Nitrosoureas

The nitrosoureas were discovered as a result of drug screening by the Cancer Chemotherapy National Service Center, which identified N-methyl-Af-nitroguanidine as having activity against L1210 leukemia.28 Further development of this lead compound was based on the idea that its chemical decomposition was leading to the formation of dia-zomethane (CH2N2) and subsequent alkylation of DNA. This led to the nitrosoureas, where it was found that activity could be enhanced by attachment of a 2-haloethyl substituent to both nitrogens (Fig. 10.6).

These compounds are reasonably stable at pH = 4.5 but undergo both acid and base catalyzed decomposition at lower and higher pH, respectively. There are several pathways of decomposition that are possible for these compounds, but the one that appears to be most important for alkylation of DNA involves abstraction of the NH proton, which is relatively acidic (pKa = 8-9), followed by rearrangement to give an isocyanate and a diazohydroxide. The diazohydroxide, upon protonation followed by loss of water, yields a diazo species that decomposes to a reactive carbocation (Scheme 10.11).22 The isocyanate functions to carbamylate proteins and RNA, whereas the carbocation is believed to be the agent responsible for DNA alkyla-tion.29-31 Alternative mechanisms of decomposition have also been proposed involving formation of chlorovinyl carbocations. In those cases where there is a chloroethyl moiety attached to the N-nitroso urea functionality, cross-linking of DNA occurs. Alkylation occurs preferentially at the N-7 position of guanine with minor amounts of alkyla-tion at guanine O-6.32

Detoxification pathways of the nitrosoureas are also possible and can play a role in resistance to this group of agents. Two major routes of inactivation have been identified and are indicated in Scheme 10.12. The first of these involves dechlorination, which is facilitated by CYP participation and involves cyclization to give 4,5-dihydro-[1,2,3]oxadiazole and the isocyanate, which is still capable of carbamylating proteins.33 The oxadiazole can be further degraded by hydrolysis to give several inactive products. The second route involves denitrosation, which in the case of BCNU (carmus-tine) has been shown to be catalyzed by CYP monooxygen-ases and glutathione-S-reductase.34

Activation Cisplatin
Scheme 10.10 • Mechanism of cisplatin activation and formation of DNA adducts.
Hydrolyse Temozolomide

Lomustine (CCNU) Figure 10.6 • Nitrosoureas antineoplastics.

PROCARBAZINE, DACARBAZINE, AND TEMOZOLOMIDE

Procarbazine is an antineoplastic agent that was originally developed as a result of efforts to find new inhibitors of monoamine oxidase. Subsequent screening revealed anti-neoplastic activity.35 It was initially believed that the cyto-toxicity was related to the ability of the compound to undergo auto-oxidation to give hydrogen peroxide, which in the presence of Fe+2 would produce hydroxide radicals capable of cleaving DNA.36,37 Subsequent work showed that although this did occur, sufficient amounts of hydrogen peroxide were not produced to account for the observed effects. Metabolism studies revealed that oxidation of procarbazine does occur in the liver and is mediated by CYP and monoamine oxidase to give azo-procarbazine. This compound may also be generated nonenzymatically in an aerobic environment (Scheme 10.13).38-40 There are several chemical and metabolic pathways that azo-procarbazine may then undergo, and there is some disagreement regarding the exact structure of the active alkylating species. One such route involves CYP-mediated oxidation of the benzylic methylene carbon with subsequent decomposition to give methyldiazine and the aldehyde. The methyldiazine may then decompose by homolytic bond cleavage to give methyl and hydrogen radicals along with nitrogen gas or be further oxidized to give the diazo compound, which can decompose to give the methyl carbocation. Methyldiazine may also be produced by a minor route involving isomerization of azo-procarbazine to give the hydrazone, which subsequently undergoes hydrolysis to give the aldehyde and methylhy-drazine. Methylhydrazine may react with oxygen to give methyldiazine, which then decomposes as before. Studies utilizing radiolabeled procarbazine indicated that the terminal methyl group was found covalently bound to the N-7 position of guanine especially on tRNA disrupting its function and preventing protein, RNA, and DNA synthesis.41 There was also a small amount of methylation at the O-6 position of guanine.42 Hydrazines are also capable of inhibiting monoamine oxidase as seen with isocarboxazid and phenelzine; however, procarbazine is only a weak inhibitor of this enzyme. The agent is also capable of inhibiting aldehyde dehydrogenase and producing a disulfiram-like reaction. Given the involvement of the CYP system in its activation, the action of procarbazine is subject to drug interactions with both inducers and inhibitors of this system.

Somewhat related is dacarbazine, which was initially thought to act as an inhibitor of purine biosynthesis, but latter was shown to be an alkylating agent.43 Activation of the agent occurs through the action of CYP (isozymes 1A1, 1A2, and 2E1) to give the demethylated product monomethyl tri-azeno imidazole carboxamide (MTlC) (Scheme 10.14).44 Tautomerization allows for decomposition to give the amino-carboxamido-imidazole and diazomethane, which is capable of alkylating DNA.45 An alternative pathway involves acid catalyzed or photoinduced loss of dimethylamine to give an alternative diazo compound (diazo-IC), which may not only

Nitrosoureas
Scheme 10.11 • Mechanism of DNA alkylation by nitrosoureas.
Imidazole Alkylating Agents

Scheme 10.12 • Metabolic and chemical inactivation of nitrosoureas.

Scheme 10.12 • Metabolic and chemical inactivation of nitrosoureas.

generate a carbocation but also undergoes internal cycliza-tion to give 2-azo-hypoxanthine.46 Formation of diazo-IC has been associated with pain at the injection site, which is often seen during dacarbazine administration.47 Methylation of DNA occurs at N-7, N-3 and O-6 of guanine among other sites.48 Dacarbazine proved to be more active against murine tumors than against human tumors. This was attributed to the enhanced ability of mice to metabolize the agent to MTIC

and the subsequent conversion to a methylating species.49 Building on this idea was temozolomide, which undergoes conversion to the same intermediate, MTIC, as dacarbazine, but it does not require metabolic activation to do so.50,51 Hydrolysis of temozolomide gives the carboxy-triazene, which spontaneously loses CO2 to give MTIC. Dacarbazine must be administered intravenously; however, the related temozolomide may be administered orally.

Hydrolyse Temozolomide

DNA alkylation

Scheme 10.13 • Metabolic and chemical activation of procarbazine.

DNA alkylation

Scheme 10.13 • Metabolic and chemical activation of procarbazine.

Hydrolyse Temozolomide
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