR (see Chapter 12). The optimum ratio of the two components may not... 

Purines, pyrimidines and their nucleosides and nucleoside triphosphates are synthesized in the cytoplasm. At this stage the antifolate drugs (sulphonamides and dihydrofolate reductase inhibitors) act by interfering with the synthesis and recycling of the co-factor dihydrofolic acid (DHF). Thymidylic acid (2-deoxy-thymidine monophosphate, dTMP) is an essential nucleotide precursor of DNA synthesis. It is produced by the enzyme thymidylate synthetase by transfer of a methyl group from tetrahydrofolic acid (THF) to the uracil base on uridylic acid (2-deoxyuridine monophosphate, dUMP) (Fig. 12.5). THF is converted to DHF in this process and must be reverted to THF by the enzyme dihydrofolate reductase (DHFR) before... 

Inhibition of folic acid synthesis in susceptible microorganisms and ultimately the synthesis of nucleic acids. By competing with para-aminobenzoic acid (PABA) for the enzyme dihydropteroate synthetase, sulphonamides prevent the incorporation of PABA into dihydrofolate, while trimethoprin, by selectively inhibiting dihydrofolate reductase, prevents the reduction of dihydrofolate to tetrahydrofolate (folic acid). Animal cells, unlike bacteria, utilize exogenous sources of folic acid. Pyrimethamine inhibits protozoal dihydrofolate reductase, but is less selective for the microbial enzyme and therefore more toxic than trimethoprim to mammalian species. 

At least some sulphonamide-resistant bacteria can, like mammalian cells, utilize preformed folic acid for nucleic acid synthesis. 

Compounds of this class inhibit the synthesis of dihydropteroate (DHP, 3) from PABA and DHP pyrophosphate (2), which is achieved by competing with PABA for the enzyme involved in the conversion of 2 to 3. Sulphonamides and sul-... 

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