prof. aza Drugs that Target Nucleic Acids Reference: Gareth Thomas Week 15

prof. aza 13. Drugs that Target Nucleic Acids Drugs that target DNA and RNA either inhibit their synthesis or act on existing nucleic acid molecules. Those that inhibit the synthesis of nucleic acids usually act as either antimetabolites or enzyme inhibitors. Drugs that target DNA and RNA either inhibit their synthesis or act on existing nucleic acid molecules. Those that inhibit the synthesis of nucleic acids usually act as either antimetabolites or enzyme inhibitors.

The drugs that target existing nucleic acid molecules can, for convenience be broadly classified into intercalating agents, alkylating agents and chain-cleaving agents. The drugs that target existing nucleic acid molecules can, for convenience be broadly classified into intercalating agents, alkylating agents and chain-cleaving agents. prof. aza

However, it should be realised that these classifications are not rigid: drugs may act by more than one mechanism. those drugs acting on existing DNA usually inhibit transcription whereas those acting on RNA normally inhibit translation. However, it should be realised that these classifications are not rigid: drugs may act by more than one mechanism. those drugs acting on existing DNA usually inhibit transcription whereas those acting on RNA normally inhibit translation. In both cases the net result is the prevention or slowing down of cell growth and division. In both cases the net result is the prevention or slowing down of cell growth and division.

Consequently, the discovery of new drugs that target existing DNA and RNA is a major consideration when developing new drugs for the treatment of cancer (see Appendix 4) and bacterial and other infections due to microorganisms. Consequently, the discovery of new drugs that target existing DNA and RNA is a major consideration when developing new drugs for the treatment of cancer (see Appendix 4) and bacterial and other infections due to microorganisms. prof. aza

13.1 Antimetabolites 13.1 Antimetabolites Antimetabolites are compounds that block the normal metabolic pathways operating in cells. Antimetabolites are compounds that block the normal metabolic pathways operating in cells. They act by either replacing an endogenous compound in the pathway by a compound whose incorporation into the system results in a product that can no longer play any further part in the pathway, or inhibiting an enzyme in the metabolic pathway in the cell. They act by either replacing an endogenous compound in the pathway by a compound whose incorporation into the system results in a product that can no longer play any further part in the pathway, or inhibiting an enzyme in the metabolic pathway in the cell.

Both these types of intervention inhibit the targeted metabolic pathway to a level that hopefully has it significant effect on the health of the patient. Both these types of intervention inhibit the targeted metabolic pathway to a level that hopefully has it significant effect on the health of the patient. prof. aza

The structures of antimetabolites are usually very similar to those of the normal metabolites used by the cell. Those used to prevent the formation of DNA may be classified as antifolates, pyrimidine antimetabolites and purine antimetabolites. The structures of antimetabolites are usually very similar to those of the normal metabolites used by the cell. Those used to prevent the formation of DNA may be classified as antifolates, pyrimidine antimetabolites and purine antimetabolites.

However, because of the difficult of classifying biologically active substances (see section 1.6), antimetabolites that inhibit enzyme action are also classified as enzyme inhibitors. However, because of the difficult of classifying biologically active substances (see section 1.6), antimetabolites that inhibit enzyme action are also classified as enzyme inhibitors. prof. aza

Figure (a) The structure of folic acid. In blood, folic acids usually have one glutamate residue. However, in the cell they are converted to polyglutamates. (b) A Fragment of a polyglutamate chain.

prof. aza Antifolates Folic acid (Figure 10.23) is usually regarded as the parent of a family of naturallv occurring compounds known as folates. Folic acid (Figure 10.23) is usually regarded as the parent of a family of naturallv occurring compounds known as folates. These folates are widely distributed in food. They differ from folic acid in such ways as the state of reduction of the pteridine ring and having carbon units attached to either or both of the N5 and N 10 atoms. These folates are widely distributed in food. They differ from folic acid in such ways as the state of reduction of the pteridine ring and having carbon units attached to either or both of the N5 and N 10 atoms.

In the body folates are converted by a two- step process into tetrahvdrofolates (FH4) by the action of the enzyme dihydrofolate reductase (DHFR). Tetrahydrofolic acid is an essential cofactor in the biosynthesis of purines and thymine. which are required for DNA synthesis. In the body folates are converted by a two- step process into tetrahvdrofolates (FH4) by the action of the enzyme dihydrofolate reductase (DHFR). Tetrahydrofolic acid is an essential cofactor in the biosynthesis of purines and thymine. which are required for DNA synthesis. prof. aza

Folic acid antimetabolites have structures that resemble folic acid (Figure 10.24). They have a stronger affinity for DHFR than folic acid and act by inhibiting this enzyme at both stages in the conversion of folic acid to FH4. Folic acid antimetabolites have structures that resemble folic acid (Figure 10.24). They have a stronger affinity for DHFR than folic acid and act by inhibiting this enzyme at both stages in the conversion of folic acid to FH4. This has the effect of inhibiting the formation of purines and thymine required for DNA synthesis. This has the effect of inhibiting the formation of purines and thymine required for DNA synthesis.

Methotrexate This inhibits cell growth, which prevents replication and ultimately leads to cell death. This inhibits cell growth, which prevents replication and ultimately leads to cell death. Methotrexate is the only folate antimetabolite in clinical use. It is distributed to most body fluids but has a low lipid solubility, which means, that does not readilv cross the blood-brain barrier. Methotrexate is the only folate antimetabolite in clinical use. It is distributed to most body fluids but has a low lipid solubility, which means, that does not readilv cross the blood-brain barrier. prof. aza

Figure A comparison of the structures of folic acid antimetabolites with folic acid.

prof. aza It is transported into cells by the folate transport system and at high blood levels an additional second transport mechanism comes into operation. It is transported into cells by the folate transport system and at high blood levels an additional second transport mechanism comes into operation. Once in the cell it is metabolised to the polyglutamate, which is retained in the cell for considerable periods of time. This is probably due to the polar nature of the polymer. Once in the cell it is metabolised to the polyglutamate, which is retained in the cell for considerable periods of time. This is probably due to the polar nature of the polymer.

Methotrexate is used to treat a variety of cancers, including head and neck tumours, and, in low doses, rheumatoid arthritis. Methotrexate is used to treat a variety of cancers, including head and neck tumours, and, in low doses, rheumatoid arthritis. It can cause vomiting, nausea, oral and gastric ulceration and depression of bone marrow, a well as other unwanted side effects. It can cause vomiting, nausea, oral and gastric ulceration and depression of bone marrow, a well as other unwanted side effects. prof. aza

Purine Antimetabolites Purine antimetaholites are exogenous compounds, such as 6-mercaptopurine and 6-thioguanine, with structures based on the purine nucleus (Figure 1O.25). Purine antimetaholites are exogenous compounds, such as 6-mercaptopurine and 6-thioguanine, with structures based on the purine nucleus (Figure 1O.25). They inhibit the synthesis of DNA and in some cases RNA by a number of different mechanisms. For example, 6- mercaptopurine is metabolised to the ribonucleotide 6-thioguanosine-5’- pltosphate. They inhibit the synthesis of DNA and in some cases RNA by a number of different mechanisms. For example, 6- mercaptopurine is metabolised to the ribonucleotide 6-thioguanosine-5’- pltosphate.

prof. aza Figure Examples of purine antimetabolites. The purine nucleus, on which the structures of the antimetabolites and the endogenous compounds they replace are based, is shown in square brackets.

This exogenous nucleotide inhibits several pathways for the biosynthesis of endogenous purine nucleotides. This exogenous nucleotide inhibits several pathways for the biosynthesis of endogenous purine nucleotides. In contrast, 6-thioguanine is converted in the cell to the ribonucleotide 6- thioinosine-5’-phosphate. In contrast, 6-thioguanine is converted in the cell to the ribonucleotide 6- thioinosine-5’-phosphate. prof. aza

This ribonucleotide disrupts DNA synthesis by being incorporated into the structure of DNA as a false nucleic acid. This ribonucleotide disrupts DNA synthesis by being incorporated into the structure of DNA as a false nucleic acid. Resistance to these two drugs arises because of a loss of the posphorybosil transferase required for the formation of their ribonucleotides. Resistance to these two drugs arises because of a loss of the posphorybosil transferase required for the formation of their ribonucleotides. prof. aza

Pyrimidine Antimetabolltes These are antimetabolites whose structures closely to those of the endogenous pyrimidine bases (Figure l0.26a). These are antimetabolites whose structures closely to those of the endogenous pyrimidine bases (Figure l0.26a). They usually act by inhibiting one or more of the enzymes that are required for DNA synthesis. They usually act by inhibiting one or more of the enzymes that are required for DNA synthesis.

The presence of the unreactive C5 F bond in FUdRP blocks this methylation, which prevents the formation of deoxythymidylic acid (TdRP) and its subsecquent incorporation into DNA (Figure ). The presence of the unreactive C5 F bond in FUdRP blocks this methylation, which prevents the formation of deoxythymidylic acid (TdRP) and its subsecquent incorporation into DNA (Figure ). prof. aza

Fluorine was chosen to replace hydrogen at the C5 position of uracil because it is of a similar size to hydrogen (atomic radii: F nm: l2nrn). Fluorine was chosen to replace hydrogen at the C5 position of uracil because it is of a similar size to hydrogen (atomic radii: F nm: l2nrn). It was thought that this similarity in size would give a drug that ould cause little steric disturbance to the biosynthetic pathway as well as being chemically inert. It was thought that this similarity in size would give a drug that ould cause little steric disturbance to the biosynthetic pathway as well as being chemically inert. prof. aza

Analogues containing larger halogen atoms do not have any appreciable activity. Analogues containing larger halogen atoms do not have any appreciable activity. For example, fluorouracil is metabolised by the same metabolic pathway as uracil to 5-fluoro-2’- deoxyuridylic acid (FUdRP). For example, fluorouracil is metabolised by the same metabolic pathway as uracil to 5-fluoro-2’- deoxyuridylic acid (FUdRP). prof. aza

FUdRP inhibits the enzyme thymidylate synthetase, which in its normal role is responsible for the transfer (of a methyl group from the coenzyme melhylenetetrahydrofolic acid (MeFI 14) to the C5 atom of deoxyuridylic acid (UdRP). FUdRP inhibits the enzyme thymidylate synthetase, which in its normal role is responsible for the transfer (of a methyl group from the coenzyme melhylenetetrahydrofolic acid (MeFI 14) to the C5 atom of deoxyuridylic acid (UdRP). prof. aza

Figure (a) Examples of pyrimidines that act as antimetabolites. It should be noted that cytarabine only differs from cytidine by the stereochemistry of the 2’ carbon. (b) The intervention of fluorouracil in pyrimidine biosynthesis.

prof. aza Figure Examples of topoisomerase inhibitors. Ellipticene acts h intercalation and inhibition of topoisomerase II enzymes. It is active against nasophar ngeal carcinomas. Amsacrinc is used to treat oarian carcinomas. lymphoinas and myelogenous leukaemias. (camptotheci n is an antitumour.

prof. aza Enzyme Inhibitors Enzyme Inhibitors Enzyme inhibitors may be classified for convenience as those that inhibit the enzymes directly responsible for the formation of nucleic acids or the variety of enzymes that catalyse the various stages in the formation of the pirimidine and purine bases required for the formation of nucleic acids. Enzyme inhibitors may be classified for convenience as those that inhibit the enzymes directly responsible for the formation of nucleic acids or the variety of enzymes that catalyse the various stages in the formation of the pirimidine and purine bases required for the formation of nucleic acids.

prof. aza Topoisomerases Topoisomerases Topoisomerases are a group of enzymes that are responsible for the supercoiling, the cleavage and rejoining of DNA. Topoisomerases are a group of enzymes that are responsible for the supercoiling, the cleavage and rejoining of DNA. Their inhibition has the effect of preventing transcription. A number of compounds (Figure 10.27) are believed to act by inhibiting these enzymes. Their inhibition has the effect of preventing transcription. A number of compounds (Figure 10.27) are believed to act by inhibiting these enzymes.

It is thought that some intercalators act in this manner although it is not clear whether the drug binds to the topoisomerase prior to or after the enzyme has formed a DNA—enzyme complex. It is thought that some intercalators act in this manner although it is not clear whether the drug binds to the topoisomerase prior to or after the enzyme has formed a DNA—enzyme complex. prof. aza

Enzyme Inhibitors for Purine and Primidine Precursor Systems A wide range of compounds are active against a number of the enzyme s stems that are involved in the biosynthesis of purines and pyrimidines in bacteria. A wide range of compounds are active against a number of the enzyme s stems that are involved in the biosynthesis of purines and pyrimidines in bacteria. In both of these examples the overall effect is the inhibit ion of purine and pyrirmidine synthesis, which results in the inhibition of the synthesis of DNA. In both of these examples the overall effect is the inhibit ion of purine and pyrirmidine synthesis, which results in the inhibition of the synthesis of DNA.

This restricts the growth of the bacteria and ultimately prevents it from replicating, which gives the bodys natural defences time to destroy the bacteria. This restricts the growth of the bacteria and ultimately prevents it from replicating, which gives the bodys natural defences time to destroy the bacteria. Because sulphonamides and trimethoprim inhibit different stages in the same metabolic pathway, they are often used in conjunction (Figure ).This allows the clinician to use lower and there fore safer doses. Because sulphonamides and trimethoprim inhibit different stages in the same metabolic pathway, they are often used in conjunction (Figure ).This allows the clinician to use lower and there fore safer doses. prof. aza

For example, sulphonamides inhibit dihydropteroate synthetase (see section ), which prevents the formation of folic acid, whereas trimethoprim inhibits dihydrofolate reductase, which prevents the conversion of folic acid to tetrahydrofolate (see section ). For example, sulphonamides inhibit dihydropteroate synthetase (see section ), which prevents the formation of folic acid, whereas trimethoprim inhibits dihydrofolate reductase, which prevents the conversion of folic acid to tetrahydrofolate (see section ). prof. aza

In both of these examples the overall effect is the inhibit ion of purine and pyrimidine synthesis, which results in the inhibition of the synthesis of DNA. This restricts the growth of the bacteria and ultimately prevents it from replicating, which gives the bodys natural defences time to destroy the bacteria. In both of these examples the overall effect is the inhibit ion of purine and pyrimidine synthesis, which results in the inhibition of the synthesis of DNA. This restricts the growth of the bacteria and ultimately prevents it from replicating, which gives the bodys natural defences time to destroy the bacteria. prof. aza

Because sulphonamides and trimethoprim inhibit different stages in the same metabolic pathway, they are often used in conjunction (Figure ).This allows the clinician to use lower and therefore safer doses. Because sulphonamides and trimethoprim inhibit different stages in the same metabolic pathway, they are often used in conjunction (Figure ).This allows the clinician to use lower and therefore safer doses. prof. aza

Figure Sequential blocking using sulphamethoxazole and Trimethoprim.

prof. aza Intercalating Agents Intercalating Agents Intercalating agents are compounds that insert themselves between the bases of the DNA helix (Figure 10.29). This insertion causes the DNA helix to partially unwind at the site of the intercalated molecule. Intercalating agents are compounds that insert themselves between the bases of the DNA helix (Figure 10.29). This insertion causes the DNA helix to partially unwind at the site of the intercalated molecule. This inhibits transcription, which blocks the replication process of the cell containing the DNA. This inhibits transcription, which blocks the replication process of the cell containing the DNA.

However, it is not known how the partial unwinding presents transcription but some workers think that it inhibits topoisomerases (see section ). Inhibition of cell replication can lead to cell death, which reduces the size of a tumour, the number of ‘free’ cancer cells or the degree of infection, all of which will contribute to improving the health of the patient. However, it is not known how the partial unwinding presents transcription but some workers think that it inhibits topoisomerases (see section ). Inhibition of cell replication can lead to cell death, which reduces the size of a tumour, the number of ‘free’ cancer cells or the degree of infection, all of which will contribute to improving the health of the patient. prof. aza

Figure A schematic representation of the distortion of the DNA helix by intercalating agents. The horizontal lines represent the hydrogen-bonded bases. The rings of these bases and intercalating agent are edge on to the reader.

prof. aza The insertion of an intercalation agent appears to occur via either the minor or major grooves of DNA. The insertion of an intercalation agent appears to occur via either the minor or major grooves of DNA. Compounds that act as intercalating agents must have structures that contain a flat fused aromatic or heteroarornatic ring section that can fit between the flat structures of the bases of the DNA. Compounds that act as intercalating agents must have structures that contain a flat fused aromatic or heteroarornatic ring section that can fit between the flat structures of the bases of the DNA.

It is believed that these aromatic structures are held in place by hydrogen bonds, van der Waals’ forces and charge-transfer bonds (see section 5.2). It is believed that these aromatic structures are held in place by hydrogen bonds, van der Waals’ forces and charge-transfer bonds (see section 5.2). prof. aza

Figure Examples of intercalating agents. Trade name.

prof. aza Drugs whose mode of action includes intercalation are the antimalarials quinine and chloroquine, the anticancer agents mitoxantrone and doxorubicin, and the antibiotic proflavine (Figure 10.30). Drugs whose mode of action includes intercalation are the antimalarials quinine and chloroquine, the anticancer agents mitoxantrone and doxorubicin, and the antibiotic proflavine (Figure 10.30). In each of these compounds it is the flat aromatic ring system that is responsible for the intercalation. In each of these compounds it is the flat aromatic ring system that is responsible for the intercalation.

However, other groups in the structures may also contribute to the binding of a drug to the DNA. However, other groups in the structures may also contribute to the binding of a drug to the DNA. For example, the amino group of the sugar residue of doxorubicin forms an ionic bond with the negatively charged oxygens of the phosphate groups of the DNA chain, which effectively locks the drug into place. For example, the amino group of the sugar residue of doxorubicin forms an ionic bond with the negatively charged oxygens of the phosphate groups of the DNA chain, which effectively locks the drug into place. prof. aza

A number of other drugs appear to have groups that act in a similar manner. A number of other drugs appear to have groups that act in a similar manner. Some intercalating agents exhibit a preference to certain combinations of bases in DNA. Some intercalating agents exhibit a preference to certain combinations of bases in DNA. For example, mitoxantrone appears to prefer to intercalate with cytosine— guanosine-rich sequences. This type of behaviour does open out the possibility of selective action in some cases. For example, mitoxantrone appears to prefer to intercalate with cytosine— guanosine-rich sequences. This type of behaviour does open out the possibility of selective action in some cases. prof. aza

13.4 Alkylating Agents Alkylating agents are believed to bond to the nucleic acid chains in either the major or minor grooves. Alkylating agents are believed to bond to the nucleic acid chains in either the major or minor grooves. In DNA the alkylating agent frequently forms either intrastrand or interstrand crosslinks. In DNA the alkylating agent frequently forms either intrastrand or interstrand crosslinks. Intrastrand cross-linking agents form a bridge between two parts of the same chain (Figure 10.31). This has the effect of distorting the strand, which inhibits transcription. Intrastrand cross-linking agents form a bridge between two parts of the same chain (Figure 10.31). This has the effect of distorting the strand, which inhibits transcription.

prof. aza Figure A schematic representation of the intrastrand cross-linking.

prof. aza lnterstrand cross—links are formed between the two separate chains of the DNA,which has the effect of blocking them together (Figure 10.32). This also inhibits transcription. lnterstrand cross—links are formed between the two separate chains of the DNA,which has the effect of blocking them together (Figure 10.32). This also inhibits transcription. In RNA only intrastrand cross-links are possible. However, irrespective of whether or not it forms a bridge. the bonding of an alkylating agent to a nucleic acid inhibits replication of that nucleic acid In RNA only intrastrand cross-links are possible. However, irrespective of whether or not it forms a bridge. the bonding of an alkylating agent to a nucleic acid inhibits replication of that nucleic acid

In the case of bacteria this prevents an increase in the size of the infection and so buys the time for its immune system to destroy the existing bacteria. However, in the case of cancer it may lead to cell death and a beneficial reduction in tumour size. In the case of bacteria this prevents an increase in the size of the infection and so buys the time for its immune system to destroy the existing bacteria. However, in the case of cancer it may lead to cell death and a beneficial reduction in tumour size. prof. aza

Figure (a) The general structure of nitrogen mustards (h) The proposee mechanism for tormimu’ interstrand cross-links by the action of aliphatic nitrogen mustards.

prof. aza The nucleophilic nature of the nucleic acids means that alkylating agents are usually electrophiles or give rise to electrophiles. The nucleophilic nature of the nucleic acids means that alkylating agents are usually electrophiles or give rise to electrophiles. For example, it is believed that a weakly electrophilic β-carbon atom of an aliphatic nitrogen mustard alkylating agent, such as mechlorethamine (Mustine), For example, it is believed that a weakly electrophilic β-carbon atom of an aliphatic nitrogen mustard alkylating agent, such as mechlorethamine (Mustine),

is converted to the more highly electrophilic aziridine ion by an internal nucleophilic substitution of a b-chlorine atom. is converted to the more highly electrophilic aziridine ion by an internal nucleophilic substitution of a b-chlorine atom. This is thought to be followed by the nucleophilic attack of the N7 of a guanine residue on this ion by what appears to bean SN2 type of mechanism. This is thought to be followed by the nucleophilic attack of the N7 of a guanine residue on this ion by what appears to bean SN2 type of mechanism. prof. aza

Since these drugs have two hydrocarbon chains with b-chlorogroups, each of these chlorogroups is believed to react with a guanine residue in a different chain of the DNA strand to form a cross-link between the two nucleic acid chains (Fig ). Since these drugs have two hydrocarbon chains with b-chlorogroups, each of these chlorogroups is believed to react with a guanine residue in a different chain of the DNA strand to form a cross-link between the two nucleic acid chains (Fig ). prof. aza

Figure (a) The structure of chlorambucil and (b) a proposed mode of action for some aromatic nitrogen mustards.

prof. aza The electrophilic nature of alkylating agents means that they can also react with a wide variety of other nucleophilic biomacromolecules. The electrophilic nature of alkylating agents means that they can also react with a wide variety of other nucleophilic biomacromolecules.

This accounts for many of the unwanted toxic effects that are frequently observed with the use of these drugs. In the case of the nitrogen mustards. attempts to reduce these side effects have centred on reducing their reactivity by discouraging the formation of the aiziridine ion before the drug reaches its site of action. This accounts for many of the unwanted toxic effects that are frequently observed with the use of these drugs. In the case of the nitrogen mustards. attempts to reduce these side effects have centred on reducing their reactivity by discouraging the formation of the aiziridine ion before the drug reaches its site of action. prof. aza

The approach adopted has been to reduce the nucleophilic character of the nitrogen atom by attaching it to an electron-withdrawing aromatic ring. This produced analogues that would only react with strong nucleophiles and resulted in the development of chlorambucil. The approach adopted has been to reduce the nucleophilic character of the nitrogen atom by attaching it to an electron-withdrawing aromatic ring. This produced analogues that would only react with strong nucleophiles and resulted in the development of chlorambucil. prof. aza

This drug is one of the least toxic nitrogen mustards, being active against malignant lymphomas, carcinomas of the breast and ovary and lymphocytic leucaemia. This drug is one of the least toxic nitrogen mustards, being active against malignant lymphomas, carcinomas of the breast and ovary and lymphocytic leucaemia. prof. aza

It has been suggested that because of the reduction in the nucleophilicity of the nitrogen atom these aromatic nitrogen mustards do not form an aziridine ion. It has been suggested that because of the reduction in the nucleophilicity of the nitrogen atom these aromatic nitrogen mustards do not form an aziridine ion. Instead they react by direct substitution of the 13-chlorine atoms by guanine, which is a strong nucleophile, by an S.I type of mechanism (Figure 10.33). Instead they react by direct substitution of the 13-chlorine atoms by guanine, which is a strong nucleophile, by an S.I type of mechanism (Figure 10.33). prof. aza

Figure Cyclophosphamide and the formation of phosphoramide mustard, the active of the drugs

prof. aza Further attempts to reduce the toxicity of nitrogen mustards were based on making the drug more selective. Those approaches have yielded useful drugs. The first was based on the fact that the rapid synthesis of proteins that occurs in tumour cells requires a large supply of amino acid raw material from outside the cell. Further attempts to reduce the toxicity of nitrogen mustards were based on making the drug more selective. Those approaches have yielded useful drugs. The first was based on the fact that the rapid synthesis of proteins that occurs in tumour cells requires a large supply of amino acid raw material from outside the cell.

Consequently, it was thought that the presence of an amino acid residue in the structure of a nitrogen mustard might lead to an increased uptake of that compound. Consequently, it was thought that the presence of an amino acid residue in the structure of a nitrogen mustard might lead to an increased uptake of that compound. This approach resulted in the synthesis of the phenylalanine mustard meiphalan (Table 10.6) This approach resulted in the synthesis of the phenylalanine mustard meiphalan (Table 10.6) prof. aza

The L-form of this drug is more active than the D-form and so it has been suggested that the L-form may be transported into the cell by means of a L -phenylalanine active transport system. The L-form of this drug is more active than the D-form and so it has been suggested that the L-form may be transported into the cell by means of a L -phenylalanine active transport system. prof. aza

The second approach was based on the fact that some tumours were thought to contain a high concentration of phosphoramidases. The second approach was based on the fact that some tumours were thought to contain a high concentration of phosphoramidases. This resulted in the synthesis of nitrogen mustard analogues mechanism, whose structures contained phosphorus functional groups that could be attacked by this enzyme. This resulted in the synthesis of nitrogen mustard analogues mechanism, whose structures contained phosphorus functional groups that could be attacked by this enzyme.

It lead to the development of the cyclophosphamide (Figure 10.34). which has a wide spectrum of activity. It lead to the development of the cyclophosphamide (Figure 10.34). which has a wide spectrum of activity. However, the action of this prodrug has now been shown to be due to phosphoramide mustard formed by oxidation by microsomal enzymes in the liver rather than hydrolysis by tumour phosphoramidases. However, the action of this prodrug has now been shown to be due to phosphoramide mustard formed by oxidation by microsomal enzymes in the liver rather than hydrolysis by tumour phosphoramidases. prof. aza

The acrolein produced in this proces be- lieved to be the source of myelo- suppression and haemorrhagic cystitis associated with the use of cyclophosphamide. The acrolein produced in this proces be- lieved to be the source of myelo- suppression and haemorrhagic cystitis associated with the use of cyclophosphamide. However, coadministration of the drug with sodium 2-mercaptoethane sulphonate (MESNA) can relieve some of these symptoms. However, coadministration of the drug with sodium 2-mercaptoethane sulphonate (MESNA) can relieve some of these symptoms. MESNA forms a water-soluble adduct with the acrolein, which is then excreted in the urine. MESNA forms a water-soluble adduct with the acrolein, which is then excreted in the urine. prof. aza

Some alkylating agents act by decomposing to produce an electrophile that bonds to a nucleophilic group of a base in the nucleic acid. Some alkylating agents act by decomposing to produce an electrophile that bonds to a nucleophilic group of a base in the nucleic acid. For example. temozolomide (Table 10.6) enters the major groove of DNA where it reacts with water to from nitrogen. carbon dioxide, an aminomidazole and a methyl carbonium ion (CH3). For example. temozolomide (Table 10.6) enters the major groove of DNA where it reacts with water to from nitrogen. carbon dioxide, an aminomidazole and a methyl carbonium ion (CH3).

This methyl carbonium ion then methylates the strongly nucleophilic N7 of the guanine bases in the major groo e. This methyl carbonium ion then methylates the strongly nucleophilic N7 of the guanine bases in the major groo e. prof. aza

A range of different classes of compound can act as nucleic acid alkylating agents (Table 10.6). A range of different classes of compound can act as nucleic acid alkylating agents (Table 10.6). Within these classes a number of compounds have been found to be useful drugs. Within these classes a number of compounds have been found to be useful drugs. In many, cases their effectiveness is improved by the use of combinations of drugs. In many, cases their effectiveness is improved by the use of combinations of drugs. prof. aza

Their modes of action are usually not fully understood but a large amount of information is available concerning their structure-action relationships. Their modes of action are usually not fully understood but a large amount of information is available concerning their structure-action relationships. prof. aza

Table Some examples of the classes and compounds of anticancer agents that act by aik alkylation of nucleic acids. it is emphasised that this table only lists some of the classes of alkylating compound that are active against cancers.

prof. aza

Figure Development routes for antisense drugs. Examples of: (a) a section of the backbone of a deoxy ribonu CWICIId cleic chain; (b) backbone modifications; (c) sugar residue modifications; and (d) base modifications,